Meckel-Gruber Syndrome

Autosomal recessive ciliopathy lethal in the prenatal or perinatal period, defined by the association of cystic renal dysplasia, central nervous system malformation (above all occipital encephalocele), hepatic ductal plate malformation and postaxial polydactyly; the severe end of the allelic Joubert–Meckel–nephronophthisis spectrum.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

0.2. Subtypes, genes and identifiers

The phenotype numbers and provisional status (marked in OMIM by «?») come from OMIM phenotypic series PS249000, consulted in October 2026, which agrees with the 2016 EuroGentest clinical utility gene card for MKS1–MKS12 [2, 3]; in OMIM, the same phenotype entry 617562 covers MKS13 and JBTS29, and 614175 covers MKS10 and JBTS34 [3]; cytobands, OMIM gene numbers and MANE (Matched Annotation from NCBI and EMBL-EBI) transcripts come from the HGNC (HUGO Gene Nomenclature Committee) [6], and gene-disease validity from ClinGen (Clinical Genome Resource), download of October 2026 [18]. The EuroGentest card assigns to TCTN2, B9D1 and B9D2 gene numbers that coincide with the phenotype numbers, which is a typographical error in the source; the table uses the HGNC numbers [2, 6]. OMIM assigns MKS14 (619879) to TXNDC15 [3, 19]. Of the two numbers that Orphanet cross-references with ORPHA:564 without stating the subtype, 619879 is MKS14 and 609345 is the cerebro-reno-digital syndrome with limb malformations and triradiate acetabula, described in two siblings (section 6) [1, 20]. OMIM places TMEM216 at 11q12.2, and the HGNC at 11q13.1 [3, 6]. ClinGen groups Meckel syndrome and Joubert syndrome under the designation «ciliopathy», which corresponds to a spectrum lumping approach [18].

1. Introduction

1.1. Clinical description and historical delineation

Johann Friedrich Meckel described in 1822 two siblings who died shortly after birth with occipital encephalocele, polycystic kidneys and polydactyly [5]. Gruber revisited the description in 1934 under the designation dysencephalia splanchnocystica, which emphasises the association between the brain malformation and the visceral cysts [5, 21]. The modern delineation of the syndrome is owed to Opitz and Howe (1969), and the criteria were refined in the following years by Hsia and colleagues (1971), by Mecke and Passarge (1971), who characterised the triad of encephalocele, polycystic kidneys and polydactyly as an autosomal recessive trait, by Fraser and Lytwyn (1981) and by Salonen (1984) [5, 21]. These original works are cited here through the reviews that summarise them.

Salonen's Finnish national study gathered 67 cases from 48 families, with retrospective collection between 1970 and 1979 and prospective collection between 1980 and 1981. Cystic renal dysplasia was present in all cases with sufficient information and, in the 41 cases in which the liver could be examined, all had fibrosis with proliferation and dilatation of the bile ducts; heterozygotes had no manifestations [22]. That study gave rise to Salonen's minimum criteria (cystic renal dysplasia, fibrotic hepatic changes and occipital encephalocele or another central nervous system (CNS) malformation) and to the demonstration, from the proportion of affected siblings corrected for ascertainment of 0.261, that inheritance is autosomal recessive [7, 22]. Fraser and Lytwyn showed, in a series of siblings of probands, that none of the anomalies of the triad was constant apart from renal dysplasia, which anticipated the current debate on minimum criteria [21, 23].

1.2. Milestones of molecular discovery

The first locus (MKS1) was mapped in 1995 to 17q21-q24, in a 13 cM region, in Finnish families [24]. Two years later, the lack of cosegregation with 17q in an Austrian family of Turkish origin and in three British families (Caucasian, Pakistani and Bangladeshi) demonstrated locus heterogeneity [25]. The Finnish locus was then refined to less than 1 cM at 17q22, with a haplotype common to most Finnish patients, suggesting a single ancient major mutation [26].

In 2006, two papers published in the same issue of Nature Genetics identified the first two genes: MKS1, encoding a component of the flagellar apparatus basal body proteome [27], and TMEM67, which encodes meckelin, a 995-amino-acid protein with seven transmembrane domains, mutated in five consanguineous families linked to the MKS3 locus and in the wpk rat [28]. In 2007 came CEP290 (MKS4), already known in Joubert syndrome (JS) and Leber congenital amaurosis [29], and RPGRIP1L (MKS5), also mutated in cerebro-oculo-renal syndrome [30]. In the same year, the demonstration of TMEM67 variants in 4 of 22 patients with JS (JBTS6) established allelism between the two syndromes [31]. In 2008, shared homozygosity mapping in 10 unrelated Finnish fetuses identified CC2D2A (MKS6) [32], and hypomorphic variants of MKS1, TMEM67 and CEP290 were associated with Bardet-Biedl syndrome (BBS) [33]. In 2010, TMEM216 was linked simultaneously to MKS2, JBTS2 and oral-facial-digital syndrome type VI (OFD VI) [34].

The second decade added genes at an accelerating pace, almost always from consanguineous families or fetal series: TCTN2 (MKS8) in a Saudi family [35]; B9D1 (MKS9) by targeted sequencing of 31 ciliary genes and deletion analysis in a cohort of 46 families [36]; B9D2 (MKS10), with the demonstration that loss of the B9 complex causes MKS [37]; TCTN3 in Mohr-Majewski syndrome (OFD IV) with fetuses whose phenotype overlapped with MKS [38]; TMEM231 (MKS11) [39]; KIF14 (MKS12) in a recurrent lethal fetal syndrome [40]; CSPP1, with phenotypes ranging from JS to lethal MKS [41]; TMEM107 (MKS13) [42]; and TXNDC15, the first MKS-associated protein that does not localise to the cilium [43]. In 2017, CEP55 was associated with a lethal fetal syndrome resembling MKS [44, 45], and in 2021 TMEM218 with JS and MKS phenotypes [46]. Between 2025 and 2026, TMEM17 was established as an MKS gene in four families with homozygous loss-of-function variants and in a founder missense variant [47, 48].

1.3. Nomenclature, reclassifications and definition

MKS is now understood as the lethal end of a continuous spectrum of transition zone ciliopathies, which includes JS and COACH syndrome (cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma and hepatic fibrosis), described as an intermediate phenotype between MKS and JS, nephronophthisis and some forms of oral-facial-digital syndrome [49, 50]. The identification of CEP290 variants in JS and in MKS is considered the first genetic proof of this spectrum, and JS and MKS have been described in the same family with the same variants [49, 51]. ClinGen reflects this view by curating most of these genes under the common designation «ciliopathy» [18].

The history of the Hutterite patients illustrates the risk of classification by isolated phenotype. Schurig and colleagues described in 1980 at least three Hutterite patients, children of consanguineous parents, with occipital meningocele, cystic kidneys, polydactyly and microphthalmia, and survival of 5 to 13 months [52]. Reassessment of 10 Hutterite patients, seven of whom had a previous diagnosis of MKS, showed the molar tooth sign on magnetic resonance imaging (MRI), cognitive delay, hypotonia, ataxia and an abnormal breathing pattern: this was a cerebro-oculo-renal syndrome of the Joubert group [53], later linked in part to CSPP1 [41].

Within the scope of this article, MKS is defined as a lethal prenatal or perinatal multiple malformation, of autosomal recessive inheritance, characterised by bilateral cystic renal dysplasia associated with at least one of three other major manifestations (CNS malformation, most often occipital encephalocele; polydactyly, usually postaxial; a hepatic anomaly of the ductal plate malformation type) [5, 11]. The Meckel-like syndrome due to complete loss of function of NPHP3 (ORPHA:3032, with 10 cases or families described) [4, 54] and the lethal fetal phenotypes due to CEP55 and KIF14 are treated as closely related forms. JS with encephalocele and COACH, nephronophthisis, Leber congenital amaurosis due to CEP290 (LCA10) and BBS enter the differential.

2. Molecular Genetics and Pathophysiology

2.1. The primary cilium and the transition zone

The primary cilium is a microtubule-based organelle, one per cell, that functions as a chemical and mechanical antenna and coordinates developmental signalling pathways, in particular the Sonic hedgehog (Shh) pathway and the canonical and non-canonical Wnt pathways [5, 50]. Most MKS-associated proteins localise to the transition zone (TZ), a proximal ciliary compartment that acts as a diffusion barrier between the ciliary membrane and the plasma membrane and controls the entry and exit of proteins and lipids [5, 49]. When both alleles of a TZ gene lose function, the barrier fails and cilium-dependent signalling is lost, on which neural tube closure, renal tubulogenesis, remodelling of the biliary ductal plate, limb patterning and maintenance of photoreceptor outer segments depend; this is why the organs affected are the same across the whole severity spectrum, from nephronophthisis to MKS [16, 49]. Abnormal Hedgehog signalling is documented for 14 of 19 MKS-associated genes, 31 of 42 JS genes and 7 of 19 nephronophthisis genes [49].

The relationship between ciliary failure and the malformations explains the triad. Cystic renal dysplasia results from disturbed tubulogenesis and begins in the glomeruli of the cortex, progressing along the tubules and collecting ducts of the medulla [5]. Ductal plate malformation results from incomplete development of the intrahepatic biliary tree, with proliferation and dilatation of the ducts and an excess of collagenous connective tissue [5, 22]. Processing of the GLI transcription factors of the Shh pathway depends on TZ proteins [38], and this pathway participates in limb patterning and neural tube closure [16]; mice lacking B9d1 reproduce polydactyly and abnormal neural tube patterning [37]. The histological feature common to the affected parenchymas is proliferation of stromal connective tissue with enlargement and dilatation of epithelial ductal structures [26].

2.2. Protein modules, the B9 complex and proteins outside the transition zone

The proteins TMEM216, TMEM231 and TMEM107, of the tetraspanin family, localise to the TZ membrane together with the tectonics (TCTN1, TCTN2 and TCTN3) and with the Frizzled-like receptor TMEM67, and interact with C2 domain proteins such as RPGRIP1L and CC2D2A [5]. TCTN1 forms a complex with CC2D2A, TCTN2, TMEM216, TMEM67, MKS1, CEP290 and B9D1; CC2D2A and B9D1 are required to localise TMEM231 to the TZ, and the latter regulates the entry of ciliary G protein-coupled receptors (SSTR3, HTR6) [5]. Loss of TCTN1 does not prevent ciliogenesis but displaces Smoothened, polycystin-2, adenylyl cyclase 3 and ARL13B from the cilium, showing that the main defect is one of ciliary composition and not of cilium formation [5]. RPGRIP1L belongs to a distinct assembly module, and a third module associates with the nephronophthisis proteins [5]. The 2022 review advises against naming these modules by phenotype («MKS module» or «NPHP module»), because the protein groups do not correspond consistently to clinical phenotypes [49].

MKS1, B9D1 and B9D2 form the B9 complex in the TZ. Mice lacking B9d1 have polydactyly, renal cysts, ductal plate malformation and abnormal neural tube patterning, with impaired ciliogenesis, ciliary protein localisation and Hedgehog signalling; the human variant B9D2 NM_030578.4:c.301A>C p.(Ser101Arg), homozygous in a family with MKS10, abolishes the interaction between B9D2 and MKS1 [37]. MKS1 is also required for apical migration of the centrosome at the onset of ciliogenesis and for normal cilium number and length [16]. Meckelin (TMEM67) negatively regulates the canonical Wnt pathway, binds Wnt5a and activates the non-canonical pathway together with ROR2 [16, 49]. In 2025 it was shown that the metalloproteinase ADAMTS9 cleaves the extracellular domain of TMEM67: the cleaved C-terminal form is required for ciliogenesis at the TZ, and the uncleaved form for non-canonical Wnt signalling; three patient variants in the cleavage motif impair ciliary structure and function, and the mouse with non-cleavable TMEM67 reproduces the severe ciliopathy of the Tmem67-null with normal Wnt signalling [55]. CEP290 is a centrosomal and TZ protein that recruits RAB8A and is required for the trafficking of phototransduction proteins in the connecting cilium, which explains its association with LCA10 [16].

Three genes associated with MKS phenotypes do not encode TZ proteins. TXNDC15 is a thioredoxin domain-containing disulfide isomerase that does not localise to the cilium, but its loss prevents the localisation of TMEM67 to the TZ; it interacts with 224 proteins of the endomembrane system enriched in ciliary proteins [43]. The mouse homozygous for Txndc15 c.512delA (the authors' murine numbering), equivalent to the human variant NM_024715.4:c.560del p.(Asn187IlefsTer4), shows at embryonic day 15.5 fetal lethality, exencephaly, omphalocele, postaxial polydactyly and polycystic kidneys [56]. CEP55 acts at the midbody during cytokinetic abscission, and the truncated protein does not localise to the midbody [16, 44]. KIF14 is a kinesin that links cytokinesis to the primary cilium [40].

2.3. Genetic architecture and contribution of each gene

Genetic heterogeneity is great and the contribution of each gene depends on the population. Variants in the known genes explained 50 to 60% of MKS cases according to the 2017 reviews and Smith's textbook [5, 21]. The EuroGentest card considers MKS1, TMEM67 and CC2D2A the main genes, followed by CEP290, and states that most variants are truncating, although in TMEM67 missense variants are frequent [2]. The number of genes cited varies with date and criterion: about 16 according to the GeneReviews entry on nephronophthisis [9], 14 genes with a numbered subtype (MKS1 to MKS14, four of them provisional) in the OMIM phenotypic series in October 2026 [3], 17 in Smith's textbook [21] and in the 2022 review, which counts the genes associated with both JS and MKS [49], at least 17 in 2019 [57], and at least 14 with a numbered subtype in 2025 [58]. Table 2.1 summarises the series with molecular study.

Table 2.1. Proportion of cases solved and contribution of genes in MKS series

In Finland, MKS1 accounts for about 70% of cases, compared with about 7% across the international series [5]. TMEM67 is the most frequent single cause outside founder populations, with 16% in a French and Italian fetal series and half of the solved families in the British cohort [63, 64]. The proportion solved depends on the cohort, consanguinity, the number of genes studied and the method; it should not be read as the clinical sensitivity of a test. In consanguineous families the proportion is higher, and in the Saudi cohort with targeted RNA analysis it reached 85% [43]. The candidate genes EVC2 (homozygous in-frame insertion of 8 amino acids, without signs of Ellis-van Creveld) and EXOC4 (homozygous missense variant) were described in isolated fetuses with an MKS phenotype, children of consanguineous parents of Arab origin [2, 65].

2.4. Gene-disease validity

ClinGen classifies as definitive the relationship with autosomal recessive ciliopathy for MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, B9D1, TMEM231, TCTN1 (February 2026) and TCTN3; as definitive with specific diseases of the spectrum for NPHP3 (nephronophthisis), TCTN2 (Joubert 24), CSPP1 (Joubert 21), CPLANE1 (Joubert 17) and TMEM237 (Joubert 14); as strong for TXNDC15; and as moderate for B9D2 (March 2026) and TMEM138 (June 2026) [18]. KIF14, TMEM107, CEP55, TMEM17, TMEM218, EXOC4 and EXOC3L2 had no ClinGen curation in the October 2026 download [18]. The authors of the 2025 TMEM17 series applied the ClinGen criteria and raised the relationship from limited to moderate, which does not constitute an official curation [47]. The moderate classification of B9D2 reflects the small number of families: the index family with p.(Ser101Arg) and a second Indian family with a homozygous variant [37, 67].

2.5. Founder and recurrent variants

The variants in table 2.2 were normalised in VariantValidator (GRCh38, MANE Select transcript) [68]. The historical nomenclature column reproduces the published form, and corrections result from discordance between the published notation and the reference sequence.

Table 2.2. Founder and recurrent variants in MKS

Three corrections result from normalisation. The Pakistani TMEM67 variant is c.1575+1G>A, and the form c.1546+1G>A in the 2012 text does not correspond to the reference sequence [64, 68]. The European RPGRIP1L variant is p.(Thr615Pro), and not p.Thr625Pro as it appears in the 2017 review [5, 68]. The Finnish MKS1 deletion appears in VariantValidator shifted one nucleotide 3′, by the 3′ alignment rule of HGVS (Human Genome Variation Society) nomenclature, without change to the 29 bp event [68]. For the Finnish CC2D2A variant, VariantValidator predicts p.(Gln588Ter), but the complementary DNA study demonstrated altered splicing with p.Val587fs, a consequence that prevails over the prediction [61, 68]. Tallila and colleagues recorded nomenclature inconsistencies in published variants, mainly in insertions and deletions not aligned to the 3′ rule [61].

2.6. Genotype-phenotype correlations

The general rule is that biallelic null alleles cause MKS, and hypomorphic alleles cause JS, BBS or nephronophthisis; but the phenotype is not predicted by the gene alone, and a family may cross the boundary [5, 16].

MKS1. All MKS1 variants described in MKS are null; hypomorphic MKS1 alleles have been described in BBS and in mild JS [5, 33, 72]. Patients with MKS1 more often have polydactyly, encephalocele, bone dysplasia, cleft palate and laterality defects [5]. The main Finnish variant is associated with skeletal involvement with shortening and bowing of the long bones, the «campomelic» variant of MKS: in the German series, 6 of the 8 fetuses with the deletion had this form, and the authors consider the deletion very probably causal in Europeans with campomelic MKS [5, 69]. In the British cohort, the Finnish variant was present in all non-consanguineous patients with MKS1, including two homozygous British patients [64]. Comparison between Finnish cases due to MKS1 and due to CC2D2A showed no clear phenotypic differences [61].

TMEM67. Compared with MKS1, MKS due to TMEM67 has fewer CNS defects and less polydactyly, and cases without CNS malformation or with less CNS involvement were associated with hypomorphic missense variants [60]. In the British cohort, polydactyly occurred in 3 of 19 patients with TMEM67, compared with 4 of 6 with RPGRIP1L or CC2D2A (p<0.001); ductal plate malformation in 10 of 19; retinal colobomas only with TMEM67 (2 of 19); and laterality or intestinal rotation defects in no patient with TMEM67, compared with 4 of 17 with MKS1, TMEM216, CEP290 or RPGRIP1L (p<0.05) [64]. Missense variants in exons 8 to 15, which encode the extracellular domain, are enriched in lethal cases, especially when the second allele is truncating [5, 63]. TMEM67 covers the whole spectrum: nephronophthisis occurs only with biallelic missense variants; in JS, about half of patients have two missense variants and half one missense and one truncating variant; in MKS, about half have two truncating variants, a quarter one missense and one truncating, and a quarter two missense variants [49]. TMEM67 explains 57 to 83% of COACH syndrome [5].

CC2D2A. Missense variants are associated with JS and null alleles with MKS [5, 62]. In the French series, structural brain anomalies (holoprosencephaly and agenesis of the corpus callosum, in addition to encephalocele) were present in 16 of 21 cases [62, 73]. MKS variants in CC2D2A are mainly small deletions in the calcium-binding domain [61]. In JS, homozygosity for NM_001378615.1:c.2848C>T p.(Arg950Ter) is associated with a more severe phenotype [16].

RPGRIP1L. Homozygous truncating variants cause severe MKS, with anencephaly and shortening and bowing of the long bones; missense variants, homozygous or with a truncating allele, cause JS [5, 30]. The missense variants of cerebro-oculo-renal syndrome reduce the interaction with nephrocystin-4 [30].

CEP290. This is the gene with the broadest spectrum: isolated LCA10, nephronophthisis, Senior-Løken syndrome, JS, COACH, BBS14 and MKS4 [2, 5]. In the 2007 series, homozygous or compound heterozygous truncating variants caused MKS in four families and cerebro-reno-digital syndrome, an intermediate phenotype between MKS and JS, in another four [29]. A Finnish family compound heterozygous for c.3444_3445delAA (published designation; = NM_025114.4:c.3446_3447del p.(Lys1149SerfsTer2) by the 3′ rule) and NM_025114.4:c.1219_1220del p.(Met407GlufsTer14) had no polydactyly [61].

TMEM216. MKS2, JBTS2 (cerebro-oculo-renal syndrome 2, often with nephronophthisis and polydactyly) and OFD VI are allelic; skeletal dysplasia is frequent in fetuses with MKS due to TMEM216 [34].

NPHP3. Hypomorphic alleles cause adolescent nephronophthisis; complete loss of function causes embryonic lethality in the mouse and, in humans, Meckel-like syndrome (MKS7) with early patterning defects (situs inversus, polydactyly, CNS malformations, structural heart disease) or renal-hepatic-pancreatic dysplasia, with multicystic dysplastic kidneys, dysgenetic bile ducts and a cystic and fibrotic pancreas [16, 54]. The residual function of the alleles, and not the gene, defines the phenotype [16].

TMEM231. The same family may have JS and MKS: in a family studied at the NIH (National Institutes of Health), the variants NM_001077416.2:c.784G>A p.(Asp262Asn) and c.406T>G p.(Trp136Gly) coexisted with a gene conversion event with loss of exon 4 [51]. In another family with three fetuses with MKS, long-read sequencing resolved the apparent heterozygous deletion of exon 4 as gene conversion from a pseudogene, with four missense variants invisible on short-read sequencing, in trans with c.929+1A>G [74]. The variants c.12T>A p.(Tyr4Ter) and c.625G>A p.(Asp209Asn) are founder variants in French-Canadian JS [16]. Allelic phenotypes include OFD III [75].

B9D1. The spectrum ranges from lethal MKS9 to mild JS [36, 72]. The 12 pathogenic or likely pathogenic variants reviewed in 2025 all lie in the B9 domain (amino acids 11 to 174 of 204), with the exception of NM_015681.6:c.529G>C p.(Asp177His) [76]. Lethal cases include compound heterozygosity for c.505+2T>C (published designation at the exon 4 splice donor, without transcript version; not mappable as intronic in NM_015681.6) with a de novo 1.713 Mb deletion at 17p11.2 (survival of 1.75 hours) and homozygosity for NM_015681.6:c.508_510del p.(Leu170del) [36, 76].

TCTN1, TCTN2 and TCTN3. TCTN1 is associated with four distinct syndromes, with the variants c.32_43del p.(Val11_Leu14del) and c.1385dup p.(Trp463ValfsTer58) (NM_001082538.2) in patients with MKS and c.342-2A>G in families with JS and JS/OFD [43]. The variant NM_001082538.3:c.16del p.(Leu6SerfsTer15), homozygous in a Turkish fetus, was the third published case of MKS due to TCTN1 [58]. In the Saudi cohort, the TZ genes CC2D2A, TCTN2, TMEM237 and CEP290 almost always resulted in JS or MKS [43]. Truncating TCTN3 variants cause OFD IV (Mohr-Majewski), and four additional truncating variants were found in fetuses with MKS/OFD IV overlap in a screen of 184 individuals [38].

TMEM17. Loss of function causes MKS, and other variants are associated with OFD VI and JS [47, 48]. The 2025 series described the homozygous variants NM_198276.3:c.4del p.(Glu2SerfsTer58), c.366dup p.(Pro123ThrfsTer9) and c.368C>G p.(Pro123Arg) in four families with a severe prenatal phenotype [47]. The p.(Arg94Trp) variant, in the second transmembrane domain, destabilises and mislocalises the protein, alters ciliary composition and abolishes Shh signalling; residue Arg94 corresponds to Arg73 of TMEM216, mutated in JS and MKS, suggesting a functional hotspot [48]. A homozygous exonic deletion was described in India in 2026 [77].

CEP55 and KIF14. Biallelic loss-of-function variants of CEP55 cause a lethal fetal syndrome designated MARCH (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly; ORPHA:500135), also described as Meckel-like: the homozygous variant NM_018131.5:c.256C>T p.(Arg86Ter) caused two affected fetuses in a Swedish family [44, 45], and a founder frameshift variant was described in Amish families [71]. A fetus with hydranencephaly and cystic dysplastic kidneys without occipital encephalocele or polydactyly should prompt consideration of CEP55 [16]. Biallelic truncating variants of KIF14 cause a lethal fetal syndrome with intrauterine growth restriction, severe microcephaly, cystic renal dysplasia or agenesis and complex brain and genitourinary malformations [40]; the spectrum extends to primary microcephaly with moderate delay [16].

TMEM218 and TXNDC15. Among 655 families with JS, biallelic missense variants in TMEM218 were found in 6 families, four of them at the same residue 115; the fetuses had occipital encephalocele (n=5), and the living individuals retinal dystrophy (n=4), without liver involvement [46]. TXNDC15 was associated with MKS in two consanguineous families and in a third patient with a homozygous truncating variant [43], then in an Indian family [67], in the first non-consanguineous family, from Estonia [57], and in a Chinese fetus homozygous for NM_024715.3:c.560delA p.(Asn187IlefsTer4) (MANE NM_024715.4:c.560del) [19, 68].

2.7. Inheritance, penetrance, expressivity and modifiers

Inheritance is autosomal recessive, with equal frequency in both sexes, concordance in monozygotic twins, affected siblings and frequent parental consanguinity [5]. Heterozygotes have no recognised manifestations [21, 22]. Expressivity is variable even within the same family, including monozygotic twins with the same variant [5, 78].

The question of modifiers has contradictory data. In the Saudi cohort, the ciliopathies behaved as fully penetrant Mendelian diseases: the burden of rare variants (allele frequency <0.01) in 89 ciliary genes was the same in patients (7.0 per sample, 31 exomes) and in 64 controls with non-ciliopathic intellectual disability (6.98; p=0.91), and phenotypic concordance was 97% between siblings (69 of 71), 92% between unrelated patients with the same founder variant (34 of 37) and 97% with published patients with the same variant (76 of 78); discordances always occurred with splicing variants [43]. The authors conclude that the phenotype is mainly allele-specific, with stochastic effects more relevant than modifiers, and warn that 17 variants classified as causal in HGMD (Human Gene Mutation Database) in ciliary genes have an allele frequency >0.01, eight of them observed in the homozygous state in people without ciliopathy [43]. Digenic and oligogenic inheritance were largely excluded in a JS cohort [5].

There are, however, isolated observations compatible with oligogenicity that have not been demonstrated: French siblings compound heterozygous in CEP290 with a third variant p.(Leu63Arg) in TMEM216 (published protein designation, MANE NM_001173990.3) [64], and a fetus with biallelic B9D1 and an additional CEP290 variant NM_025114.4:c.6628C>T p.(Arg2210Cys) inherited from the mother [36]. In the Finnish family with a fetus homozygous for CC2D2A c.1762C>T whose mother was also a carrier of the main MKS1 variant, the fetus did not inherit the latter, which confirms MKS as a monogenic disease and reinforces the requirement for two variants in the same gene before attributing causality [61]. Hypomorphic variants of MKS1, TMEM67 and CEP290 have been described with an epistatic effect on BBS loci [33].

2.8. Allelic disorders

Table 2.3. Allelic phenotypes of the main MKS genes

Sources: [2, 5, 10, 34, 38, 48, 49, 75]. The JS genes also implicated in MKS (CC2D2A, CEP290, RPGRIP1L, TCTN2, TMEM67, TMEM138, TMEM216, TMEM231, TMEM237), the BBS genes (CEP290, MKS1) and the nephronophthisis genes (CEP290, NPHP3, RPGRIP1L, TMEM67) limit the clinical specificity of a molecular result, because the same genotype may correspond to different phenotypes [2]. AHI1 is associated with JS and retinal dystrophy but not with MKS, and dominant inheritance (SUFU) has been described only in mild JS [49].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Overview and frequency of manifestations

The core phenotype combines posterior fossa anomalies (most often occipital encephalocele), enlarged bilateral cystic kidneys and defects of hepatic development with ductal plate malformation, fibrosis and cysts; postaxial polydactyly, usually of the hands and feet, occurs in 70 to 80% of cases [5]. Occasional findings, present in 25 to 40% of fetuses, include bowing and shortening of the long bones, male genital anomalies, microcephaly or anencephaly, cleft lip or palate and other craniofacial anomalies, congenital heart disease and pulmonary hypoplasia; rare findings (<20%) include cystic dysplasia of the lung or thyroid, retinal colobomas and laterality defects [5]. Variability is considerable, even between siblings [21, 78].

The population series of EUROCAT (the European network of congenital anomaly registries) is the largest systematic description available: 191 cases from 34 registries in 16 countries, between January 1990 and December 2011, included when they had at least two of the three classic manifestations and reviewed by a geneticist [11]. Table 3.1 compares the frequencies of this series with the historical series.

Table 3.1. Frequency of manifestations in MKS series

Sources: [1, 11, 21–23]. The Fraser and Lytwyn series has 65 cases in the EUROCAT comparative table; the percentages of 100%, 63%, 55% and 18% refer to the subset of 38 cases with secondary ascertainment, that is, siblings of probands [11, 21, 23].

Two cautions are needed in reading these data. The frequency of orofacial clefts is given as 31.8% in the abstract of the EUROCAT article and as 25.4% (44 of 173) in the table, an internal discrepancy in the source; the table has the explicit denominator [11]. Microcephaly, club foot and pulmonary hypoplasia are under-recorded in the European series, because registries code them as part of the oligohydramnios sequence, which explains the difference from the autopsy-based Finnish series [11]. In the EUROCAT series, 64 cases (37%) had anomalies beyond the triad: one additional anomaly in 29 (16.8%), two in 21 (12.1%) and three or more in 14 (8.1%) [11].

3.2. Central nervous system

The CNS defect is considered obligatory in some definitions, but it is variable: it ranges from total craniorachischisis to partial defects of the corpus callosum and Dandy-Walker malformation, occipital encephalocele being the most frequent [5]. Smith's textbook describes occipital encephalomeningocele, microcephaly with a sloping forehead, cerebral and cerebellar hypoplasia, anencephaly, hydrocephalus with or without Arnold-Chiari malformation, and absence of the olfactory lobes and tracts, the corpus callosum and the septum pellucidum [21]. In the EUROCAT series, among the 145 encephaloceles, 99 were occipital, one nasofrontal, one orbital and 44 of unspecified location; also recorded were cervical rachischisis in 4 cases, holoprosencephaly in 5, agenesis or hypoplasia of the corpus callosum in 3, cerebellar agenesis or hypoplasia in 11, atresia of the foramina of Magendie and Luschka in 3 and Arnold-Chiari malformation in 2 [11]. The 2022 review adds cerebellar hypoplasia, hydrocephalus, holoprosencephaly and anencephaly to the accessory features [49]. Smith's textbook includes MKS, along with Smith-Lemli-Opitz syndrome, among the multiple malformation syndromes in which holoprosencephaly occurs, which places it in the differential diagnosis of a fetus with holoprosencephaly and other anomalies [79]. Encephalocele is a skin-covered neural tube defect, which has consequences for biochemical screening (section 5) [23].

3.3. Kidney and urinary tract

Cystic renal dysplasia is the most characteristic feature and is distinguished from polycystic kidney disease [5]. The kidneys are often greatly enlarged, with massive abdominal distension and palpable flank masses; they contain thin-walled cysts of varying size [5, 21, 50]. The cysts begin in the cortical glomeruli and progress along the tubules and medullary collecting ducts [5]. On first-trimester or early second-trimester ultrasound, the distinguishing signs are abnormal corticomedullary differentiation and small pyramidal cysts; later, oligohydramnios, a non-visualised bladder and a discrepancy between the biparietal diameter and the abdominal diameter appear [11]. Urinary tract anomalies include absent or duplicated ureters, absent or hypoplastic bladder, urethral atresia and patent urachus [1, 21]. In the EUROCAT series, renal agenesis was recorded in 6 cases (3.5%) and renal hypoplasia or dysplasia in 24 (13.9%) [11].

3.4. Liver, biliary tract and pancreas

Hepatic involvement was considered obligatory by Salonen: proliferation and dilatation of the bile ducts with an excess of collagenous connective tissue, resulting from incomplete development of the biliary tree (ductal plate malformation) [5, 22]. Immunohistochemistry for cytokeratin 19 (CK19) highlights the ductal plate malformation, and figure 1 of the 2017 review illustrates it according to the authors' legend [5]. In the EUROCAT series, fibrosis, hepatic cysts or ductal plate malformation were recorded in 74 of the 113 cases with autopsy (65.5%) [11]. The absence of hepatic changes does not exclude the diagnosis: in the Chinese case published in 2026, with biallelic CC2D2A variants, the liver had no histological changes [73]. Pancreatic fibrosis and cysts are occasional [1].

3.5. Limbs and skeleton

Polydactyly is usually postaxial and affects the hands and feet; preaxial polydactyly of the hand is occasional [1, 21]. Club foot is part of the oligohydramnios sequence [21]. Shortening and bowing of the long bones occurs in 25 to 40% of fetuses and defines the campomelic variant associated with the Finnish MKS1 variant [5, 69]; skeletal dysplasia is also frequent with TMEM216 and RPGRIP1L [30, 34]. Smith's textbook also mentions syndactyly, single palmar crease and clinodactyly as occasional findings [21].

3.6. Face, eyes and oral cavity

The face may show microphthalmia, cleft palate, micrognathia and slanting or posteriorly rotated ears; occasionally, iris coloboma, optic nerve hypoplasia, hypo- or hypertelorism, hypoplastic philtrum and nasal septum, cleft lip, sometimes median, lobulated tongue, cleft epiglottis and natal teeth [21]. Orphanet records as frequent (30 to 79%) microcornea, cataract, chorioretinal anomalies, sclerocornea, optic atrophy and aplasia or hypoplasia of the iris [1]. Retinal colobomas were associated with TMEM67 in the British cohort [64], and the 2022 review includes oral hamartomas among the accessory features [49].

3.7. Heart, lung, genitalia and laterality

Congenital heart disease occurred in 16.2% of the EUROCAT series: ventricular septal defect (9), atrial septal defect (4), pulmonary stenosis (2), persistent left superior vena cava (2), coarctation of the aorta (2), double outlet right ventricle (1), dextrocardia (1) and single ventricle (1) [11]. Pulmonary hypoplasia is secondary to oligohydramnios [5, 80]. Genital anomalies include cryptorchidism, incomplete development of the external or internal genitalia, ambiguous genitalia (10.4% in the European series), hypoplastic scrotum and uterine malformations (double, unicornuate or bifid uterus) [11, 21]. Laterality defects, including situs inversus totalis, asplenia and accessory spleen, are occasional and, in the British cohort, did not occur with TMEM67 [1, 64]. The placenta may be enlarged, and single umbilical artery, omphalocele, intestinal malrotation and imperforate anus have been described [11, 21].

3.8. Oligohydramnios sequence

From 14 weeks, amniotic fluid depends on fetal urine; with about 250 mL at 16 weeks and 800 mL in the third trimester, the lack of urine production due to renal dysplasia leads to oligohydramnios or anhydramnios [80]. The resulting Potter sequence includes pulmonary hypoplasia, growth restriction, club feet and contractures, a sloping forehead, a flattened nose and low-set ears [5]. The canalicular period, between 16 and 24 weeks, is critical for lung development; across all causes, a deepest vertical pocket of fluid below 1 cm is associated with perinatal mortality above 95%, especially if it occurs in that interval [80]. Late severe oligohydramnios hampers ultrasound visualisation of polydactyly and encephalocele, which favours diagnosis in the first trimester [5, 81].

3.9. Natural history and survival

MKS is lethal in utero or shortly after birth, often owing to pulmonary hypoplasia [5]. Table 3.2 summarises the documented outcomes. The data are mostly natural history modified by termination of pregnancy for medical reasons (TOP): the survival of live births mainly describes comfort care, not active treatment.

Table 3.2. Outcomes and survival

The causes of early death are renal failure with oligohydramnios, pulmonary hypoplasia and liver disease [11]; in the neurosurgical series, the most common cause was pneumonia [84]. In the Qatar series, the absence of evident polycystic kidneys and of severe oligohydramnios was associated with live birth [82]. The 2022 review records survival beyond infancy in isolated cases [49]; the reclassification of the Hutterite patients, with survival of 5 to 13 months, as a Joubert group syndrome shows that prolonged survival should prompt review of the diagnosis [52, 53].

3.10. Gene-specific forms and related entities

Some forms have their own features. MKS due to MKS1, especially with the Finnish variant, is associated with polydactyly, encephalocele and campomelic skeletal dysplasia; MKS due to TMEM67 has less polydactyly and milder CNS defects, with ductal plate malformation and coloboma more frequent [5, 60, 64]. Meckel-like syndrome due to NPHP3 is associated with situs inversus, structural heart disease and renal-hepatic-pancreatic dysplasia, with about 10 cases or families described [4, 54]. The CEP55 phenotypes (MARCH) have hydranencephaly, anhydramnios, dysplastic kidneys and cerebellar hypoplasia, usually without occipital encephalocele or polydactyly [16, 45], and the KIF14 phenotypes have severe microcephaly and renal agenesis or dysplasia with genitourinary malformations [40]. The fetuses with TMEM218 had occipital encephalocele, polycystic kidneys and polydactyly without liver involvement [46].

4. Clinical Recognition and Warning Signs

4.1. First-trimester ultrasound

Most cases are now recognised prenatally: in the EUROCAT series, 90.2% of the 183 cases with known timing of diagnosis were diagnosed before birth, at a mean of 14.3±2.6 weeks (range 11 to 36) [11]. The 2023 ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) guideline establishes that the scan at 11+0 to 14+0 weeks should assess fetal anatomy, not only crown-rump length and nuchal translucency, in all pregnant women, because most severe anomalies occur in low-risk pregnancies [12]. The minimum planes defined by that guideline include skull ossification, visible at 11 completed weeks; the midsagittal plane of the head for the posterior fossa and intracranial translucency (fourth ventricle), which screen for open neural tube defects and cystic posterior fossa malformations; both kidneys; the bladder, visible at 12 weeks with a longitudinal diameter below 7 mm; and the four limbs with three segments, hands and feet [12]. The guideline does not mention MKS, but each component of the triad can be assessed in that scan. Polycystic kidneys can be detected from 9 weeks, polydactyly from 11 and occipital encephalocele from 13, in high- and low-risk pregnancies [5]. The transvaginal route improves resolution when the transabdominal route is limited [5, 12].

4.2. Second and third trimesters

In the second trimester, the warning signs are bilaterally enlarged, hyperechogenic and cystic kidneys, progressive oligohydramnios, a non-visualised bladder and a discrepancy between the biparietal diameter and the abdominal circumference [5, 11]. Maternal serum alpha-fetoprotein may be raised and second-trimester serum screening may be abnormal [5, 81]. Enlarged bilateral multicystic kidneys prenatally should prompt a targeted search for CNS malformations and polydactyly [81]. Late severe oligohydramnios hampers visualisation of the limbs and skull [81].

4.3. Family context

Suspicion increases with a previous sibling with similar anomalies, unexplained neonatal death or stillbirth, parental consanguinity and origin from a population with a founder variant (Finland, Gujaratis, Mirpuri Pakistanis, Ashkenazi Jews, Arab populations with high consanguinity) [5, 50, 64, 80]. In the Qatar series, half of the multiparous women had already had an affected child [82], and in the EUROCAT series 16.8% of cases were familial [11]. In a family with a previous case, early diagnosis does not require the complete triad [82].

4.4. Newborn and stillbirth

At birth, the signs are occipital encephalocele, postaxial polydactyly, an abdomen distended by bulky palpable kidneys and Potter facies [21, 50]. The case described in Smith's textbook was a 2-day-old newborn with a palpable enlarged kidney and frequent seizures [21]. In every stillbirth, neonatal death or terminated fetus with cystic renal dysplasia, complete autopsy with renal and hepatic histology is the means of confirming or excluding the diagnosis, especially in atypical cases [22, 85]. There is no newborn screening for MKS.

4.5. Signs that should prompt review of the diagnosis

Some findings argue against the diagnosis or point to related entities (section 6). Normal-appearing kidneys with polyhydramnios, severe hydrocephalus and a «keyhole» opening of the skull base suggest hydrolethalus syndrome [86]. Hydranencephaly with cystic dysplastic kidneys and anhydramnios, without occipital encephalocele or polydactyly, suggests a CEP55-related syndrome [16]. Holoprosencephaly with orofacial clefts and heart disease suggests trisomy 13 [78, 87]. Vermis hypoplasia with the molar tooth sign on MRI, or survival beyond the first months with hypotonia and delay, suggests Joubert syndrome with encephalocele [10, 53]. Large, uniformly bright kidneys without encephalocele or polydactyly suggest autosomal recessive polycystic kidney disease (ARPKD) [78, 80]. A fetal renal anomaly should also prompt renal ultrasound of the parents before recurrence counselling, to exclude a dominant cause [80].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no evidence-based diagnostic criteria validated by consensus [49]. The published proposals diverge on the obligatory manifestation, and this divergence has practical consequences: a criterion requiring hepatic fibrosis cannot be applied to a fetus terminated at 12 weeks, in which ductal plate malformation may not yet be evident.

Table 5.1. Proposed minimum criteria for MKS

In the EUROCAT series, at least two anomalies were detected on ultrasound in all cases except three with isolated cystic renal dysplasia, in which autopsy revealed other malformations [11]. Cases with isolated encephalocele or isolated renal dysplasia may correspond to unrecognised MKS [11], and molecular diagnosis is now the means of resolving cases with an incomplete phenotype.

5.2. Prenatal imaging

Table 5.2. Detection by ultrasound and magnetic resonance imaging

The prenatal detection rate in Europe was 93.8% (165 of 176; 95% CI 89.1–98.4), 91% between 1990 and 2000 and 95.5% between 2001 and 2011 (p=0.07) [11]. This rate measures the proportion of registered cases diagnosed before birth, in a population with access to anomaly scanning, and not the sensitivity of the first-trimester scan alone. A published example from the USA describes diagnosis at 11 to 14 weeks in a low-risk pregnancy, with encephalocele and cystic-appearing kidneys, later confirmed by a panel with two CC2D2A variants [88].

5.3. Biochemical markers

Maternal serum or amniotic fluid alpha-fetoprotein may be raised in MKS [5, 81], but encephalocele is a closed, skin-covered neural tube defect, and alpha-fetoprotein does not detect closed defects; its cut-off of 2.5 multiples of the median at 16 weeks was defined for open spina bifida [23]. Cell-free DNA screening does not detect structural anomalies, and the presence of a structural anomaly favours invasive testing [12]. There is no MKS-specific biomarker.

5.4. Autopsy and histopathology

The diagnosis can be made without genetic testing by autopsy with histological verification [2]. The histological elements are cystic renal dysplasia, with cysts of glomerular and tubular origin, cortical thinning and glomerular atrophy, and ductal plate malformation with proliferation and dilatation of the bile ducts and portal fibrosis [5, 22, 73]. In the EUROCAT series, autopsy was available in 113 cases (59%) [11]. Autopsy also allows tissue to be collected for genetic study, which is preferable to sequencing the parents alone [13]. Genomic autopsy (trio exome or genome after death) clarified the genetic basis in five Australian cases of atypical prenatal polycystic kidney disease, including biallelic PKD1, and is relevant to the differential between MKS and polycystic kidney diseases of prenatal onset [89].

5.5. Genetic strategy

The karyotype is normal in MKS: it was normal in all 94 cases studied in the EUROCAT series [11], and the chromosomal microarray is usually normal [73]. Single-gene testing has low sensitivity because of heterogeneity and the blurred genotype-phenotype correlation, except in populations with a known founder variant [5, 10]. Efficient testing became possible only with next-generation sequencing, which allows all genes to be studied in a fetus simultaneously [2]. The applicable recommendations are general, on prenatal sequencing, and not specific to MKS; they come from the ACMG (American College of Medical Genetics and Genomics), the ISPD (International Society for Prenatal Diagnosis) and the EuroGentest consortium.

Table 5.3. Recommendations on prenatal sequencing and divergence between sources

The main divergence is one of order: the ACMG favours targeted testing when the phenotype is specific, and the ISPD accepts genomic sequencing as first line when the pattern suggests a monogenic disorder [13, 14]. In MKS, both approaches are compatible if the panel is broad and includes the recent genes; a panel with few genes may miss the diagnosis, as in the Estonian case with a negative 10-gene panel and diagnosis by exome in TXNDC15 [57]. In China, trio exome is used as first line after suggestive ultrasound, and panels are rarely used prenatally [73].

Table 5.4. Yield of prenatal sequencing in relevant categories

These yields refer to categories of anomalies and not to MKS alone; the yield in clinically typical MKS is higher than in unselected categories, but the fraction without a molecular diagnosis was 40 to 50% in the series from 2012 to 2017 [5, 64].

5.6. Limits of the tests

The EuroGentest card estimates analytical sensitivity and specificity at about 100%, clinical sensitivity as unknown, and positive predictive value at 100%; clinical specificity is limited by allelism with JS, BBS and nephronophthisis [2]. A negative result does not exclude MKS. Table 5.5 gathers the documented false-negative mechanisms.

Table 5.5. Documented mechanisms that escape conventional sequencing

The sensitivity of exome for heterozygous CNVs is poorly defined [66]. An apparent deletion, especially of a single exon, requires validation by another method before being reported, because it may correspond to gene conversion [74]. An apparently homozygous variant requires parental study, because it may result from deletion of the other allele or from uniparental disomy, with direct consequences for recurrence risk [2, 8, 9]. When only one parent is a carrier, with confirmed paternity, a de novo variant in the proband or parental postzygotic mosaicism should be considered [9, 10].

5.7. Report content and variant interpretation

The report should state the gene, the transcript with version (preferably MANE Select), the variant in HGVS nomenclature with the protein consequence, zygosity, allele phase when known and the classification according to the ACMG and the AMP (Association for Molecular Pathology); the pathogenic and likely pathogenic classes are equivalent for clinical decisions, and a VUS neither confirms nor excludes the diagnosis [10, 14]. Variants in candidate genes without an established gene-disease relationship should be classified at most as VUS, and unrelated fetal carrier status should not be reported [14]. Missense variants recorded in HGMD as causal should be interpreted with caution when the population frequency is high [43]. The classification of the Italian case published in 2025, B9D1 NM_015681.6:c.151T>C p.(Ser51Pro) in the homozygous state as likely pathogenic (PM3, PM2, PP3), is an example of applying the criteria to a missense variant with parental segregation [76]. In a fetus with two variants in different genes, causality requires two variants in the same gene [61]. The proband's DNA should be stored when no molecular diagnosis is obtained, and reanalysis is recommended in the event of a new pregnancy or after 12 months [10, 14].

5.8. Practical algorithm

Faced with a fetus with enlarged cystic kidneys and at least one other major manifestation: (1) targeted anomaly scan at 11 to 14 weeks or at the gestational age of presentation, with fetal MRI if oligohydramnios limits assessment [5, 12]; (2) genetic counselling and collection of fetal material by chorionic villus sampling or amniocentesis, with quantitative fluorescent polymerase chain reaction (QF-PCR) or karyotype and microarray to exclude aneuploidy (trisomy 13) [80, 87]; (3) broad ciliopathy panel with CNV analysis or trio exome, in parallel with microarray [13, 14]; (4) parental segregation of all variants; (5) if the result is negative and there is TOP or death, autopsy with renal and hepatic histology and storage of tissue and DNA, with genome, RNA or long reads in strongly suggestive cases [74, 85, 92]; (6) renal ultrasound of the parents when the cause has not been clarified [80]. Prenatal diagnosis and preimplantation genetic testing are covered in section 8.

6. Differential Diagnosis

The diagnosis is clear in most cases from the combination of major manifestations, but the incomplete first-trimester phenotype, oligohydramnios and allelism with other ciliopathies make the differential relevant [5, 11]. Table 6.1 summarises the entities to consider.

Table 6.1. Differential diagnosis of Meckel-Gruber syndrome

Hydrolethalus syndrome is the classic differential in Finland, where both syndromes are frequent owing to a founder effect; it is distinguished by polyhydramnios, the keyhole opening of the skull base and normal kidneys [86, 96, 99]. Trisomy 13 shares postaxial polydactyly, clefts and cystic kidneys, and is the most common chromosomal cause of postaxial polydactyly; QF-PCR or karyotype resolves the question and should precede or accompany sequencing [87, 96]. ARPKD gives large, bright kidneys with oligohydramnios, but without CNS malformation or polydactyly; Chen's review recommends that enlarged bilateral multicystic kidneys always prompt a search for these malformations [80, 81].

The boundary with JS is the most difficult, because many genes are shared and occipital encephalocele also occurs in JS. Vermis hypoplasia with the molar tooth sign, survival beyond the neonatal period and the absence of severe cystic renal dysplasia point to JS; the history of the reclassified Hutterite patients illustrates this boundary [10, 53]. OMIM entry 609345 describes two siblings with occipital encephalocele, polycystic kidneys and polydactyly, as in MKS, but with severe, bilateral and symmetrical short and bowed distal long bones and triradiate acetabula, a finding not described in MKS; the authors proposed a distinct syndrome, with no gene identified [20]. Bowing of the long bones occurs in about one sixth of MKS cases and polydactyly is sometimes preaxial [100]. Acromelic frontonasal dysplasia, OFD syndromes 1 and 2, cerebro-reno-digital syndrome, the MURCS association (Müllerian duct aplasia, renal aplasia and cervicothoracic somite dysplasia) and renal-hepatic-pancreatic dysplasia syndrome with Dandy-Walker cyst were listed as difficult diagnoses in the EUROCAT series [11]. In fetuses with an MKS phenotype and EVC2 variants, the absence of signs of Ellis-van Creveld shows that a gene associated with another dysplasia may be a candidate in a consanguineous context [2].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no targeted treatment or approved drug for MKS, and therapy is considered not relevant in lethal cases [2, 16]. Management focuses on prenatal diagnosis, the informed decision of the pregnant woman or couple, delivery planning, comfort care for the newborn, diagnostic confirmation and reproductive counselling [15, 16]. No MKS-specific guideline was identified; the applicable recommendations come from general documents on perinatal palliative care, first-trimester ultrasound, prenatal sequencing and preimplantation genetic testing, and from the EuroGentest clinical utility gene card, which is not a formal guideline [2, 12, 13, 15, 101].

7.2. Decision after prenatal diagnosis

The American College of Obstetricians and Gynecologists (ACOG) document on perinatal palliative care (Committee Opinion No. 786, 2019, reaffirmed in 2024) establishes that, in the face of a life-limiting condition, including lethal ones, comfort-focused palliative care is one of the options in a spectrum that includes termination of pregnancy and full neonatal resuscitation and treatment, and that all should be presented to the pregnant woman [15]. Termination of pregnancy is the option chosen by many couples after a prenatal diagnosis of MKS [2]. In Europe, between 1990 and 2011, 145 of the 191 cases (75.9%) ended in TOP, at a mean of 18.1±2.53 weeks (range 12 to 39), which corresponds to about 88% of cases with a prenatal diagnosis [11]. Decisions depend on the couple's religious and cultural beliefs and previous experience [5]. The Islamic fatwa cited by the 2017 review allows termination before 120 days of gestation in cases of severe disability, such as MKS, or of maternal risk, but knowledge of this fatwa among Muslims is limited [5]. The sources consulted do not describe the legal framework for termination of pregnancy for lethal fetal anomaly in Portugal or Brazil.

Prenatal diagnosis of a lethal prognosis is reliable but not infallible: in a study of 49 pregnant women cited by ACOG, in 4 the specific diagnosis was not confirmed after birth, although all the newborns had substantial comorbidity [15]. This uncertainty should be acknowledged in counselling, and postnatal or autopsy confirmation should be sought [15]. In MKS, the distinction from JS with encephalocele, which has different survival and prognosis, is the main source of prognostic uncertainty (section 6) [53].

7.3. Perinatal palliative care

When the pregnant woman chooses to continue the pregnancy, perinatal palliative care is a coordinated strategy of obstetric and neonatal care focused on comfort and quality of life [15]. The recommended components are a formal prenatal consultation, an individualised birth plan, access to neonatal and paediatric specialties, and prenatal, intrapartum and postnatal support, including bereavement support [15]. The birth plan should clarify intrapartum fetal monitoring and the mode of delivery: antepartum testing and intrapartum monitoring may be omitted, and the parents should know that unmonitored fetal death may occur; caesarean section for fetal indication carries maternal surgical risks without lasting neonatal benefit [15]. Monitoring, planned delivery or caesarean section may, however, be requested by an informed pregnant woman who wishes for a live birth, for example for a religious ceremony; in a trial of labour after caesarean section, monitoring may help to watch the uterine scar [15]. The team should prepare the family for possible disagreements among relatives and with the neonatal team [15]. The pregnant woman continues careful obstetric surveillance, and in the differential of oligohydramnios, premature rupture of membranes may be associated with chorioamnionitis and fetal or, less frequently, maternal death [80].

With continuation of pregnancy, the Qatar series recorded 7 stillbirths and 5 live births among 12 pregnancies followed until delivery, with 100% mortality within a few weeks [82]. The sources consulted do not quantify the obstetric complications specific to MKS, such as dystocia due to bulky kidneys or encephalocele, or the caesarean section rate in these pregnancies.

7.4. Newborn

Neonatal comfort care, focused on comfort and quality of life, follows the plan defined prenatally with the neonatal and paediatric team [15]. In the Potter sequence of any cause, aggressive treatment of postnatal kidney disease is associated with high infant mortality, and the prognosis depends on the correct diagnosis [80]. Mechanical ventilation was the most common complication in the neurosurgical series [84].

The 2024 systematic review, following the PRISMA method (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), gathered 10 newborns with MKS and occipital encephalocele or meningocele who underwent surgical repair. The mean gestational age at birth was 36±2 weeks, weight 3.14±0.85 kg, head circumference 33.82±2.17 cm and sac diameter 5.91±1.02 cm; hydrocephalus, Dandy-Walker malformation and agenesis of the corpus callosum were frequent; 40% needed ventricular shunting; surgery was performed at a median of 2.5 days of life (1.5 to 6.5); the most common cause of death was pneumonia, with a median age at death of 6.66 months (0.03 to 18) [84]. The authors suggest a possible improvement in survival, but the series is small, selected and subject to publication bias, and the operated patients had characteristics (gestational age and weight close to term) that already distinguish them from most live births in the European series [11, 84]. Neurosurgical repair is not routine management and its benefit remains uncertain; in a patient with prolonged survival, the diagnosis should be reviewed in the light of the Joubert spectrum [53].

7.5. Diagnostic confirmation after death

Fetal or neonatal autopsy with renal and hepatic histology is recommended to confirm the diagnosis, especially in atypical or unsuspected cases [2, 22, 85]. Collection of fetal tissue and parental DNA (trio) should be planned before TOP or delivery, because material from the affected individual is preferable to parental sequencing alone and allows prenatal or preimplantation diagnosis in subsequent pregnancies [10, 13, 80].

7.6. Regulatory status

Table 7.1 summarises the situation at the FDA (Food and Drug Administration, USA) and the EMA (European Medicines Agency, EU).

Table 7.1. Regulatory status of drugs related to the spectrum

7.7. Clinical trials

A search of ClinicalTrials.gov for the condition «Meckel» (API v2, October 2026) returned 12 records, none therapeutic for MKS [102]. Ten relate to the allelic disorder LCA10 due to CEP290, to other retinal dystrophies or to studies of JS and ARPKD, and two to unrelated conditions (Meckel's diverticulum and another); the relevant ones are in table 7.2 only to delimit the scope.

Table 7.2. Records returned by the «Meckel» search on ClinicalTrials.gov

Source: [102]. The absence of registered therapeutic trials does not prove the absence of research, especially preclinical; nor are there trial results applicable to MKS that would allow effects to be estimated with confidence intervals. The LCA10 trials assess visual outcomes in a disease without the lethal malformations of MKS, and their results are not transferable to MKS.

7.8. Developments in the last 12 months

Table 7.3. Developments between October 2025 and October 2026, by level of evidence

Immediately before this window, in May 2025, cleavage of TMEM67 by ADAMTS9 was described, which separates the ciliogenesis function from Wnt signalling [55]. No regulatory process (FDA or EMA) related to MKS was identified [102].

7.9. Preclinical research in the spectrum

The investigational therapies for the Joubert–Meckel–nephronophthisis spectrum are exon-skipping antisense oligonucleotides, with rescue in fibroblasts and renal epithelial cells, and premature termination codon readthrough drugs; both are at the preclinical stage and are aimed at the viable forms of the spectrum, not at MKS [49]. The animal models of Txndc15 and of non-cleavable TMEM67 serve to study the mechanism, not to test therapy [55, 56].

7.10. Pregnancy, agents to avoid, perioperative care and transition

The woman pregnant with a fetus with MKS has no disease-specific risk of her own, because carriers are asymptomatic [9, 22]. The maternal risks are those of pregnancy with oligohydramnios and of the chosen mode of delivery, which the birth plan should discuss (section 7.3) [15, 80]. Periconceptional folic acid does not prevent MKS: supplementation with 400 μg per day from at least one month before conception until 12 weeks, or 5 mg per day for prevention of recurrence, applies to multifactorial neural tube defects, and a recurrence of neural tube defect despite the high dose should prompt reconsideration of a syndromic cause [23]. Maternal ACE inhibitors cause a phenocopy of renal tubular dysgenesis, with fetal anuria and Potter sequence, which should be excluded by the medication history [80]. There are no specific agents to avoid in the carrier, nor questions of transition to adult care, because there is no prolonged survival in confirmed MKS. The sources consulted do not describe specific anaesthetic risks in the newborn with MKS.

7.11. Recommendations of guidelines and consensus documents

Table 7.4. Documents applicable to MKS and recommendations

In the sources consulted, no MKS-specific guideline from North American or European societies or from European reference networks was identified.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

The parents of an affected individual are presumed heterozygous, and each subsequent pregnancy has a 25% probability of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier [5, 9, 10]. The proportion of affected siblings corrected for ascertainment was 0.261 in the Finnish series, consistent with autosomal recessive inheritance [7]. Testing of the parents after molecular diagnosis is recommended to confirm that both are heterozygous and to allow a reliable risk calculation [9, 10]. Carriers are not at risk of developing the disease [9].

The 25% risk has exceptions that only parental study reveals. In uniparental disomy, the proband's apparently homozygous variant comes from a single carrier parent, and the recurrence risk is very low: this was the case for MKS due to TMEM67 with maternal isodisomy of chromosome 8 and for a fetus with TMEM17 p.(Arg94Trp) and maternal isodisomy of chromosome 2 [8, 48]. A deletion of the second allele may mimic homozygosity [2, 9]. When only one parent is a carrier and paternity is confirmed, a de novo variant in the proband or parental mosaicism should be considered [9], as in the de novo 1.713 Mb deletion encompassing B9D1 [36].

The observed recurrences confirm the risk: in the EUROCAT series, 32 cases (16.8%) were familial, 27 with an affected sibling and 5 with another relative with an anomaly of the spectrum [11]; in Qatar, half of the multiparous women had already had an affected child [82]. The 25% recurrence risk contrasts with the empirical risk of multifactorial neural tube defects, of 2 to 5% for a sibling depending on population incidence, which makes the distinction between syndromic and isolated encephalocele decisive [23]. Without an aetiological diagnosis after assessment of a fetus with anomalies, the recurrence risk may be 25% if the cause is recessive [14].

8.2. Relatives and carrier screening

The parents' siblings have a 50% probability of being carriers, and carrier testing in relatives requires prior identification of the familial variants [9, 10]. Carrier screening is especially relevant in consanguineous couples and in people of Finnish origin, because of the MKS1 founder variant [2]. The carrier frequency of the Finnish MKS1 deletion was 1 in 260 among 519 healthy Germans [69]; the gene frequency was estimated at 0.01 in Finland and at about 0.028 among the Gujaratis of Leicester [24, 105]. In consanguineous families, geneticists encourage communication of risk to relatives, but the fear that carrier status may harm marriage prospects contributes to non-disclosure, according to studies in the United Kingdom and Pakistan cited by the 2017 review [5]. Counselling should be offered to young adult carriers or those at risk, and the ideal time to determine risk and discuss options is before pregnancy [9, 10]. Carrier testing in minors has no clinical benefit for the individual, because the condition does not manifest in heterozygotes.

8.3. Family without a molecular diagnosis

When the affected fetus was not studied, the ISPD considers it appropriate to sequence both parents in search of shared carrier status for recessive variants that explain the phenotype, although it is preferable to obtain tissue from the affected individual [13]. In subsequent pregnancies in a family without a known variant, prenatal diagnosis depends on early ultrasound, with the limitation that the absence of findings does not exclude the disease [10, 11]. Exome reanalysis is recommended when planning a new pregnancy [14].

8.4. Prenatal diagnosis

With both familial variants identified, early prenatal diagnosis is performed by chorionic villus sampling [2, 5, 69]. First-trimester ultrasound, with diagnosis possible at 11 to 14 weeks in the presence of two of the three major anomalies, is complementary and is the only means when the variant is not known [11, 12]. The EUROCAT series recommends counselling on the high recurrence risk, first-trimester ultrasound and genetic testing on chorionic villus sampling in subsequent pregnancies [11]. Differences in perspective on the use of prenatal diagnosis should be acknowledged in counselling [9].

8.5. Preimplantation genetic testing

Preimplantation genetic testing for monogenic disorders (PGT-M) is possible when the familial variants are known [2, 9]. The ESHRE consensus documents identify a particular risk in consanguineous couples who share the high-risk haplotype: parental contamination, usually maternal, of an affected homozygous embryo cannot be distinguished from a carrier embryo, with a risk of transferring an affected embryo; they recommend including informative unlinked polymorphic markers or analysing two independent biopsies and, where this is not possible, prioritising the transfer of non-carrier embryos [101]. Technical risks include amplification failure, contamination and allele drop-out, and validation requires 30 to 50 samples of one or a few cells, with reference samples from an affected individual, a carrier and a non-carrier [101]. Simultaneous PGT-M for MKS due to NPHP3 and for a paternal BRCA2 variant resulted in a pregnancy in a Chinese family [104]. VUS may limit future PGT-M and prenatal diagnosis, which reinforces investment in classifying the index case's variants [14].

8.6. Content of counselling

Counselling includes the nature of the disease and its lethality, inheritance, prenatal and preimplantation diagnosis options, and bereavement support, and should respect the couple's religious and cultural beliefs and previous experience [5, 15]. Storage of fetal DNA and tissue, autopsy and renal ultrasound of the parents when the cause has not been clarified are part of the process [10, 80]. The association ARC (Antenatal Results and Choices, United Kingdom) supports parents facing fetal anomalies [80].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Estimates vary more than a hundredfold between populations, and also according to the measure: total birth prevalence (including TOP and fetal deaths), incidence in live births, hospital prevalence or expert estimate. As the disease is lethal, point prevalence is below 1 per 1,000,000 [1].

Table 9.1. Estimates of the frequency of MKS

The table shows two patterns. In populations without a founder effect and with low consanguinity, birth prevalence lies between 1 and 3 per 100,000; in founder populations and communities with high consanguinity, it is several times higher, up to 2 per 1,000 live births in Qatar [7, 11, 82]. The Oman series reports hospital prevalence, but the figure is not accessible in the bibliographic record consulted [106].

9.2. Founder populations

Finland is the classic example: MKS, hydrolethalus syndrome, Cohen syndrome and congenital nephrosis of the Finnish type have a disproportionate incidence there, and affected individuals are mostly homozygous for the same variant [99]. About 70% of Finnish cases have the intronic MKS1 deletion, and the CC2D2A variant c.1762C>T was found in the homozygous state in 11 Finnish families [5, 61]. The MKS1 deletion is not exclusive to Finland: it has been dated to 162 generations in French and English cases, explains 8 of 20 German fetuses and is the most frequent MKS1 variant in non-consanguineous Europeans [59, 64, 69]. Among Mirpuri Pakistanis in the United Kingdom, TMEM67 c.1575+1G>A has an estimated age of 5 generations [59]; among Ashkenazi Jews, TMEM216 p.(Arg73Leu) [34]; among Jews of Ethiopian and Yemenite origin, a founder variant of TCTN2 [70]; and in Amish families, a variant of CEP55 [71]. In Saudi Arabia and the Gulf countries, autozygome-guided analysis solved 71% of Arab families, with marked genetic heterogeneity [65]. A high incidence has been described in the Tatars, according to the 2017 review [5]; among the Hutterites, the cases described as MKS were reclassified as a Joubert group syndrome [53].

9.3. Portugal and Brazil

The 2012 British cohort included a non-consanguineous Portuguese family (individuals 111 and 112) with occipital encephalocele, polycystic kidneys and polydactyly, heterozygous for CEP290 c.1451delA p.(Lys484fs*8) (the authors' notation; = NM_025114.4:c.1451del p.(Lys484ArgfsTer8)), with no second allele detected by Sanger sequencing [64]. The Instituto Nacional de Saúde Doutor Ricardo Jorge participates in the EUROCAT network and is a co-author of the European series, but is not among the 16 registries used to calculate prevalence, so there is no Portuguese estimate in that source [11]. In Brazil, the genetic syndromes textbook consulted lists MKS among the syndromic causes of neural tube closure defects, whose overall frequency is 1 to 5 per 1,000 live births depending on the region; this figure refers to neural tube defects as a whole and not to MKS [94]. The sources consulted contain no estimates of the prevalence of MKS in Portugal or Brazil; absence from these sources does not demonstrate the absence of published data.

9.4. Special populations and determinants

In the EUROCAT series, the sex ratio was 1.2:1 (male:female); mean maternal age was 29.3±6.8 years and paternal age 33.5±7.1, with no difference from EUROCAT as a whole; consanguinity was recorded in 23 cases [11]. There were 6 twin pregnancies (3.14%) of undetermined zygosity, all with only one twin affected [11]. Nine of 102 pregnancies with information (8.8%) were conceived with ovulation induction and none by in vitro fertilisation or intracytoplasmic sperm injection, with no association with medically assisted reproduction [11]. Consanguinity increases the probability of homozygosity and the rate of molecular resolution: in the British cohort, 50% of consanguineous families had homozygous variants, and among the 19 non-consanguineous families two thirds were solved, 10 of 13 with compound heterozygosity [64]. Consanguineous couples who undergo PGT-M face specific technical risks (section 8.5) [101].

9.5. Reference networks and patient associations

ERN ITHACA is the European reference network for rare congenital malformations and rare intellectual disability, relevant to malformation and genetic diagnosis [17]. ERKNet (European Rare Kidney Disease Reference Network) covers renal ciliopathies, including the surviving allelic disorders [9, 107]. The European Platform on Rare Disease Registration of the Joint Research Centre hosts EUROCAT, which continues population surveillance of congenital anomalies [108]. Among patient associations, the Ciliopathy Alliance (United Kingdom) brings together families with ciliopathies [9, 50], the Joubert Syndrome & Related Disorders Foundation includes the Joubert–Meckel spectrum [109], and ARC supports parents after a prenatal diagnosis of anomaly [80]. The sources consulted identify no Portuguese or Brazilian associations dedicated to MKS.

10. Illustrative Clinical Case

10.1. First-trimester diagnosis in an Italian family with B9D1

A 30-year-old woman from the Lecce region (Italy) was referred in her fourth pregnancy for a suspected fetal brain and renal anomaly [76]. Ultrasound at 11+6 weeks, performed according to the 2023 ISUOG guidelines, showed a live fetus with a crown-rump length of 46.4 mm, a nuchal translucency of 1.4 mm and a nasal bone present. The axial and sagittal planes showed an occipital bone defect with herniation of the meninges and a cyst with brain tissue, and the absence of one of the three posterior brain spaces. The kidneys were enlarged, polycystic in appearance, with abnormal corticomedullary differentiation and small pyramidal cysts [76]. According to the authors' legend, Figure 1A shows the occipital bone defect with herniated meninges and Figure 1B the enlarged, heterogeneous kidneys, with diffuse cysts surrounded by a more echogenic cortical rim (Figure 1).

The obstetric history included a healthy 5-year-old son, born at term by caesarean section; a second pregnancy terminated at 18 weeks for fetal anomalies, with bilateral postaxial polydactyly (six digits on both feet and the left hand), ventriculomegaly and polycystic kidneys; and a miscarriage at 9 weeks [76]. The parents were healthy and denied a family history of JS or MKS. Investigation of the genealogy showed that both came from the same village and that the paternal grandmothers were first cousins through the paternal line; the pedigree is presented in Figure 2 of the article [76].

Chorionic villus sampling was performed at 13 weeks. The QFQ-banded karyotype was 46,XX. Clinical exome sequencing (4,800 genes, mean coverage of at least 40×), filtered for 16 MKS-associated genes, identified the variant NM_015681.6:c.151T>C p.(Ser51Pro) in B9D1, in the homozygous state, with both parents heterozygous [76]. The variant has an allele frequency of 0.00005778 in the gnomAD (Genome Aggregation Database) population database, affects a conserved residue (phyloP100 of 5.384) and was classified by the authors as likely pathogenic according to the ACMG criteria (PM3, PM2, PP3); it was the first description of this variant in the homozygous state, previously known only in compound heterozygosity in a 22-year-old patient with JS [76]. The couple chose elective termination of pregnancy, decided independently of the genetic result [76].

10.2. Critical reading of the case

The case brings together several elements discussed in the previous sections. The suspected diagnosis was made on the 11–14-week scan with two of the three major manifestations, as the EUROCAT series anticipates, and the assessment followed the ISUOG anatomical planes [11, 12]. Remote consanguinity, identified only by targeted genealogical enquiry, explains the homozygosity of a rare variant [76]. The sibling terminated at 18 weeks had a compatible phenotype, but the text does not mention genetic study of that fetus; the recurrence illustrates the 25% risk and the value of keeping material from the first affected individual [13, 76]. The 16-gene filter applied to the exome did not include genes such as TMEM231, TMEM107, TXNDC15, KIF14 or TMEM17, which in a negative case would have required broader reanalysis [57, 76]. The classification of a missense variant as likely pathogenic, without functional study, should be read in the context of the B9D1 spectrum, in which 12 pathogenic or likely pathogenic variants are concentrated in the B9 domain [76]. For subsequent pregnancies, the authors discuss early prenatal diagnosis and PGT-M [76].

10.3. Complementary case: second-trimester diagnosis due to CC2D2A

A 30-year-old primigravida from Shandong (China), from a non-consanguineous couple, was referred at 23 weeks [73]. Ultrasound at 23+6 weeks showed bilaterally enlarged, hyperechogenic and polycystic kidneys, with a transverse diameter of 35 mm (above the 95th centile), displacing the liver; a 29×25×12 mm occipital meningoencephalocele with a bone defect of about 2.5×1.2 cm; bilateral postaxial hexadactyly; and oligohydramnios [73]. After counselling on the prognosis, the pregnancy was terminated. Autopsy confirmed the occipital meningoencephalocele (bone defect of 3×2.7 cm), postaxial polydactyly of the hands and feet and polycystic kidneys occupying the whole abdomen; histology showed polycystic dysplastic kidneys with partial fibrous hyperplasia, cortical thinning and glomerular atrophy, and a liver without histological changes [73]. Trio exome identified in CC2D2A a maternally inherited duplication, published as c.2390dupC and normalised as NM_001378615.1:c.2391dup p.(Ser798LeufsTer7), and a paternally inherited splicing variant, NM_001378615.1:c.3594+1G>T, both classified as pathogenic; CNV analysis was normal [68, 73]. Counselling covered the 25% recurrence risk and the options of PGT or first-trimester chorionic villus sampling [73]. The figures in the article include, according to the legends, the ultrasound at 23+6 weeks (Figure 1), the external appearance of the fetus (Figure 2) and the kidneys at autopsy (Figure 3).

This second case shows that ductal plate malformation may be absent despite a biallelic null genotype and a typical renal and brain phenotype, which supports the position that no single manifestation should be obligatory for the diagnosis [11, 73]. The published notation of the duplication did not follow the HGVS 3′ rule, an example of the nomenclature inconsistencies that require normalisation before comparing variants between laboratories [61, 68].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

MKS is lethal in the prenatal or perinatal period [2, 9]. In the EUROCAT series (1990–2011), 75.9% of pregnancies ended in TOP, 6.8% in fetal death and 17.3% in live birth; of the 33 live births, only 6 survived the first week [11]. In Qatar, all live births died within a few weeks [82]. The maximum published survival is 28 months, in a case cited by the reviews [5, 11], and there are isolated cases with about 5 months [21, 83]. In the selected series of newborns operated on for encephalocele, the median age at death was 6.66 months [84]. The causes of death are pulmonary hypoplasia with oligohydramnios, renal failure and liver disease [5, 11].

The factors associated with live birth in the Qatar series were the absence of evident polycystic kidneys and of severe oligohydramnios [82]. Prolonged survival should prompt review of the diagnosis in the light of the Joubert spectrum, as shown by the reclassification of the Hutterite patients with survival of 5 to 13 months [52, 53]. The survival data come almost entirely from patients without active treatment, and the series with intervention are small and biased [84].

11.2. Follow-up of the family and of subsequent pregnancies

There is no long-term patient surveillance, and the sources consulted do not describe follow-up protocols for the rare survivors. The applicable follow-up is that of carrier couples and relatives. Ultrasound surveillance intervals in a pregnancy at risk of MKS are not defined in any guideline; the time points in table 11.1 come from general guidelines, series and reviews.

Table 11.1. Follow-up of the family and surveillance of subsequent pregnancies

12. Summary and Final Considerations

Meckel-Gruber syndrome is a lethal autosomal recessive ciliopathy that occupies the severe end of the spectrum of ciliary transition zone disorders, shared with Joubert syndrome, COACH syndrome and nephronophthisis. Bilateral cystic renal dysplasia is present in almost all cases (97.7% in the European series), and is associated with encephalocele, mainly occipital, postaxial polydactyly and hepatic ductal plate malformation, with oligohydramnios and Potter sequence. There is no consensus diagnostic criterion; the most widely used criterion requires two of the three major manifestations, and the population series show that no manifestation should be considered obligatory when the diagnosis is made in the first trimester.

Total birth prevalence in Europe is 2.6 per 100,000, but reaches about 1 in 9,000 in Finland and higher values in communities with high consanguinity, such as the Gujaratis and the populations of the Gulf and Saudi Arabia. More than twenty genes are associated with the phenotype; MKS1, TMEM67, CC2D2A and CEP290 are the main ones, with founder variants in Finland, among Mirpuri Pakistanis and among Ashkenazi Jews, and TMEM17 is the most recently added gene. Biallelic null alleles tend to cause MKS and hypomorphic alleles JS, BBS or nephronophthisis, but the same gene, and sometimes the same family, crosses the boundary.

In Europe, more than 90% of cases are diagnosed before birth, at a mean of 14 weeks, and the 11–14-week scan allows a suspected diagnosis when two of the three major manifestations are present. Molecular investigation is by broad ciliopathy panel or trio exome, in parallel with microarray, and must take account of the documented limits: deep intronic variants, retrotransposon insertions, deletions, gene conversion with a pseudogene and uniparental disomy. Parental segregation is indispensable, because it alters the recurrence risk. Autopsy with histology and storage of fetal material allow the diagnosis to be confirmed and, in subsequent pregnancies, chorionic villus sampling or PGT-M to be offered.

There is no targeted treatment and there are no therapeutic trials for MKS. Management consists of presenting all options after prenatal diagnosis, including termination of pregnancy and perinatal palliative care with an individualised birth plan, and reproductive counselling of a couple with a 25% recurrence risk. Survival beyond the first months is exceptional and should prompt reconsideration of a diagnosis of Joubert syndrome; nephronophthisis and the renal forms of the spectrum also enter the differential.

13. References

1. Orphanet. Meckel syndrome (ORPHA:564) [Internet]. Paris: INSERM; Orphadata (epidemiology, natural history, cross-references, associated genes and HPO phenotypes), version of 2026-06-23 [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/564
2. Bergmann C, Frank V, Salonen R. Clinical utility gene card for: Meckel syndrome - update 2016. Eur J Hum Genet. 2016;24(8):e1-e3. doi:10.1038/ejhg.2016.33. PMID: 27094752. PMC4970697.
3. Online Mendelian Inheritance in Man (OMIM). Phenotypic Series PS249000: Meckel syndrome [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 10]. Available from: https://www.omim.org/phenotypicSeries/PS249000
4. Orphanet. NPHP3-related Meckel-like syndrome (ORPHA:3032) [Internet]. Paris: INSERM; Orphadata (epidemiology), version of 2026-06-23 [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/3032
5. Hartill V, Szymanska K, Sharif SM, Wheway G, Johnson CA. Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances. Front Pediatr. 2017;5:244. doi:10.3389/fped.2017.00244. PMID: 29209597. PMC5701918.
6. HUGO Gene Nomenclature Committee (HGNC). Gene records for MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, B9D2, TMEM231, KIF14, TMEM107, TXNDC15, TCTN1, TCTN3, TMEM237, TMEM138, CSPP1, CPLANE1, CEP55, TMEM17 and HYLS1 [Internet]. Hinxton: EMBL-EBI; [accessed 2026 Oct 10]. Available from: https://www.genenames.org/
7. Salonen R, Norio R. The Meckel syndrome in Finland: epidemiologic and genetic aspects. Am J Med Genet. 1984;18(4):691-8. doi:10.1002/ajmg.1320180415. PMID: 6486168.
8. Bruechle NO, Steuernagel P, Zerres K, Kurth I, Eggermann T, Knopp C. Uniparental disomy as an unexpected cause of Meckel-Gruber syndrome: report of a case. Pediatr Nephrol. 2017;32(10):1989-1992. doi:10.1007/s00467-017-3710-8. PMID: 28620746.
9. Stokman M, Lilien M, Knoers N. Nephronophthisis-Related Ciliopathies. 2016 Jun 23 [updated 2023 Mar 2]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 27336129. Available from: https://www.ncbi.nlm.nih.gov/books/NBK368475/
10. Glass IA, Dempsey JC, Parisi M, Doherty D. Joubert Syndrome. 2003 Jul 9 [updated 2025 Mar 13; revised 2026 Feb 12]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 20301500. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1325/
11. Barisic I, Boban L, Loane M, Garne E, Wellesley D, Calzolari E, et al. Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe. Eur J Hum Genet. 2015;23(6):746-52. doi:10.1038/ejhg.2014.174. PMID: 25182137. PMC4795048.
12. Bilardo CM, Chaoui R, Hyett JA, Kagan KO, Karim JN, Papageorghiou AT, et al. ISUOG Practice Guidelines (updated): performance of 11-14-week ultrasound scan. Ultrasound Obstet Gynecol. 2023;61(1):127-143. doi:10.1002/uog.26106. PMID: 36594739.
13. Van den Veyver IB, Chandler N, Wilkins-Haug LE, Wapner RJ, Chitty LS. International Society for Prenatal Diagnosis Updated Position Statement on the use of genome-wide sequencing for prenatal diagnosis. Prenat Diagn. 2022;42(6):796-803. doi:10.1002/pd.6157. PMID: 35583085. PMC11220784.
14. Monaghan KG, Leach NT, Pekarek D, Prasad P, Rose NC. The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(4):675-680. doi:10.1038/s41436-019-0731-7. PMID: 31911674.
15. American College of Obstetricians and Gynecologists' Committee on Ethics; Committee on Obstetric Practice. Perinatal Palliative Care: ACOG Committee Opinion, Number 786. Obstet Gynecol. 2019;134(3):e84-e89 (reaffirmed in 2024). doi:10.1097/AOG.0000000000003425. PMID: 31441826.
16. GeneGuidance. Curated records for genes MKS1, TMEM67, CEP290, RPGRIP1L, CC2D2A, TMEM216, B9D1, B9D2, TCTN2, TMEM231, TMEM107, NPHP3, CSPP1, KIF14, CEP55 and TCTN3 [database]. Version of 2026-09-26 [accessed 2026 Oct 10].
17. ERN ITHACA. European Reference Network on rare congenital malformations and rare intellectual disability [Internet]. [accessed 2026 Oct 10]. Available from: https://ern-ithaca.eu/
18. ClinGen. Gene-Disease Validity curations [Internet]. Clinical Genome Resource; CSV file downloaded on 2026 Oct 10. Available from: https://search.clinicalgenome.org/kb/gene-validity
19. Deng T, Xie Y. Novel homozygous mutations in TXNDC15 causing Meckel syndrome. Mol Genet Genomic Med. 2024;12(3):e2343. doi:10.1002/mgg3.2343. PMID: 38156946. PMC10958169.
20. Online Mendelian Inheritance in Man (OMIM). 609345 Cerebrorenodigital syndrome with limb malformations and triradiate acetabula [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 10]. Available from: https://www.omim.org/entry/609345
21. Jones KL, Jones MC, del Campo M. Meckel-Gruber syndrome (dysencephalia splanchnocystica). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 246–7.
22. Salonen R. The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet. 1984;18(4):671-89. doi:10.1002/ajmg.1320180414. PMID: 6486167.
23. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 500–5 (Neural tube defects).
24. Paavola P, Salonen R, Weissenbach J, Peltonen L. The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. Nat Genet. 1995;11(2):213-5. doi:10.1038/ng1095-213. PMID: 7550354.
25. Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, et al. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997;101(1):88-92. doi:10.1007/s004390050592. PMID: 9385376.
26. Salonen R, Paavola P. Meckel syndrome. J Med Genet. 1998;35(6):497-501. doi:10.1136/jmg.35.6.497. PMID: 9643292. PMC1051345.
27. Kyttälä M, Tallila J, Salonen R, Kopra O, Kohlschmidt N, Paavola-Sakki P, et al. MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat Genet. 2006;38(2):155-7. doi:10.1038/ng1714. PMID: 16415886.
28. Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S, et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet. 2006;38(2):191-6. doi:10.1038/ng1713. PMID: 16415887.
29. Baala L, Audollent S, Martinovic J, Ozilou C, Babron MC, Sivanandamoorthy S, et al. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am J Hum Genet. 2007;81(1):170-9. doi:10.1086/519494. PMID: 17564974. PMC1950929.
30. Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K, et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007;39(7):875-81. doi:10.1038/ng2039. PMID: 17558409.
31. Baala L, Romano S, Khaddour R, Saunier S, Smith UM, Audollent S, et al. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet. 2007;80(1):186-94. doi:10.1086/510499. PMID: 17160906. PMC1785313.
32. Tallila J, Jakkula E, Peltonen L, Salonen R, Kestilä M. Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet. 2008;82(6):1361-7. doi:10.1016/j.ajhg.2008.05.004. PMID: 18513680. PMC2427307.
33. Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008;40(4):443-8. doi:10.1038/ng.97. PMID: 18327255.
34. Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, et al. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet. 2010;42(7):619-25. doi:10.1038/ng.594. PMID: 20512146. PMC2894012.
35. Shaheen R, Faqeih E, Seidahmed MZ, Sunker A, Alali FE, AlQahtani K, et al. A TCTN2 mutation defines a novel Meckel Gruber syndrome locus. Hum Mutat. 2011;32(6):573-8. doi:10.1002/humu.21507. PMID: 21462283.
36. Hopp K, Heyer CM, Hommerding CJ, Henke SA, Sundsbak JL, Patel S, et al. B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. Hum Mol Genet. 2011;20(13):2524-34. doi:10.1093/hmg/ddr151. PMID: 21493627. PMC3109998.
37. Dowdle WE, Robinson JF, Kneist A, Sirerol-Piquer MS, Frints SG, Corbit KC, et al. Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am J Hum Genet. 2011;89(1):94-110. doi:10.1016/j.ajhg.2011.06.003. PMID: 21763481. PMC3135817.
38. Thomas S, Legendre M, Saunier S, Bessières B, Alby C, Bonnière M, et al. TCTN3 mutations cause Mohr-Majewski syndrome. Am J Hum Genet. 2012;91(2):372-8. doi:10.1016/j.ajhg.2012.06.017. PMID: 22883145. PMC3415538.
39. Shaheen R, Ansari S, Mardawi EA, Alshammari MJ, Alkuraya FS. Mutations in TMEM231 cause Meckel-Gruber syndrome. J Med Genet. 2013;50(3):160-2. doi:10.1136/jmedgenet-2012-101431. PMID: 23349226. PMC3585488.
40. Filges I, Nosova E, Bruder E, Tercanli S, Townsend K, Gibson WT, et al. Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype. Clin Genet. 2014;86(3):220-8. doi:10.1111/cge.12301. PMID: 24128419.
41. Shaheen R, Shamseldin HE, Loucks CM, Seidahmed MZ, Ansari S, Ibrahim Khalil M, et al. Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans. Am J Hum Genet. 2014;94(1):73-9. doi:10.1016/j.ajhg.2013.11.010. PMID: 24360803. PMC3882732.
42. Shaheen R, Almoisheer A, Faqeih E, Babay Z, Monies D, Tassan N, et al. Identification of a novel MKS locus defined by TMEM107 mutation. Hum Mol Genet. 2015;24(18):5211-8. doi:10.1093/hmg/ddv242. PMID: 26123494.
43. Shaheen R, Szymanska K, Basu B, Patel N, Ewida N, Faqeih E, et al. Characterizing the morbid genome of ciliopathies. Genome Biol. 2016;17(1):242. doi:10.1186/s13059-016-1099-5. PMID: 27894351. PMC5126998.
44. Bondeson ML, Ericson K, Gudmundsson S, Ameur A, Pontén F, Wesström J, et al. A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy. Clin Genet. 2017;92(5):510-516. doi:10.1111/cge.13012. PMID: 28295209.
45. Frosk P, et al. A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis. J Med Genet. 2017;54(7):490-501. PMID: 28264986. Available from: https://pubmed.ncbi.nlm.nih.gov/28264986/
46. Van De Weghe JC, Giordano JL, Mathijssen IB, Mojarrad M, Lugtenberg D, Miller CV, et al. TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes. HGG Adv. 2021;2(1). doi:10.1016/j.xhgg.2020.100016. PMID: 33791682. PMC8009330.
47. Pardo LM, Martini J, Zonic E, Almeida LS, Iqbal M, Sadagopan M, et al. Biallelic Variants in TMEM17 Cause Meckel-Gruber Syndrome Within the Ciliopathy Spectrum. Clin Genet. 2025;108(5):582-588. doi:10.1111/cge.14767. PMID: 41054827.
48. Boutaud L, Li C, Moncler C, Verlin L, Garfa-Traoré M, Bourgon N, et al. Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies. Clin Genet. 2026;109(2):305-315. doi:10.1111/cge.70042. PMID: 40841990. PMC12779253.
49. Van De Weghe JC, Gomez A, Doherty D. The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies. Annu Rev Genomics Hum Genet. 2022;23:301-329. doi:10.1146/annurev-genom-121321-093528. PMID: 35655331. PMC9437135.
50. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 366–8 (Ciliopathies).
51. Maglic D, Stephen J, Malicdan MC, Guo J, Fischer R, Konzman D, et al. TMEM231 Gene Conversion Associated with Joubert and Meckel-Gruber Syndromes in the Same Family. Hum Mutat. 2016;37(11):1144-1148. doi:10.1002/humu.23054. PMID: 27449316.
52. Schurig V, Bowen P, Harley F, Schiff D. The Meckel syndrome in the Hutterites. Am J Med Genet. 1980;5(4):373-81. doi:10.1002/ajmg.1320050408. PMID: 7395917.
53. Boycott KM, Parboosingh JS, Scott JN, McLeod DR, Greenberg CR, Fujiwara TM, et al. Meckel syndrome in the Hutterite population is actually a Joubert-related cerebello-oculo-renal syndrome. Am J Med Genet A. 2007;143A(15):1715-25. doi:10.1002/ajmg.a.31832. PMID: 17603801.
54. Bergmann C, Fliegauf M, Brüchle NO, et al. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet. 2008;82(4):959-70. doi:10.1016/j.ajhg.2008.02.017. PMID: 18371931.
55. Ahmed M, Fischer S, Robert KL, Lange KI, Stuck MW, Best S, et al. Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis. Nat Commun. 2025;16(1):4946. doi:10.1038/s41467-025-60294-3. PMID: 40436881. PMC12119803.
56. Liu Y, Wang H, Chen L, Wu X, Xu Z, Huang Q, et al. CRISPR-Cas9-Generated TXNDC15 c.560delA Homozygous Mouse Model Exhibits Meckel-Gruber Syndrome Phenotype. Genesis. 2026;64(1):e70040. doi:10.1002/dvg.70040. PMID: 41518077. PMC12789988.
57. Ridnõi K, Šois M, Vaidla E, Pajusalu S, Kelder L, Reimand T, et al. A prenatally diagnosed case of Meckel-Gruber syndrome with novel compound heterozygous pathogenic variants in the TXNDC15 gene. Mol Genet Genomic Med. 2019;7(5):e614. doi:10.1002/mgg3.614. PMID: 30851085. PMC6503012.
58. Turan L, Gökpinar Ili E, Doğan M, Erenel H, Gezdirici A. Meckel-Gruber Syndrome due to Homozygous c.16del (p.Leu6SerfsTer15) Variant in the TCTN1: First Case from Türkiye. Mol Syndromol. 2025;16(6):640-645. doi:10.1159/000544931. PMID: 41378242. PMC12688354.
59. Khaddour R, Smith U, Baala L, Martinovic J, Clavering D, Shaffiq R, et al. Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online. Hum Mutat. 2007;28(5):523-4. doi:10.1002/humu.9489. PMID: 17397051.
60. Consugar MB, Kubly VJ, Lager DJ, Hommerding CJ, Wong WC, Bakker E, et al. Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Hum Genet. 2007;121(5):591-9. doi:10.1007/s00439-007-0341-3. PMID: 17377820.
61. Tallila J, Salonen R, Kohlschmidt N, Peltonen L, Kestilä M. Mutation spectrum of Meckel syndrome genes: one group of syndromes or several distinct groups?. Hum Mutat. 2009;30(8):E813-30. doi:10.1002/humu.21057. PMID: 19466712. PMC2718326.
62. Mougou-Zerelli S, Thomas S, Szenker E, Audollent S, Elkhartoufi N, Babarit C, et al. CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. Hum Mutat. 2009;30(11):1574-82. doi:10.1002/humu.21116. PMID: 19777577. PMC2783384.
63. Iannicelli M, Brancati F, Mougou-Zerelli S, Mazzotta A, Thomas S, Elkhartoufi N, et al. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. Hum Mutat. 2010;31(5):E1319-31. doi:10.1002/humu.21239. PMID: 20232449. PMC2918781.
64. Szymanska K, Berry I, Logan CV, Cousins SR, Lindsay H, Jafri H, et al. Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies. Cilia. 2012;1(1):18. doi:10.1186/2046-2530-1-18. PMID: 23351400. PMC3579735.
65. Shaheen R, Faqeih E, Alshammari MJ, Swaid A, Al-Gazali L, Mardawi E, et al. Genomic analysis of Meckel-Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes. Eur J Hum Genet. 2013;21(7):762-8. doi:10.1038/ejhg.2012.254. PMID: 23169490. PMC3722952.
66. Watson CM, Crinnion LA, Berry IR, Harrison SM, Lascelles C, Antanaviciute A, et al. Enhanced diagnostic yield in Meckel-Gruber and Joubert syndrome through exome sequencing supplemented with split-read mapping. BMC Med Genet. 2016;17:1. doi:10.1186/s12881-015-0265-z. PMID: 26729329. PMC4700600.
67. Radhakrishnan P, Nayak SS, Shukla A, Lindstrand A, Girisha KM. Meckel syndrome: Clinical and mutation profile in six fetuses. Clin Genet. 2019;96(6):560-565. doi:10.1111/cge.13623. PMID: 31411728.
68. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-8. doi:10.1002/humu.23348. PMID: 28967166. PMC5765404.
69. Auber B, Burfeind P, Herold S, Schoner K, Simson G, Rauskolb R, et al. A disease causing deletion of 29 base pairs in intron 15 in the MKS1 gene is highly associated with the campomelic variant of the Meckel-Gruber syndrome. Clin Genet. 2007;72(5):454-9. doi:10.1111/j.1399-0004.2007.00880.x. PMID: 17935508.
70. Litz Philipsborn S, Hartmajer S, Shtorch Asor A, Vinovezky M, Regev M, Singer A, et al. A founder mutation in TCTN2 causes Meckel-Gruber syndrome type 8 among Jews of Ethiopian and Yemenite origin. Am J Med Genet A. 2021;185(5):1610-1613. doi:10.1002/ajmg.a.62119. PMID: 33590725.
71. Rawlins LE, et al. An Amish founder variant consolidates disruption of CEP55 as a cause of hydranencephaly and renal dysplasia. Eur J Hum Genet. 2019;27(4):657-62. PMID: 30622327. Available from: https://pubmed.ncbi.nlm.nih.gov/30622327/
72. Romani M, Micalizzi A, Kraoua I, Dotti MT, et al. Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome. Orphanet J Rare Dis. 2014;9:72. doi:10.1186/1750-1172-9-72. PMID: 24886560. Available from: https://pubmed.ncbi.nlm.nih.gov/24886560/
73. Liu L, Lv Y, Zhou X. Compound heterozygous mutations in CC2D2A cause Meckel-Gruber syndrome: a case report and review of the literature. J Med Case Rep. 2026;20(1). doi:10.1186/s13256-026-06070-3. PMID: 42083041. PMC13288813.
74. Watson CM, Dean P, Camm N, Bates J, Carr IM, Gardiner CA, et al. Long-read nanopore sequencing resolves a TMEM231 gene conversion event causing Meckel-Gruber syndrome. Hum Mutat. 2020;41(2):525-531. doi:10.1002/humu.23940. PMID: 31663672.
75. Jones KL, Jones MC, del Campo M. Oral-facial-digital syndrome type I. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 380–3.
76. Campobasso G, Mercuri L, De Razza F, Cosentino A, Mele M, Monittola A, et al. Investigating the Role of B9D1 in Meckel-Gruber Syndrome: A Case Report and Comprehensive Literature Review. Genes (Basel). 2025;16(6). doi:10.3390/genes16060643. PMID: 40565534. PMC12192128.
77. Panigrahi I, Sagarkar S, Kotecha U, Tamhankar V, Tamhankar PM. Novel Homozygous Exonic Deletion of the TMEM17 Gene Associated With Meckel-Gruber Syndrome Phenotype. Am J Med Genet A. 2026;200(11):2581-2585. doi:10.1002/ajmg.a.70227. PMID: 42307204.
78. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 796–9 (Urinary tract and renal anomalies — CAKUT).
79. Jones KL, Jones MC, del Campo M. Holoprosencephaly sequence. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 870–3.
80. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 770–1 (Oligohydramnios, including Potter/oligohydramnios sequence).
81. Chen CP. Meckel syndrome: genetics, perinatal findings, and differential diagnosis. Taiwan J Obstet Gynecol. 2007;46(1):9-14. doi:10.1016/S1028-4559(08)60100-X. PMID: 17389183.
82. Al-Belushi M, Al Ibrahim A, Ahmed M, Ahmed B, Khenyab N, Konje JC. A review of Meckel-Gruber syndrome--incidence and outcome in the state of Qatar. J Matern Fetal Neonatal Med. 2016;29(12):2013-6. doi:10.3109/14767058.2015.1072162. PMID: 26333300.
83. Aydin Ozturk P, Asena M, Katar S, Ozturk U. Meckel-Gruber Syndrome: A Case Who Lived for 5 Months. Pediatr Neurosurg. 2019;54(4):277-280. doi:10.1159/000500766. PMID: 31261150.
84. Junior JHMF, Junior SP, Pustilnik HN, de Almeida Leão L, da Paz MGDS, Araujo TB, et al. Neurosurgical intervention for the Meckel-Gruber Syndrome: A systematic review. Childs Nerv Syst. 2024;40(7):2161-2168. doi:10.1007/s00381-024-06346-3. PMID: 38459147.
85. Alexiev BA, Lin X, Sun CC, Brenner DS. Meckel-Gruber syndrome: pathologic manifestations, minimal diagnostic criteria, and differential diagnosis. Arch Pathol Lab Med. 2006;130(8):1236-8. doi:10.5858/2006-130-1236-MS. PMID: 16879033.
86. Jones KL, Jones MC, del Campo M. Hydrolethalus syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 254–5.
87. Jones KL, Jones MC, del Campo M. Trisomy 13 syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 14–7.
88. Jones D, Fiozzo F, Waters B, McKnight D, Brown S. First-trimester diagnosis of Meckel-Gruber syndrome by fetal ultrasound with molecular identification of CC2D2A mutations by next-generation sequencing. Ultrasound Obstet Gynecol. 2014;44(6):719-21. doi:10.1002/uog.13381. PMID: 24706459.
89. Frank MSB, Bennett MK, Ha TT, Moore L, Arts P, Byrne AB, et al. Atypical presentations of fetal polycystic kidney disease demonstrates the utility of a genomic autopsy for accurate post-mortem diagnoses. Hum Genomics. 2025;19(1):132. doi:10.1186/s40246-025-00844-4. PMID: 41225654. PMC12607061.
90. Zhu X, Zhang Q, Gao Z, Ren H, Xue S, Sun G, et al. Clinical and Molecular Features of Ciliopathies Diagnosed by Prenatal Exome Sequencing in Fetuses With Ultrasound Abnormalities. Prenat Diagn. 2026;46(2):277-289. doi:10.1002/pd.70053. PMID: 41402916.
91. Chretien M, Osouf J, Abel C, Afenjar A, Attie-Bitach T, Brischoux-Boucher E, et al. Evaluation of the contribution of trio-exome sequencing in selected prenatal indications. Front Genet. 2026;17:1761449. doi:10.3389/fgene.2026.1761449. PMID: 42186459. PMC13198924.
92. Miyamoto S, Nakamura K, Kato M, Nakashima M, Saitsu H. Identification of pathogenic deep intronic variant and exonic LINE-1 insertion in a patient with Meckel syndrome. Ann Hum Genet. 2023;87(4):196-202. doi:10.1111/ahg.12507. PMID: 36970932.
93. Jing H, Xu B, Wang H, Liu S, Wang H, Mai J, et al. Compound heterozygous missense and intronic variants in B9D1 contribute to a recurrent Meckel syndrome pedigree. Front Genet. 2025;16:1663455. doi:10.3389/fgene.2025.1663455. PMID: 40933483. PMC12417117.
94. Banhos H, Barbosa MA, Ribeiro EM. Defeitos de fechamento do tubo neural. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 160–2.
95. Nowaczyk MJM, Wassif CA. Smith-Lemli-Opitz Syndrome. 1998 Nov 13 [updated 2020 Jan 30]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 20301322. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1143/
96. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 284–7 (Polydactyly).
97. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Asphyxiating thoracic dysplasia. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 380–4.
98. Lemire G, Marshall AE, Patel TS, Trejo Martinez J, Lerman-Sagie T, Mears W, et al. Bi-allelic variants in CDK20 cause a severe ciliopathy with midline brain and facial anomalies. Am J Hum Genet. 2026;113(8):1754-1761. doi:10.1016/j.ajhg.2026.06.009. PMID: 42409022. PMC13504332.
99. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 10–1 (Autosomal recessive inheritance).
100. Online Mendelian Inheritance in Man (OMIM). #249000 Meckel syndrome, type 1; MKS1 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 10]. Available from: https://www.omim.org/entry/249000
101. Carvalho F, Moutou C, Dimitriadou E, Dreesen J, Giménez C, Goossens V, et al. ESHRE PGT Consortium good practice recommendations for the detection of monogenic disorders. Hum Reprod Open. 2020;2020(3):hoaa018. doi:10.1093/hropen/hoaa018. PMID: 32500103. PMC7257022.
102. ClinicalTrials.gov. API v2 search, condition «Meckel» [Internet]. Bethesda (MD): National Library of Medicine; [accessed 2026 Oct 10]. Available from: https://clinicaltrials.gov/api/v2/studies?query.cond=Meckel
103. Yang Q, He W, Zhang Q, Yi S, Zhou X, Zhang S, et al. Novel Compound Heterozygous Variants in the TCTN2 Gene Causing Meckel-Gruber Syndrome 8 in a Non-Consanguineous Chinese Family. Mol Genet Genomic Med. 2025;13(12):e70160. doi:10.1002/mgg3.70160. PMID: 41317100. PMC12664088.
104. Zhang Y, Huang X, Qiu P, Ji H, Ding L, He X, et al. Preimplantation genetic testing for concurrent Meckel Syndrome and hereditary breast cancer in a Chinese family harboring a novel NPHP3 pathogenic variant and a canonical BRCA2 frameshift variant. Genet Mol Biol. 2026;49(3):e20250063. doi:10.1590/1678-4685-GMB-2025-0063. PMID: 42714266. PMC13555780.
105. Young ID, Rickett AB, Clarke M. High incidence of Meckel's syndrome in Gujarati Indians. J Med Genet. 1985;22(4):301-4. doi:10.1136/jmg.22.4.301. PMID: 4045959. PMC1049454.
106. Sawardekar KP. Meckel-Gruber syndrome: prevalence from a hospital-based study in Oman. J Matern Fetal Neonatal Med. 2016;29(22):3696-8. doi:10.3109/14767058.2016.1141883. PMID: 26788898.
107. ERKNet. The European Rare Kidney Disease Reference Network [Internet]. [accessed 2026 Oct 10]. Available from: https://www.erknet.org/
108. European Commission, Joint Research Centre. EUROCAT — European Platform on Rare Disease Registration [Internet]. [accessed 2026 Oct 10]. Available from: https://eu-rd-platform.jrc.ec.europa.eu/eurocat_en
109. Joubert Syndrome & Related Disorders Foundation [Internet]. [accessed 2026 Oct 10]. Available from: https://jsrdf.org/