Inverted Duplication Deletion 8p Syndrome (invdupdel(8p)) and Other Chromosome 8p Disorders

Literature and regulatory information updated: 6 November 2026.

0. Initial Reference Table

The table brings together the main entity, the inverted duplication with terminal deletion of the short arm of chromosome 8, and the other recurrent chromosome 8p disorders with which it shares mechanism, genomic region and differential diagnosis. invdupdel(8p) has no phenotype entry of its own in OMIM (Online Mendelian Inheritance in Man) and no GeneReviews chapter; the reference guideline is the French National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé (HAS), from 2022 [1].

1. Introduction

1.1 Definition

Inverted duplication deletion syndrome of the short arm of chromosome 8, abbreviated invdupdel(8p) or inv dup del(8p), is a complex structural chromosomal anomaly in which the same chromosome 8 contiguously carries a loss of the terminal segment of 8p and a gain of an interstitial 8p segment whose orientation is inverted. The French PNDS defines it as a rearrangement that combines the gain of an inverted fragment of the short arm and the loss of the end of the same arm, responsible for variable developmental anomalies, isolated or as multiple malformations, associated with a neurodevelopmental disorder that may amount to multiple disability [1]. In the recurrent form, the molecular structure has three components: a distal deletion of about 6.7 Mb (8p23.3-p23.1), an intermediate normal-copy segment of about 5 Mb located between two blocks of 8p23.1 repeats, and an inverted duplication whose distal end coincides with that repeat block and whose proximal end varies from patient to patient, between 8p22 and 8p11 [7, 8, 15]. Karyotyping usually describes the chromosome as der(8)del(8)(p23.1)dup(8)(p23.1p11.2) or as inv dup del(8)(qter→p23.1::p23.1→p11.2:) [16, 17].

1.2 Historical overview

The first report attributed to the entity is that of Weleber and colleagues, in 1976, who described a child with psychomotor delay and multiple anomalies, including agenesis of the corpus callosum and cleft palate, born after artificial insemination by donor, whose additional chromosomal material was interpreted as a duplication-deficiency of the short arm of chromosome 8 [8, 18]. In 1982, Jensen and colleagues, with at least 13 cases already published and 8 unpublished, characterised inv dup(8p) as a non-random de novo structural aberration and used erythrocyte glutathione reductase activity, increased only in the patient whose duplication included 8p21.1, to assign the GSR gene to that sub-band; this also showed that the breakpoints differed between patients [19]. In 1993, Feldman and colleagues brought together 10 North American patients and noted that inv dup(8p) was one of the most frequent duplications in their laboratories, comparable in frequency to the classic Wolf-Hirschhorn and cri-du-chat deletions, while Minelli and colleagues, in the same year, showed in 10 patients that the 8p12-p22 duplication was always accompanied by deletion of the D8S7 locus at 8p23.1 and that the anomaly was of maternal origin [20, 21].

The demonstration that almost all inv dup(8p) had a telomeric deletion came with FISH: Guo and colleagues confirmed loss of 8p23.3-pter in 3 of 7 cases and proposed the name inv dup del(8p) [16]. Floridia and colleagues, in 16 cases in 1996, showed that these chromosomes may be dicentric or monocentric, that the distal 8p23 region is always deleted, that a proximal 8p23 segment remains in single copy and that the origin is always maternal, and proposed that the rearrangement arises from abnormal pairing of the two chromosomes 8 in maternal meiosis I, with crossing-over between inverted repeat sequences [22]. In 2001, Giglio and colleagues identified these sequences as two olfactory receptor gene clusters at 8p23.1 and showed that all the mothers studied were heterozygous for a submicroscopic inversion bounded by these clusters, present in 26% of a population of European ancestry; the same mechanism explains the reciprocal supernumerary marker +der(8)(8p23.1pter) and the recurrent interstitial 8p23.1 deletion [11]. Shimokawa and colleagues confirmed the model in five Japanese patients and found the inversion in 39% of alleles in a Japanese population [15].

With chromosomal microarray analysis, the entity came to be described by genomic coordinates, and the most recent studies group it with 8p deletions and duplications under the name of chromosome 8p disorders (8p-related disorders, 8p cytogenomic disorders): the cohort of Okur and colleagues, from 2021, compared 52 patients with invdupdel(8p), 37 with deletions and 8 with 8p duplications [7]; the French series of Vibert and colleagues, from 2022, added 36 patients and reviewed 99 published ones, and established that invdupdel(8p) is the most frequent recurrent chromosomal rearrangement in patients with ID and corpus callosum anomalies [12]. The HAS PNDS, coordinated by the reference centre for intellectual disabilities of rare causes at the Pitié-Salpêtrière and with the participation of patient associations, was published in 2022 [1], and a team from Children's Hospital Colorado published in 2025 a surveillance proposal for 8p syndromes in general [23].

1.3 Nomenclature and classification

The literature uses the forms inv dup(8p), inv dup del(8p), invdupdel(8p) and, in older texts, 8p duplication-deficiency or 8p inverted tandem duplication [16, 18, 19]. Orphanet classifies the entity as a malformation syndrome (ORPHA:96092), with the synonyms invdupdel(8p) and inverted 8p duplication/deletion syndrome, and with the codes ICD-10 Q99.8 and ICD-11 LD41.P [2]. Table 1.1 summarises the current classifications of the class of chromosome 8p disorders.

Table 1.1. Classifications of recurrent chromosome 8p disorders

2. Molecular Genetics and Pathophysiology

2.1 Genomic architecture of 8p

The short arm of chromosome 8 is about 45 Mb long and contains approximately 250 coding genes, almost all of which are included in at least one of the recurrent rearrangements described [7]. The 8p23.1 region contains two blocks of low copy repeats (LCRs), called the distal repeat (REPD) and the proximal repeat (REPP), rich in olfactory receptor and defensin genes, located at hg19 coordinates of about 6.7–8.0 Mb and 11.5–12.5 Mb [7, 8]. Between the two blocks there is a segment of about 5 Mb which, in a high proportion of the population, is inverted: the 8p23.1 inversion was found in the heterozygous state in 26% of a population of European ancestry and with an allele frequency of 39% in a Japanese population [11, 15]. The PNDS cites values of about 25% and 30%, respectively, without giving the source of the second [1]. The analysis of 12 8p rearrangements by Redaelli and colleagues showed a continuum of fragility along the whole arm, with breakpoints concentrated at the telomere and at 8p23.1, near the beta-defensin cluster and the olfactory receptor LCRs [26]; Yu and colleagues, in 966 children with developmental disorders studied by microarray, found 10 pathogenic CNVs (copy-number variants) on 8p (about 1%) and identified hotspots at ~10.45, 24.32–24.82, 32.19–32.77 and 38.94–39.72 Mb [27].

2.2 Mechanism of formation of recurrent invdupdel(8p)

The accepted model is based on a mother heterozygous for the 8p23.1 inversion. In maternal meiosis I, the inverted chromosome and its normal homologue form a pairing loop; unequal crossing-over between the REPD and REPP blocks, mediated by non-allelic homologous recombination (NAHR), produces a dicentric chromosome with two long arms and a mirror-image portion of 8p [11, 15, 22]. Breakage of this dicentric, between the two centromeres, leaves a monocentric chromosome that has lost the segment distal to REPD, retains in single copy the segment between REPD and REPP and has duplicated, in inverted orientation, a proximal segment whose length depends on where the breakage occurred [7]. For this reason the deletions of recurrent invdupdel(8p) are practically identical, whereas the proximal end of the duplication varies: in the Okur cohort, the shared deleted interval was from 1 to 6,697,895 (hg19) and the shared duplicated interval from 12,635,000 to 23,675,945, with proximal ends well beyond this interval [7]; in the French series of Vibert, characterised by CMA in all 36 patients and confirmed by FISH, the proximal end of the deletion lay between 5,078,168 and 7,753,583 (GRCh37), the distal end of the duplication was recurrent, between 12,404,003 and 12,711,820, in 29 of the 36 patients, and the size of the duplication ranged from 4.9 to 33.7 Mb [12]; in Yang's 12 prenatal cases, 11 had a deletion of 4.5–6.8 Mb, a normal-copy segment of 4.9–5.5 Mb and a duplication of 8.2–31.3 Mb [8]. Shimokawa and colleagues noted that formation requires two independent events, recombination within the loop and subsequent rescue of the dicentric, which may explain why invdupdel(8p) is rare despite the frequency of the inversion [15]. Maternal origin, maternal heterozygosity for the inversion and the presence, in the duplicated segment, of maternal alleles that are sometimes heterozygous and sometimes homozygous were confirmed by polymorphic markers [15, 22].

The broken end must acquire a telomere. In the typical form, stabilisation occurs by direct addition of telomeric repeats (telomere healing) [28]; Buysse and colleagues described an exception with capture of the 8q telomere (additional duplication of 8q24.13-qter) and a duplication of only 3.4 Mb, invisible on the karyotype [28], and Yu and Graf observed telomere capture in several inv dup del of different chromosomes [29]. A minority of invdupdel(8p) have no intermediate normal-copy segment: in Yang's case 12, a deletion of 1.4–1.8 Mb was immediately followed by a duplication of 33.0 Mb, an architecture better explained by a U-type exchange (formation of a mirror-image dicentric from a single chromatid), a mechanism also identified in one of eight Russian cases [8, 24]. Kato and colleagues, by sequencing the junctions of non-recurrent inv-dup-del, found small intervening regions of 1741–3728 bp with microhomology, suggesting a replicative template-switching mechanism that generates unstable dicentrics [30]; Brewer and colleagues proposed a unifying model for inverted CNVs from an inverted triplication with unstable palindromic junctions [31]. These non-recurrent forms differ from classic invdupdel(8p), which Zuffardi and colleagues excluded from their review of inv-dup del precisely because it is known to arise from NAHR in maternal meiosis, whereas the non-recurrent forms are predominantly of paternal origin [32].

2.3 Mosaicism and fetoplacental discrepancy

The dicentric may reach the zygote intact and break later, in early post-zygotic divisions, at different points in different cells; this gives rise to lines with del(8p) and lines with inv dup del(8p), and selection of the most viable lines leads to confined placental mosaicism, with the embryo retaining only the invdupdel line, or to children with both lines [33]. Soler and colleagues found an i(8q)/del(8)(p11.2) mosaic in chorionic villi and a dup(8)(p23p11.2) of maternal meiotic origin in amniotic fluid [34], and Huynh and colleagues reported an i(8)(q10)/del(8)(p23) mosaic in direct villus preparations, with typical invdupdel(8p) (6.69 Mb deletion and 31.49 Mb duplication) in the cultures and fetal tissues and a mother carrying the cryptic inversion [35]. Hand and colleagues described a girl with del(8p)/inv dup del(8p) mosaicism and a mild phenotype, without the malformations of the homogeneous forms [36]. Ciccone and colleagues also showed that an 8p dicentric of paternal origin, formed on the same polymorphic inversion but with a different breakpoint, can generate non-contiguous terminal deletions, detectable only by high-resolution microarray [37]. The PNDS indicates that invdupdel(8p) is homogeneous in most cases and only rarely mosaic [1].

2.4 Gene content and dosage mechanisms

invdupdel(8p) combines monosomy of 8p23.3-p23.1 and trisomy of part of 8p23.1-p11, so the phenotype results from haploinsufficiency in the deleted region and from triple-dosage effects in the duplicated region. In induced pluripotent stem cells (iPSCs) from a patient, genes in the deleted region were expressed on average 43% lower and those in the duplicated region 56% higher than in a euploid revertant clone from the same patient, and 361 genes, within and outside 8p, showed differential expression [38]. Table 2.1 places the genes of interest in relation to the segments of the recurrent rearrangement, using Ensembl GRCh37 coordinates [39] and the shared intervals of the Okur cohort (also in hg19/GRCh37).

Table 2.1. Genes of interest and position relative to the segments of recurrent invdupdel(8p)

The position of GATA4 and SOX7 in the normal-copy segment has a direct clinical consequence: in the Okur cohort, all patients with GATA4 deletion had an atrial septal defect (ASD) and/or ventricular septal defect (VSD), and 75% also had pulmonary stenosis, but GATA4 and SOX7 were in normal copy in all patients with invdupdel(8p) and, even so, more than a third of them (38%) had a VSD and/or ASD, which points to another gene or genes in the duplicated segment [7]. GeneGuidance highlights the difference between an intragenic GATA4 variant, which mainly causes septation heart disease without extracardiac involvement, and the contiguous 8p23.1 deletion, which adds diaphragmatic hernia and developmental problems [42]. Okur's authors prioritised DLGAP2 and CSMD1 for the distal deletion and RHOBTB2 and CHRNA2 for the duplication, and listed three genes within the shared duplication (TUSC3, VPS37A, RHOBTB2) and ten beyond it (NKX2-6, NEFL, CHRNA2, FZD3, TTI2, ERLIN2, PLPBP, ASH2L, DDHD2, KAT6A) associated with neurodevelopmental disorders through biallelic, loss-of-function or gain-of-function mechanisms; whether any of these genes is triplosensitive remains unknown [7]. Lee and colleagues highlighted NAV3, related to neuronal migration, and CNTN4, a neuronal membrane protein, among the genes dysregulated in the patient's cells [38].

The presence of recessive genes in the deleted segment, such as MCPH1 and CLN8, means that the single remaining allele is exposed: the Oxford Desk Reference notes, for CNVs in general, that a deletion may unmask a recessive phenotype when the other allele carries a loss-of-function variant, and cites the example of CEDNIK syndrome in the 22q11.21 deletion [44]. According to Vibert and colleagues, the terminal deletion removes at most 73 canonical genes, of which only three are associated with disease in OMIM: CLN8 (neuronal ceroid lipofuscinosis), ARHGEF10 (reduced nerve conduction velocity) and MCPH1 (primary microcephaly 1); thinning of the corpus callosum has been described in three patients with pathogenic CLN8 variants, but none of these three genes has been associated with other corpus callosum anomalies [12]. The sources consulted do not describe cases of invdupdel(8p) with unmasked recessive disease in these genes.

Tokutake and Chiba reported an infant with severe respiratory syncytial virus bronchiolitis, low natural killer (NK) cell activity and low α-defensin concentration, and proposed that haploinsufficiency of the 8p23.1 defensin cluster contributes to the severity of viral infections; this is a single report [45].

2.5 Genotype-phenotype correlations

Severity correlates mainly with the size of the duplication. The PNDS states that ID is proportional to the size of the duplication [1], and García-Santiago and colleagues, in seven Spanish children with similar deletions and duplications of different sizes, considered that the duplication explains the phenotypic variability [13]. Fisch and colleagues, in four children, found no correlation between ID and the size of the deletion, but did find one with the length of the duplication at 8p21.1/8p22, and a small over-expressed locus at 8p21.3 was common to the three patients with autistic traits [46]. In the Okur cohort, motor seizures were more frequent when the proximal end of the duplication went beyond 37 Mb (9 of 25, 36%) than when it fell short of it (4 of 25, 17%); among patients with the end before 37 Mb, 36% had hypoplasia and 5% agenesis of the corpus callosum, and among those with it before 32 Mb only 2 of 12 had hypoplasia, whereas, with the end beyond 37 Mb, 35% had hypoplasia and 57% agenesis [7]. In the French series of Vibert, as the deletions were almost identical, the analysis focused on the duplication: the severity of ID correlated with the size of the duplication (Mann-Whitney test), with a mean of 10 Mb (8.4–16.5) in patients with mild ID and 21.4 Mb (10.4–30.3) in patients with severe ID (p = 0.0045), and the only child without delay, assessed at 18 months, had the smallest duplication in the series (4.9 Mb) [12]. By combining 27 of their own patients with known corpus callosum structure and 17 patients from the literature (15 published patients with CMA and imaging and two patients of Sajan and colleagues with an inverted duplication without deletion and corpus callosum anomaly), the authors narrowed the 10.7 Mb critical interval previously proposed by Sajan to a duplicated region of 5.1 Mb common to all patients with corpus callosum anomaly (chr8:22,553,631–27,672,961, GRCh37; the figure legend gives 22,553,621 as the start) [12]. The region contains 51 canonical genes, 37 of them in OMIM, four with a neurological phenotype: RHOBTB2 (developmental and epileptic encephalopathy 64, dominant, with a thin corpus callosum in some patients), NEFL (Charcot-Marie-Tooth), CHRNA2 (nocturnal frontal lobe epilepsy type 4) and GNRH1 (hypogonadotropic hypogonadism 12); it also includes NEFM and DPYSL2, linked to axonal growth and guidance [12]. RHOBTB2 is the most plausible candidate, because DEE64 variants alter the function of the protein rather than causing loss of function and over-expression of the orthologue in Drosophila increases seizure susceptibility, but the presence of duplications of this gene in the Database of Genomic Variants weighs against it; no gene stands out, and the authors propose disruption of chromatin topologically associating domains (TADs) as an alternative mechanism [12]. By contrast, Yurchenko and colleagues found no association between the mechanism of formation (ectopic recombination or U-type exchange) and the clinical picture [24]. Mosaicism attenuates the phenotype, as in Hand's case [36], and Yang's case 11, with the smallest duplication in the series (8.2 Mb) and a 4.5 Mb deletion, was inherited from a father without a previous diagnosis and, at five years of age, the child had no apparent anomalies [8].

2.6 Penetrance and expressivity

Recurrent invdupdel(8p) is associated with developmental delay in almost all carriers (97% in the Vibert series) [12], but expressivity ranges from multiple disability to mild forms, such as those described by Yenamandra and colleagues and by Hand and colleagues [36, 47]. Familial transmission, which is rare, occurs from carriers with mild impairment: the PNDS cites a family with transmission over two generations, the French series included five individuals from the same family (two siblings and their children, over two generations), all with mild to moderate ID without major malformation and carrying one of the smallest duplications in the series (8.4 Mb), and Yang reported a paternal transmission [1, 8, 12].

2.7 Preclinical research in cell models

Lee and colleagues, in 2026, derived iPSCs from a patient with invdupdel(8p) and sought to eliminate the rearranged chromosome 8. As spontaneous loss of the abnormal chromosome would require, in a single lineage, loss of the rearranged homologue and duplication of the normal homologue, no spontaneous revertant was isolated; the authors used two strategies, the TTK (MPS1) kinase inhibitor AZ3146 at a sublethal dose to increase chromosome mis-segregation, and the KaryoCreate system, in which a catalytically inactive dCas9 directs a checkpoint-deficient kinetochore protein to the centromere of chromosome 8, passing through a trisomic intermediate [38]. They obtained a euploid revertant clone, confirmed by low-coverage genome sequencing and with paternal isodisomy of chromosome 8 demonstrated by STR markers. The revertant proliferated faster; the patient's cells had a defect of survival and of neuronal specification (MAP2+ neurons) during neural differentiation, partially corrected by the CEPT cytoprotective cocktail (chroman-1, emricasan, polyamines and trans-ISRIB), and the revertant's dendrites were more mature [38]. This is a preclinical, in vitro result from a single patient; the authors stress that the resulting isodisomy and imprinting require evaluation before a chromosome therapy can be considered, and there is no study in humans [38].

3. Clinical Spectrum and Manifestations by System

3.1 Data sources and limits

The clinical description relies on three types of data. The French PNDS synthesises the literature and the experience of the reference centres and gives rounded percentages [1]. The cohort of Okur and colleagues (Columbia University, 2021) recruited 97 individuals, 53 from the United States, 14 from the United Kingdom and 20 from other European countries, with data from clinical records and carer interviews, and presents a comparative table for 49 patients with recurrent invdupdel(8p), of mean age 7.1 years (0.9–27.2) [7]. The French series of Vibert and colleagues, from 2022, brought together through the Achropuce network 36 new cases (33 patients and three fetuses from terminations of pregnancy for medical reasons at 27, 29 and 30 weeks, five patients from the same family), 23 female and 13 male, aged 4 months to 40 years (mean 8 years and 11 months), with data collected by a standardised questionnaire completed by clinicians and magnetic resonance imaging reviewed by a neuroradiologist in 24 patients; two patients died, one at 4 years of an unspecified cause and another at 4 months with diaphragmatic hernia; the authors also reviewed 99 patients published between 1977 and May 2021 [12]. The Children's Hospital Colorado series and the Project 8p natural history study (162 patients with 8p disorders, 81 with invdupdel) add neurological data [12, 25]. The studies recruited through specialised centres and patient associations, with data frequently reported by carers; none is population-based, and information on adolescents and adults is scarce [1, 7]. The data describe the course under usual care (rehabilitation, cardiac surgery when indicated, antiepileptic drugs); there are no descriptions of natural history without intervention.

Table 3.1. Frequency of manifestations in invdupdel(8p) according to the main sources

The percentages diverge according to the series, the mode of ascertainment and age; for example, the frequency of heart disease ranges from 25% in the Orphanet text to 65% in the Okur cohort, which counts patent foramen ovale and defects that close spontaneously [2, 7].

3.2 Prenatal and neonatal period

Intrauterine growth restriction (IUGR) is one of the most frequent prenatal signs according to the PNDS [1]. In the Okur cohort, 47% of patients with invdupdel(8p) had at least one prenatal finding, mainly single umbilical artery (16%), small for gestational age fetus (14%), cardiac finding (10%) and amniotic fluid or renal abnormalities (8%); 5 of the 7 fetuses with growth restriction were born below the 10th centile [7]. In Yang's 12 fetuses, the findings were increased nuchal translucency, lateral ventriculomegaly, agenesis of the corpus callosum, heart disease (including double outlet right ventricle with VSD), polycystic kidney, single umbilical artery and omphalocele, and some fetuses had no detectable anomalies early in gestation [8]. A fetus with severe polyvalvular dysplasia and ultrasound signs similar to those of trisomy 18 died on the 12th day of life [49]. In the Vibert series, 13 of 34 pregnancies (38%) had ultrasound signs: in the three fetuses, corpus callosum anomaly in all, IUGR in one and nasal bone hypoplasia in another; in the 31 patients, IUGR in five (isolated in one, associated in others with corpus callosum and gyration anomaly, VSD or oligohydramnios), tetralogy of Fallot in two, Blake's pouch cyst with muscular VSD in one and transiently increased nuchal translucency in another; 5 of 28 (18%) were born preterm, 5 of 28 (18%) were small and 6 of 28 (21%) large for gestational age [12]. In the neonatal period, 92% of Okur's patients had at least one problem: hypotonic infant (71%), feeding difficulty (63%), weak suck (57%), excessive sleepiness (43%), irritability (27%), prematurity (22%), respiratory distress (18%) and hypoglycaemia (18%); mean Z-scores at birth were within the normal range (weight −0.2; length 0.25; head circumference 0.1) [7].

3.3 Development, cognition and language

Global developmental delay is the rule and language is the most affected domain. According to the PNDS, 40% of the patients described do not acquire spoken language; in those who do, first words appear between 2 and 6 years and expression often remains limited to a few words or short sentences; more than 70% walk, on average between 2 and 3 years, with coordination disorders and fluctuating tone [1]. In the Okur cohort, the mean age of sitting was 17.3 months (median 12), of first words 29 months (median 24) and of walking 41 months (median 37), delays more marked than in 8p deletions (sitting at 7–8.7 months and walking at 18–19 months); only 4 of 15 patients with first words made short sentences (mean age 48 months), and the remaining 11 had a mean age of 70 months [7]. The mean Vineland adaptive behaviour composite score was 52 in 39 patients with invdupdel(8p), with communication as the most affected subdomain [7]. In the Vibert series, 27 of 29 patients (93%) had motor delay; 20 of 25 patients (80%) older than 3 years and 14 of 15 (93%) older than 6 years walked without support, with a mean age of walking of 31 months (15 months to 9 years); first words appeared between 24 months and 6 years, 16 of 28 (57%) said words and, among 11 patients with detailed data, eight only said single words, two made sentences and one could hold a conversation; among the 19 patients aged 5 years or older, all had ID, severe to profound in 58% [12]. Fisch and colleagues found mild to severe cognitive deficits and adaptive behaviour well below expectations in four children aged 3 to 15 years [46]. ID ranges from mild to severe, up to multiple disability [1].

3.4 Behaviour

The PNDS describes sociable, interactive individuals who enjoy sensory activities, in whom communication difficulties lead to intolerance of frustration and self-directed and other-directed aggression, and mentions autism spectrum disorder (ASD) and attention deficit [1]. In the Okur cohort, neurobehavioural problems were less frequent in invdupdel(8p) (43%) than in 8p deletions (75–100%): stereotypies in 22%, aggression/tantrums/impulsivity in 14%, sensory disorders in 8%, autism in 6% and attention deficit hyperactivity disorder (ADHD) in 4%, whereas in the distal deletion 50% had autism and 50% ADHD [7]. In the French series, 8 of 31 patients (26%) had a behavioural disorder (bulimia nervosa in two, ADHD in two, low frustration tolerance in two, self-directed and other-directed aggression in one and hand stereotypies in another), four of 33 (12%) had ASD red flags and one had a confirmed diagnosis [12]. Fisch and colleagues, using the Childhood Autism Rating Scale, identified autism or autistic traits in three of four children and ADHD in three [46].

3.5 Neurology

3.5.1 Tone and motor function

Moderate axial hypotonia in infancy is frequent (88% in the Okur cohort) and is followed later by hypertonia predominantly in the lower limbs (39%), sometimes with dystonia, which may be complicated by tendon retractions and contractures that limit mobility [1, 7]. In the Vibert series, 9 of 29 patients (31%) had other neurological signs: peripheral spasticity or hypertonia in six, persistent hypotonia in two, dystonia in two, parkinsonism in one and fine motor difficulties in another; the authors stress that epilepsy and progressive spasticity compromise motor function and cognition and should be detected [12]. Microcephaly was rare (4%) and macrocephaly occurred in 10%, three of the five cases with hydrocephalus or ventriculomegaly [7].

3.5.2 Epilepsy

The PNDS estimates seizures in 30–50% of patients, with a mean age at onset of 4 years (2 months to 9 years) and varied types: absences, generalised tonic-clonic, myoclonic, focal motor seizures and infantile spasms [1]. Okur recorded at least one seizure in 27 patients (55%): absences in 37%, febrile seizures in 18%, tonic-clonic in 12%, atonic in 8% and myoclonic in 4%; 11 of 27 had more than one type; onset was generally between 1 and 4 years; the lifetime number of seizures was 1–10 or more than 100; absences lasted less than a minute and two patients had status epilepticus; half of the 36 with an EEG had an abnormal tracing, mainly generalised slowing (26%) and epileptiform activity (20%), and four had an abnormal EEG without seizures [7]. In the French series, 11 of 32 patients (34%) had epilepsy, with a mean onset at 3.9 years (2 months to 9 years): absences in five, generalised tonic-clonic seizures in three, myoclonic in two and focal motor in two [12]. In the series of Abbott and colleagues, the most recent and the largest, 37% (30/81) of patients with invdupdel(8p) had had at least one seizure, compared with 35% in 8p deletions and 15% in 8p duplications, with a mean onset at 3.4 years (from the neonatal period to 16.9 years); at the Colorado centre, 14 of 42 patients had epilepsy, one was refractory and nine became seizure-free, five of them without medication [25].

3.5.3 Brain malformations

According to the PNDS, 75–85% of patients with imaging have brain malformations, the most typical of which is a developmental anomaly of the corpus callosum (complete or partial agenesis, short or dysgenetic corpus callosum); other anomalies described are enlargement of the subarachnoid spaces or ventricles, white matter abnormalities, cerebellar or brainstem hypoplasia, cortical and subcortical atrophy, dysplasia of the vertebral and basilar arteries, Dandy-Walker malformation, arachnoid cysts, dilatation of Blake's pouch, mega cisterna magna and gyration anomalies [1]. In the Okur cohort, 84% of imaging studies were abnormal: hypoplasia or aplasia of the corpus callosum in 67%, hydrocephalus or ventriculomegaly in 27% (usually mild and not requiring shunting), cerebral or cerebellar atrophy in 16%, Dandy-Walker in 9% and intracranial cysts in 9% [7]. In the Vibert series, 21 of 28 patients and fetuses with imaging or neuropathology (75%) had brain anomalies and 17 of 27 (63%) a corpus callosum anomaly: complete agenesis in 6 (22% of the total; 35% of callosal anomalies), partial agenesis in 5 (19%), short and thin corpus callosum in 4 (15%) and hypoplasia (thin with normal anteroposterior extent) in 2 (7%); 12 of the 17 had other associated anomalies (enlarged subarachnoid spaces or ventricles in eight, white matter abnormalities in four, cerebellar hypoplasia and posterior fossa arachnoid cyst in two each, Dandy-Walker complex in one), and among the 11 with a normal corpus callosum four had other anomalies, such as cortical and subcortical atrophy, mega cisterna magna or simplified frontal gyration with a lipoma of the pituitary stalk; in the literature reviewed, 36 of 43 patients with described callosal structure (84%) had a corpus callosum anomaly [12]. The frequency of agenesis increases with the size of the duplication (section 2.5).

3.5.4 Sleep

Difficulty falling asleep, night waking and sleep apnoea are described by the PNDS, and 45% of Okur's patients had sleep problems [1, 7].

3.6 Heart

Congenital heart defects occur in about 40–65% of patients, mainly VSD (30%) and ASD (15%), but also tetralogy of Fallot, bicuspid aortic valve, patent ductus arteriosus (PDA) and patent foramen ovale (PFO) [1]. In the Okur cohort, 26 of 40 patients assessed (65%) had cardiovascular findings; the defects tended to be minor and to close spontaneously (19 of 26, 73%), unlike proximal 8p deletions, which include GATA4 (4 of 16, 25%); dextroposition of the great arteries, double outlet right ventricle, right heart hypoplasia, coarctation, aortic stenosis and regurgitation, dilatation of the ascending aorta, mitral prolapse, cardiomegaly and arrhythmia were also rarely described [7]. In the Vibert series, 12 of 29 (41%) had congenital heart disease: VSD in three, tetralogy of Fallot in three, bicuspid aortic valve in two, and ASD, PFO, PDA, bifid apex with small left ventricle and intermittent aortic regurgitation in one patient each; in the literature reviewed, the frequency was 19–26% [12]. Other series describe tetralogy of Fallot, complex dextrocardia and pulmonary stenosis [17].

3.7 Musculoskeletal system

The PNDS describes osteoarticular features in about 30% of patients, absent or subtle at birth and worsening with growth: ligamentous hyperlaxity, scoliosis, kyphosis or hyperlordosis, narrow or deformed chest, delayed bone maturation, polydactyly, flat feet and femoral anteversion [1]. Okur recorded musculoskeletal abnormalities in 59%: scoliosis in 22%, vertebral anomalies, joint hypermobility, hip anomalies, talipes equinovarus or equinovalgus and inguinal hernia in 8% each, rib anomalies in 6% and flat foot in 4% [7]. In the Vibert series, 10 of 34 (29%) had orthopaedic anomalies: hypermobility in five, scoliosis in four, hammer toes in three, kyphosis in two and, in one case each, pectus excavatum, narrow chest, delayed bone maturation, bilateral polydactyly, flat foot, valgus foot, hyperlordosis and femoral anteversion; in the literature reviewed, orthopaedic anomalies affect 58% and scoliosis 35–63% [12]. The Orphanet definition mentions scoliosis/kyphosis or hip dislocation in 60% [2].

3.8 Digestive system, feeding and growth

Sucking-swallowing disorders in the first weeks or months affect 30% of infants, may require a temporary nasogastric tube and may persist beyond the first year; gastro-oesophageal reflux (GOR) causes discomfort, hinders the development of oral skills and may be complicated by oesophagitis; constipation is frequent and worsened by little physical activity and low food and fluid intake [1]. Okur found gastrointestinal problems in 88%: constipation in 73%, GOR in 55%, persistent feeding difficulty in 22% and diarrhoea in 6% [7]. As for growth, patients tend to have below-average weight and height, there are few data in adolescents and adults [1], 37% had poor weight gain, 12% short stature (Z-score −2.44 to −3.69) and none was overweight, in contrast with 8p deletions, in which 30–67% were overweight [7].

3.9 Genitourinary system

Vesicorenal anomalies are uncommon and minor (hydronephrosis, renal hypoplasia, horseshoe kidney), and hypospadias and cryptorchidism may be present [1]. In the Okur cohort, 7 of 20 boys had cryptorchidism and 2 of 20 hypospadias, and 12% had hydronephrosis or other renal problems [7].

3.10 Sensory organs and teeth

The PNDS describes refractive errors (mainly myopia, also hypermetropia and astigmatism), strabismus, and rarely iris coloboma, microphthalmia and retinal and optic nerve anomalies, frequent otitis media with effusion and acute otitis and, in some patients, residual hearing loss [1]. In the Okur cohort, 55% had visual problems: refractive errors in 29%, strabismus in 18%, cortical visual impairment (CVI) in 12% and optic nerve abnormalities in 8% [7]. In a retrospective review of 85 patients with four neurogenetic disorders, Abbott and colleagues found CVI in 14 of 26 patients with 8p disorders (54%), the highest frequency of the four conditions, and found that the CCSA-vision questionnaire had 7% false negatives and 1% false positives [48]. In the teeth, bruxism is frequent and wears the enamel; there is hypoplastic enamel, susceptibility to caries and late eruption and shedding of deciduous teeth, and, anecdotally, supernumerary or large teeth and gingival hypertrophy [1]; 53% of Okur's patients had dental problems [7].

3.11 Infections and immunity

Frequent infections were reported in 43% of patients in the Okur cohort (otitis media in 33%, upper respiratory infections in 16% and urinary infections in 14%) [7]. The reports of severe respiratory syncytial virus bronchiolitis with low NK activity and of severe COVID-19 in an 11-month-old infant with chronic lung disease, who required mechanical ventilation and 26 days of hospital admission, are isolated and do not demonstrate a specific predisposition [45, 50].

3.12 Dysmorphism

The morphological features are not very specific, may be subtle at birth or develop during the first year and become less marked in adults: prominent forehead, sometimes with bossing, plagiocephaly, round or square face, micrognathia or retrognathia, hypertelorism, enophthalmos, epicanthus, macrostomia with a thin upper lip, macrotia, anteverted nares and dry, curly hair with temporal recession [1]. In the Okur cohort, facial photographs showed a small head, a large and prominent forehead, slightly arched eyebrows, deep-set eyes, ptosis or hooded eyelids, full cheeks, a wide mouth and micrognathia [7]. Feldman and colleagues recorded in at least five of 10 patients a high palate, a large mouth with a thin upper lip, malformed or low-set ears, a broad nasal root and joint laxity [20]. In the Vibert series, 28 of 32 (88%) had dysmorphism, mainly a wide mouth (9), a broad (6) or prominent forehead, hypertelorism (5), deep-set eyes (4), plagiocephaly (4) and macrotia (4), and the literature review gives 97% [12]; Minelli and colleagues described a large mouth with an everted lower lip and large ears [21].

3.13 Other chromosome 8p disorders

The class includes entities with an overlapping but distinct phenotype. In the Okur cohort, 8p deletions had smaller motor delays, more neurobehavioural problems and more excess weight: the distal deletion (n=4, 1–6.7 Mb, the same segment deleted in invdupdel) was associated with autism and ADHD in 50% and seizures in 25%; the proximal and distal deletion (n=9, 10.7 Mb) with VSD in 71%, ASD in 57% and pulmonary stenosis in 71%; the proximal deletion (n=12, 3.8 Mb, with GATA4 and SOX7) with ASD in all, pulmonary stenosis in 64%, microcephaly in 58% and ADHD in 58% [7]. One adult with a distal deletion attended university and another had a driving licence, with mild learning difficulties and problems with attention, anxiety and depression [7]. The 8p23.1 deletion is also a recognised cause of congenital diaphragmatic hernia (DIH2), described in isolated cases and in 2 of 256 trios with diaphragmatic hernia [9]. The 8p23.1 duplication involves mild to moderate delay in 11 of 12 postnatal patients, mild dysmorphism in 8 of 12 and heart disease in 4 of 5 fetuses and 3 of 12 postnatal patients [10]. The San Luis Valley recombinant chromosome 8 involves heart disease in 39 of 42 patients, mainly tetralogy of Fallot and other conotruncal defects, and moderate to severe ID in all [6].

4. Clinical Recognition and Red Flags

4.1 When to suspect

invdupdel(8p) is almost never recognised clinically: the signs are not very specific and the diagnosis is made by cytogenetic testing requested for a neurodevelopmental disorder or a malformation [1]. The PNDS describes the usual circumstances by age. In the fetus, suspicion arises from a corpus callosum anomaly or other malformations on obstetric ultrasound, although ultrasound follow-up may be normal [1]. After birth, investigation is triggered by congenital heart disease or by feeding difficulties requiring nutritional support in an infant with psychomotor delay and/or axial hypotonia; in the older child, by learning and school adaptation difficulties [1]. invdupdel(8p) is the most frequent chromosomal rearrangement among patients with corpus callosum anomaly and ID (3% according to the PNDS), and the combination of corpus callosum anomaly, neonatal hypotonia with feeding difficulties, disproportionate language delay and septal heart disease should prompt CMA without delay [1, 12]. The general practitioner or paediatrician refers these patients to a rare disease reference or competence centre focused on intellectual disability or developmental anomalies [1].

Table 4.1. Settings of suspicion by age

4.2 Red flags and emergencies

Regression of motor or cognitive skills, or the onset of behavioural disorders, should raise the possibility of an epileptic seizure, even in a patient without previous seizures [1]. An acute change in behaviour requires first looking for a painful somatic cause, such as GOR, dental pain, acute otitis media or faecal impaction, with pain scales adapted to non-verbal patients [1]. Worsening of epilepsy that was stable on treatment requires a search for a trigger: pain (constipation, orthopaedic or dental pain, GOR), infection (urinary, otitis), sleep disturbance, altered bowel transit, recent weight gain or poor adherence to treatment [1]. Aspiration pneumonia and oesophagitis are signs of complicated GOR [1]. In a child with heart disease and a viral respiratory infection, the reports of severe bronchiolitis and COVID-19 call for close monitoring, although there is no evidence of a specific immunological risk [45, 50]. The rare disease emergency card, prepared for invdupdel(8p) by the AnDDI-Rares network, summarises the care recommended and to be avoided in an emergency [1].

4.3 Newborn screening

There is no newborn screening for invdupdel(8p). Non-invasive prenatal screening using cell-free DNA may suggest a partial duplication of chromosome 8, as happened in Yang's case 11, but requires confirmation by invasive testing [8].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

There are no clinical criteria; the diagnosis is cytogenomic. The PNDS requires the demonstration, by CMA combined with karyotype and FISH, of a terminal 8p deletion with an interstitial inverted 8p duplication [1]. CMA defines the size and exact position of the deleted and duplicated segments; karyotype and FISH show the structure of the derivative chromosome and the inverted orientation, which CMA does not detect, and allow invdupdel(8p) to be distinguished from an 8p deletion with an 8p duplication on different chromosomes, for example due to a parental translocation [1, 8].

5.2 Tests in order

CMA is the first-line test in unexplained ID or developmental delay, ASD or multiple congenital anomalies: the consensus of the International Standard Cytogenomic Array (ISCA) Consortium, with 33 studies and 21,698 patients, showed a yield of 15–20%, compared with about 3% for the G-banded karyotype (excluding recognisable chromosomal syndromes), and reserved the karyotype for obvious chromosomal syndromes, a family history of rearrangement or multiple miscarriages [51]. The Oxford Desk Reference cites a mean yield of 18% for high-resolution array as a first test in ID [52]. The 2021 American College of Medical Genetics and Genomics (ACMG) guideline strongly recommends exome or genome sequencing (ES/GS) as a first- or second-tier test in patients with congenital anomalies with onset before 1 year or with developmental delay/ID with onset before 18 years [53]; GS detects large CNVs, but demonstration of the inversion and of the structure of the derivative still requires karyotype and FISH or techniques that read orientation [1]. The G-banded karyotype has a resolution of about 5–10 Mb [44]; it detects invdupdel(8p) with large duplications, but not duplications of 3.4 Mb such as that of Buysse [28]. CNV classification follows the 2020 ACMG/ClinGen standards, with quantitative scoring and five classes [54]; recurrent invdupdel(8p) is pathogenic.

Table 5.1. Tests and their limits

5.3 Diagnostic algorithm

In a child with developmental delay, ID, ASD or congenital anomalies, CMA is requested. If CMA shows a terminal 8p deletion followed by an 8p duplication, with or without an intermediate normal-copy segment, the structure is confirmed by karyotype and FISH, so as to demonstrate the invdupdel(8p) chromosome and exclude an unbalanced translocation, and the parents are studied by karyotype [1, 44]. The Oxford Desk Reference notes that an array may be normal in a parent with a balanced rearrangement and that, therefore, parental testing for rearrangements involving subtelomeric regions should use karyotype, FISH or GS [44]. The PNDS recommends parental karyotyping to exclude a paucisymptomatic parent carrying the invdupdel(8p) itself, and considers that testing the parents for the polymorphic 8p23.1 inversion is of limited value and should not be systematic [1]. Once the diagnosis is confirmed, the initial system-based work-up described in section 11 follows [1].

5.4 Report content

The report should state the ISCN (International System for Human Cytogenomic Nomenclature) formula for the karyotype and the CMA, with the reference genome version, the start and end coordinates of each segment and the copy number, as in the case of Lo Bianco: 46,XX,der(8)del(8)(p23.1)invdup(p12p23.1) and arr 8p23.2p23 (221,611–6,914,076)×1, 8p23.1p12 (12,583,259–32,380,292)×3 [17]. The published coordinates are in different genome versions (for example hg19 in the Okur cohort) and can only be compared after conversion to the same version, as Okur and colleagues did with the LiftOver tool [7]. The CNV class (pathogenic) follows the ACMG/ClinGen standards [54]. There are no sequence variants to normalise in HGVS: the entity is defined by a CNV.

5.5 Prenatal and preimplantation diagnosis

invdupdel(8p) can be diagnosed in chorionic villi, amniotic fluid or fetal blood by CMA and karyotype; at a Chinese centre, 12 cases were identified among 103,840 invasive prenatal diagnoses with CMA between 2016 and 2022, all confirmed by G-banding and CMA [8]. Chorionic villi may show cell lines different from those of the fetus, such as del(8p), i(8q) or mosaics, and the villus result should be confirmed in amniotic fluid or fetal tissues [33–35]. Ultrasound findings are not specific and may be absent early in gestation [8]. Prenatal diagnosis may be offered to couples with a child affected de novo, and preimplantation genetic testing is not proposed by the PNDS [1].

6. Differential Diagnosis

The differential has two levels. At the clinical level, the combination of ID, corpus callosum anomaly, epilepsy and heart disease is shared by other chromosome 8 anomalies and by several monogenic syndromes; the PNDS highlights 8p duplication, mosaic trisomy 8 and the Mowat-Wilson, Pitt-Hopkins and Vici syndromes [1]. At the cytogenomic level, a CMA with distal loss and gain of 8p must be distinguished from other 8p rearrangements with similar dosage profiles, which requires karyotype, FISH and parental testing [1, 44].

Table 6.1. Differential diagnosis of invdupdel(8p)

The most frequent distinction in practice is between invdupdel(8p) and 8p deletions, because the deleted distal segment is the same in invdupdel(8p) and in the distal deletion: what distinguishes invdupdel is the duplication, responsible for the greater motor and cognitive severity, the epilepsy and the corpus callosum anomaly, whereas the deletions have more neurobehavioural problems, more excess weight and, when they include GATA4, more severe septal heart disease with pulmonary stenosis [7]. The heart disease of invdupdel(8p), with GATA4 in normal copy, tends to be minor and to close spontaneously [7]. 8p duplication without deletion, mosaic trisomy 8 and invdupdel(8p) share agenesis of the corpus callosum; in mosaic trisomy 8, the deep palmar and plantar creases and the bone malformations guide the clinical assessment, and the mosaicism may be absent in blood [1, 56]. In a fetus, the ultrasound signs may mimic trisomy 18 [49]. Among the monogenic syndromes, invdupdel(8p) can only be ruled out by CMA, which should precede panels or the exome in a patient with corpus callosum anomaly and ID [1, 51].

7. Treatments and Risk Management Strategies

7.1 General principles

There is no curative treatment and no specific pharmacological treatment for invdupdel(8p); management is symptomatic, adapted to each patient's needs and led by a multidisciplinary team throughout life [1]. The PNDS sets out the objectives: follow the neurodevelopmental trajectory and start rehabilitation early (speech and language therapy with augmentative and alternative communication strategies, physiotherapy, psychomotor therapy, occupational therapy and orthoptics), screen for and treat neurological complications (spasticity, epilepsy) and behavioural disorders, including ASD, screen for and treat cardiac, genitourinary and osteoarticular malformations, sensory deficits and dental anomalies, monitor nutrition and growth, coordinate care and inform the family about developments in knowledge [1]. Medicines are used within the indications and conditions of the marketing authorisation, and the contraindications of any new drug, in particular psychotropics and antiepileptic drugs, should be checked before prescribing [1]. Surgical protocols for malformations and treatment of complications do not differ from those of the general population; interventions should be the subject of a discussion of the expected benefit and the risk according to general condition, and the postoperative period should be carefully prepared in patients with multivisceral involvement or multiple disability [1].

Table 7.1. Professionals and roles in follow-up, according to the PNDS [1]

7.2 Development, communication and schooling

Neurodevelopmental follow-up should be at least annual in children, and at each visit the need for an EEG or brain MRI is assessed, given the possibility of epilepsy developing [1]. As spoken language is always affected, speech and language therapy should start early, with an ENT assessment to exclude an aggravating factor, and augmentative and alternative communication (AAC) should be introduced early (picture exchange systems such as PECS, Makaton, sign language or partial signs), in a multimodal way and in parallel with work on spoken language; AAC improves receptive skills and has a favourable effect on frustration and behavioural disorders [1]. Schooling is adapted to the abilities assessed by psychometric testing: inclusion in mainstream education with a support assistant and a personalised plan, school inclusion units, or a medico-educational establishment, which is the placement of most children with invdupdel(8p) in France; multiple disability may require dedicated facilities [1]. Rehabilitation and educational adaptation needs should be reassessed regularly in childhood, adolescence and adulthood [1].

7.3 Behaviour and autism spectrum disorder

A child psychiatry assessment, especially before school entry, helps to detect behavioural disorders and ASD, if necessary with an autism resource centre; depending on the picture, behavioural, cognitive, cognitive-behavioural therapies, cognitive remediation or applied behaviour analysis may be useful [1]. In the face of an acute change in behaviour, a painful somatic cause is sought first [1]. The PNDS does not recommend specific psychotropic drugs and notes that these may slow bowel transit [1].

7.4 Epilepsy

Epilepsy is investigated in paediatric neurology or neurology and treated according to seizure type and investigations, with no features specific to invdupdel(8p) [1]. In the Okur cohort, patients with invdupdel(8p) were treated with levetiracetam, sodium valproate, oxcarbazepine, phenobarbital, topiramate and phenytoin, as monotherapy or in combination, and 20 no longer needed antiepileptic drugs; in 8p deletions, four of five patients with more frequent seizures were controlled with sodium valproate [7]. At the Colorado centre, only one of 14 patients with epilepsy was refractory and nine became seizure-free [25]. No source defines a preferred antiepileptic drug for invdupdel(8p); the doses in Table 7.2 are those of the labels for general epilepsy indications and apply by extrapolation, with the choice of drug following the seizure type.

Table 7.2. Antiepileptic drugs used in the Okur cohort: label doses (extrapolation from general epilepsy indications)

The invdupdel(8p) population combines several risk factors for valproate hepatotoxicity mentioned in the label (age under 2 years, ID with severe epilepsy, brain malformations), so its prescription in infants requires strict consideration and hepatic monitoring [60]. Therapeutic education includes the seizure action plan [1].

7.5 Spasticity, tone and orthopaedics

Spasticity and joint stiffness are frequent and cause pain, difficulty with positioning and loss of motor skills; the PNDS recommends prevention with physiotherapy and orthoses, possibly muscle relaxants or local botulinum toxin injections, PRM or orthopaedic consultation and occupational therapy input for daily activities [1]. The spine should be examined at each visit for scoliosis, which is treated as in the general population, taking reduced mobility into account [1]. To prevent fractures, calcium intake should be regular and sufficient, vitamin D supplementation is given as in all children and regular, adapted physical activity contributes to bone density [1]; the ESPGHAN Committee on Nutrition recommends 400 IU/day of oral vitamin D in infants and supplementation after 1 year in risk groups, which include children with little sun exposure [61].

Table 7.3. Botulinum toxin, melatonin, omeprazole and macrogol: label doses (extrapolation from general paediatric indications)

7.6 Sleep

Sleep disorders should be sought systematically, by history and carer questionnaire; for delayed sleep onset and night waking, prolonged-release melatonin may be useful; if apnoeas are suspected, the patient is referred to a sleep centre, and severe apnoeas may warrant nocturnal positive pressure ventilation prescribed by the specialist [1]. In the European Union, prolonged-release melatonin Slenyto® has an approved indication for children and adolescents with ASD or neurogenetic disorders with nocturnal awakenings, which covers the use described in the PNDS (Table 7.3) [63].

7.7 Heart

Heart disease, when present, is treated medically or surgically according to the usual protocols of the general population, and the frequency of follow-up is decided by the specialists; if the echocardiogram in the initial work-up is normal, systematic cardiological follow-up is not needed in the absence of symptoms [1]. In the Okur cohort, 73% of defects closed spontaneously [7].

7.8 Feeding, reflux and constipation

Sucking-swallowing and oral feeding disorders require specialised speech and language therapy [1]. Enteral nutrition via a nasogastric tube may be needed temporarily when growth is affected; if difficulties persist beyond 6 months, a gastrostomy may avoid prolonged use of the tube, which impairs oral feeding, and the indication is discussed between gastroenterology, cardiology, paediatric neurology and the other professionals involved, according to tube dependence and the risk of aspiration [1]. Overt GOR, with vomiting, needs no investigations; non-overt GOR should be confirmed by 24-hour pH monitoring before starting drugs [1]. Treatment begins with simple measures (thickening of feeds, positioning during and after meals) and continues with the usual drugs, mainly proton pump inhibitors (doses in Table 7.3); in uncontrolled complicated GOR (oesophagitis, aspiration pneumonia), a Nissen fundoplication may be discussed, possibly in the same operation as the gastrostomy [1, 64]. Constipation is treated first with fibre and hydration and, if it persists, with laxatives such as macrogol (polyethylene glycol), maintained for at least one month to avoid relapse; enemas and suppositories are reserved for exceptional situations, and drugs that slow transit, such as psychotropics, deserve attention [1]. The British SmPC for Movicol® Paediatric Plain provides for courses of 6–12 months in chronic constipation, which is consistent with the minimum duration of one month in the PNDS (Table 7.3) [65].

7.9 Growth and nutrition

Height, weight and head circumference are recorded on growth charts at least every 3 months before 1 year and then every 6 months; a deceleration or drop across the centiles requires investigation of the cause, and a dietetic assessment to optimise intake is systematic if growth is abnormal [1].

7.10 Genitourinary tract

Minor renal anomalies (hydronephrosis, renal hypoplasia, horseshoe kidney) should be diagnosed, although simple surveillance is usually sufficient and treatment is not specific; a genital malformation such as hypospadias requires a surgical opinion [1].

7.11 Vision, hearing and oral health

An annual screening ophthalmological consultation is recommended and, given the frequency of refractive errors and strabismus, an examination under cycloplegia with atropine by a paediatric ophthalmologist at least once and as early as possible; hearing is tested in the initial work-up and then whenever hearing loss is suspected [1]. Given the frequency of cortical visual impairment in 8p disorders (54% in a series of 26 patients), functional visual assessment complements the ophthalmological examination [48]. Tooth brushing begins with the eruption of the first teeth; oral follow-up is systematic, looking for malposition, crowding and caries, with prevention by fluoride varnish according to the context; some patients need professionals used to patients with disabilities and conscious sedation with an equimolar mixture of oxygen and nitrous oxide (MEOPA), in hospital or in specialised dental care networks [1].

7.12 Pain assessment

The PNDS devotes an annex to pain assessment, because self-assessment is frequently impossible. There are no scales specific to invdupdel(8p); a scale validated for the age, cognitive capacity and context is used, with self-assessment preferred when possible, and the scale used at the first assessment becomes the reference [1]. In observer assessment, any change in usual behaviour should suggest pain; in patients with multiple disability or ASD, pain may present as atonia or regression, self-directed or other-directed aggression, paradoxical laughter or an increase in abnormal movements or spasticity [1].

Table 7.4. Pain scales recommended by the PNDS and treatment thresholds [1]

7.13 Anaesthesia, surgery and emergencies

Surgery for malformations follows the usual protocols; the decision weighs benefit and risk, and the postoperative period should be anticipated in patients with multiple disability or involvement of several organs [1]. For postoperative pain, the modified FLACC and GED-DI scales are validated in this context [1]. Heart disease, epilepsy, GOR with risk of aspiration and gastrostomy should be included in the information passed to anaesthetic teams; the rare disease emergency card of the AnDDI-Rares network summarises the symptoms to consider and the actions recommended and to be avoided in an emergency, and is issued and completed by the physician at the reference centre [1].

7.14 Agents to avoid and pharmacological precautions

The sources do not identify drugs contraindicated by invdupdel(8p) itself. Precautions arise from the comorbidities: valproate carries a warning of fatal hepatotoxicity with increased risk in children under 2 years, ID with severe epilepsy and organic brain disease, and of teratogenicity [60]; botulinum toxin carries a warning of spread of effect, with risk probably greater in children with spasticity [62]; psychotropics and other drugs that slow transit worsen constipation [1].

7.15 Pregnancy and lactation

Most patients have no offspring, but carriers with mild impairment may transmit the rearrangement (section 8) [1, 8]. In a woman with invdupdel(8p) and epilepsy, valproate should only be used if other options fail, because of the risks of malformations, notably neural tube defects, reduced IQ and neurodevelopmental disorders after in utero exposure [60]. The sources consulted do not describe pregnancies in women with invdupdel(8p).

7.16 Transition to adulthood and social support

Follow-up by a multidisciplinary team continues into adulthood, with transfer to adult services (geneticist and neurologist) [1]. The PNDS describes the measures of the French system: exemption from co-payment for a long-term condition, benefits and placement through the departmental centre for persons with disabilities, rehabilitation services by age, preparation for the move to adulthood 9–12 months before 20 years of age and discussion, from 18 years, of a protection measure for the vulnerable adult (curatorship, guardianship or family authorisation) [1]. The principles apply to other health systems with each country's own instruments. Therapeutic education helps patients and families to understand the disease and the treatments, to act in the event of epileptic seizures and episodes of discomfort, to prevent complications and to master technical procedures (enteral nutrition, gastrostomy, oral hygiene) [1].

7.17 Regulatory status

There are no medicines authorised for invdupdel(8p) and no orphan designations identified in the sources consulted. Table 7.5 summarises the status of the symptomatic drugs cited.

Table 7.5. Regulatory status of the symptomatic drugs cited

7.18 Clinical trials and recent developments

There are no interventional clinical trials in invdupdel(8p) or in 8p disorders: a search of ClinicalTrials.gov on 6 November 2026, for «8p syndrome», «chromosome 8p» and «invdupdel», found no relevant studies. Recent evidence is observational or preclinical (Table 7.6).

Table 7.6. Recent studies (last 12 months or ongoing) and level of evidence

The research of Lee and colleagues is the first described step towards a therapy directed at the abnormal chromosome: the strategy is classified as ex vivo chromosome engineering, without sequence editing; the methodology uses the patient's iPSCs, induction of mis-segregation targeted to chromosome 8 (KaryoCreate) or global (TTK inhibitor), clone selection and confirmation by karyotype, STR markers and sequencing; the preclinical result is restoration of euploidy with partial correction of the cellular defects, and the risks identified are the resulting uniparental isodisomy, imprinting effects and the genomic damage of mis-segregation techniques [38]. There is no clinical phase, no efficacy in humans and no proposed route of administration; the immediate usefulness is as a platform for studying candidate genes [38].

7.19 Guideline recommendations and divergences

The 2022 French PNDS is the only comprehensive guideline consulted and is the reference for this article [1]. The North American proposal of Santucci and colleagues, from 2025, covers all 8p syndromes and proposes its own surveillance, the content of which was not accessible [23]. Between the PNDS and the other sources there are the following divergences: the PNDS indicates epilepsy in 30–50% and brain malformations in 75–85%, whereas Okur's North American and European cohort recorded 55% seizures and 84% abnormal imaging and the Abbott series 37% seizures in invdupdel [1, 7, 25]; the PNDS attributes to the 8p23.1 inversion frequencies of 25% in Europeans and 30% in Japanese, whereas the original studies gave 26% (heterozygosity in Europeans) and 39% (allele frequency in Japanese) [1, 11, 15]; the PNDS text recommends an annual ophthalmological consultation, whereas the visit table sets systematic examinations in the neonatal period, at 9 months, 2.5 years and 6 years and thereafter as needed [1]. The PNDS gives no doses; the doses in this article come from labels for general indications and from ESPGHAN for vitamin D [58–65]. The ISCA consensus and the 2021 ACMG guideline support CMA, and increasingly ES/GS, as first line, whereas the PNDS still requires karyotype and FISH to characterise the rearrangement; the recommendations are complementary [1, 51, 53].

8. Reproductive Options and Family Counselling

8.1 Origin and recurrence risk

In the vast majority of cases, invdupdel(8p) is sporadic, de novo [1]. The rearrangement forms in maternal meiosis, and when the 8p23.1 inversion was sought it was found in one of the mothers in all cases studied [1, 11, 15]. The inversion is asymptomatic and common (26% heterozygosity in Europeans, 39% allele frequency in Japanese) [11, 15], and the prevalence of invdupdel(8p) is much lower than the frequency of carriers would lead one to expect; none of the families in the Okur cohort reported recurrence of any rearrangement in other children or recurrent miscarriages, and invdupdel(8p) is not frequent in cytogenetic studies of products of conception, so the absolute risk for carriers of the inversion is considered low [7]. For this reason the PNDS considers that diagnosis of the paracentric inversion has limited clinical value, with no impact on counselling, and should not be sought systematically [1]. The situation differs from parental inversions visible on the karyotype: Feldman and colleagues described a recombinant of a maternal paracentric inv(8)(p12p23.3), for which the risk may be significant [20], and, for inversions in general, the Oxford Desk Reference indicates a risk of 10–15% in families with a previous recombinant live birth and unnecessary cascade testing when the risk of viable imbalance is below 0.5% [67]. The San Luis Valley recombinant chromosome 8 results from a different, pericentric inversion, with a risk of 6.2% for the carrier [6].

Transmission of invdupdel(8p) itself is rare but does occur: the PNDS cites a family with transmission over two generations, with carriers having mild ID; Vibert included five individuals from the same family; and in Yang's case 11, with a 4.5 Mb deletion and an 8.2 Mb duplication, the father, with secondary education and in employment, had the same CNV [1, 8, 12]. The French family, the first with transmission of invdupdel(8p) documented by CMA and FISH in several members, shows that carriers' fertility may be preserved; as there are no other families, the risk in subsequent generations cannot be estimated accurately, and Vibert and colleagues recommend informing carriers of this risk during genetic counselling [12]. For this reason the PNDS recommends, for a couple with an affected child, parental karyotyping, so as to exclude invdupdel(8p) in a paucisymptomatic parent [1]. For a carrier, the risk of transmitting a CNV in each pregnancy is about 50%, as for other inherited CNVs [44].

Table 8.1. Recurrence risks by scenario

8.2 Prenatal and preimplantation diagnosis

After a child with de novo invdupdel(8p), the recurrence risk is very low, but prenatal diagnosis by chorionic villus sampling or amniocentesis may be offered in a subsequent pregnancy [1, 44]. Preimplantation genetic testing is not proposed by the PNDS [1]. When a parent is a carrier, prenatal diagnosis is offered with caution, because expressivity varies and counselling people with learning difficulties requires adequate time and consent [44]. Villus results may not reflect the fetus and should be confirmed in amniocytes [34, 35]. In Yang's series, 11 of 12 couples chose to terminate the pregnancy and the child who was born, with the smallest duplication, had a favourable course at five years, which illustrates the difficulty of predicting prognosis from the CNV [8]. Detection of the parental inversion by optical genome mapping was only achieved with the T2T reference [55].

8.3 Disclosure of the diagnosis and support

The diagnosis should be disclosed in a dedicated consultation, in a suitable setting and with sufficient time, preferably in the presence of both parents or legal representatives; if the person who requested the test is not a specialist in chromosomal anomalies, a clinical geneticist or cytogeneticist is involved and, depending on the context, a psychologist, genetic counsellor or nurse [1]. The information includes the results, the disease and its complications, the need for regular follow-up, the planned care, the mode of transmission and genetic counselling; the presence of a psychologist is essential, during or soon after the consultation, and a follow-up consultation and the contact details of patient associations should be offered [1]. When parental karyotyping shows a carrier parent, testing is extended to relatives at risk, a role assigned by the PNDS to the clinical geneticist [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

The incidence usually cited is 1 in 10,000 to 1 in 30,000 births [1, 13, 17]. Orphanet records a birth prevalence of 3.9 per 100,000 in Italy, derived from Giglio and colleagues, a worldwide point prevalence in the class below 1 per 1,000,000 and about 60 published cases or families [2]; these entries measure different things (births in one country, estimated point prevalence and published cases) and are not comparable with each other. Since the first case in 1976, more than 100 patients diagnosed after birth have been published [8], and the French series reviewed 99 patients from the literature [12]. In referred populations, the proportions are indicators of diagnostic burden and not of prevalence: 10 of 966 North American children with developmental disorders studied by microarray had pathogenic CNVs on 8p (about 1%), two of them invdupdel(8p) [27]; 12 of 103,840 invasive prenatal diagnoses at a Chinese centre from 2016 to 2022 were invdupdel(8p) [8]; and invdupdel(8p) is the most frequent chromosomal rearrangement in patients with corpus callosum anomaly and ID (3%) [1]. Feldman and colleagues already considered it, in 1993, one of the duplications most often observed in their laboratories [20].

9.2 Population diversity

The 8p23.1 inversion that predisposes to the rearrangement is frequent in several populations: 26% heterozygosity in a population of European ancestry and 39% allele frequency in a Japanese population [11, 15]. Clinical cohorts come mainly from the United States and Europe (Okur: 53 from the USA, 14 from the United Kingdom, 20 from other European countries; series from France, Spain, Italy and Russia), with series also from Japan and China [7, 8, 12, 13, 15, 17, 24]. No founder effect is known for invdupdel(8p); the recombinant chromosome 8, with a Hispanic founder effect in southern Colorado and northern New Mexico, traced to a village in north-eastern New Mexico in the late 19th century, is a different entity [6]. The sources consulted do not present specific data for Portugal or Brazil.

9.3 Special populations

Adults are under-represented (maximum age of 27.2 years in the Okur cohort; the PNDS notes few data after adolescence) [1, 7]. Mosaic forms and forms with a small duplication may be mild and go undiagnosed until an affected child is identified [8, 36].

9.4 Reference networks and patient associations

In Europe, the relevant network is ERN ITHACA, dedicated to rare malformation syndromes, intellectual disability and other neurodevelopmental disorders [14]. In France, the reference and competence centres of the DéfiScience and AnDDI-Rares networks provide diagnosis and follow-up, and the PNDS lists the reference centres for intellectual disabilities of rare causes [1]. The patient associations cited are La Maison 8p (France), which took part in drafting the PNDS, Valentin APAC (French association of carriers of chromosomal anomalies), Unique (Rare Chromosome Disorder Support Group, United Kingdom) and the Project 8p Foundation (USA), which funds research and maintains a natural history study [1, 7, 68–71]. From the Project 8p natural history study, an individual «patient passport» was developed that places each child's data in the context of their genetic subgroup, described in a preprint [66].

10. Illustrative Clinical Case

Lo Bianco and colleagues, from Catania and the Bambino Gesù Children's Hospital in Rome, described in 2020 an 8-year-old girl with de novo invdupdel(8p) and an intermediate phenotype [17]. She was the second daughter of non-consanguineous parents, both with glaucoma; the mother had hypothyroidism diagnosed at 33 years. The pregnancy was complicated by several threatened miscarriages and placental abruption in the first trimester, and delivery was by elective caesarean section at 39 weeks, with a weight of 2640 g (5th centile), length of 46 cm (below the 3rd centile), head circumference of 36 cm (95th centile) and Apgar scores of 9 and 10. In early childhood she had growth retardation and hypothyroidism diagnosed at 2 months, treated with levothyroxine. She stood at 2 years and walked alone at 3; up to 4 years she said only a few words and, despite speech and language therapy, at 8 years she used about 10 words, without sentences [17].

At 8 years she weighed 18.9 kg (below the 3rd centile), measured 121 cm (10th centile) and had a head circumference of 51 cm (50th centile). She had transient cutis marmorata, generalised hypertrichosis and the scar of a sacrococcygeal fistula; hypotrophic and hypotonic muscle mass, external rotation of the lower limbs, genu varum, flat feet with a tendency to pronation and reduced deep tendon reflexes; dimples at the elbows and knees, a shield chest with inverted nipples and winged scapulae; and dysmorphism with a prominent forehead, arched eyebrows, a thin nose with a rounded tip and anteverted nares, a flat philtrum, thin lips with downturned corners, mild micrognathia and low-set, posteriorly rotated ears, a single palmar crease on the right and bilateral clinodactyly of the 4th and 5th fingers. Her behaviour was characterised by emotionality, impulsivity and reduced attention, with a diagnosis of ADHD and of severe developmental delay/ID. Laboratory tests were normal, except for IgE of 522 IU/ml and eosinophils of 10.5% [17].

Brain MRI showed incomplete myelination, mild dilatation of the lateral ventricles with enlargement of the cerebrospinal fluid spaces (figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC7408450/figure/brainsci-10-00451-f001/), partially cystic ectasia of the pineal gland (figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC7408450/figure/brainsci-10-00451-f002/), moderate cystic ectasia of the cisterna magna and retrocerebellar cystic ectasia without mass effect; flow MRI showed turbulence in the third and fourth ventricles with normal volume in the aqueduct, so no shunt was required. Fundoscopy showed a pale disc with sharp margins with a peripapillary pigment ring and global chorioretinal dystrophy, without signs of intracranial hypertension. Serial EEGs and the echocardiogram were normal, and the ECG showed a focal right bundle branch block. Phoniatric assessment found sialorrhoea, large palatine tonsils and an isolated high-arched palate, and tympanometry showed a type C curve with absent stapedial reflex on the left [17].

Comparative genomic hybridisation microarray (Agilent 8×60K) revealed a 6.7 Mb terminal deletion at 8p23.3p23.1 (221,611–6,914,076) and a 19.8 Mb interstitial inverted duplication at 8p23.1p12 (12,583,259–32,380,292), confirmed and oriented by FISH with probes RP11-45O16 and RP11-139G9; the karyotype was 46,XX,der(8)del(8)(p23.1)invdup(p12p23.1), and the rearrangement was de novo [17]. The absence of heart disease and of corpus callosum anomaly, with a duplication of intermediate size, placed the patient in an intermediate zone of the spectrum, consistent with the correlation between duplication size and severity described in other series [7, 17]. The report does not describe a systematic follow-up plan; in the light of the PNDS, follow-up would include an annual visit at a reference centre, ophthalmological and hearing assessment, screening for scoliosis and epilepsy and introduction of AAC, given the severe language impairment [1]. The findings of hypothyroidism and raised IgE are not part of the usual picture described in the series and may be unrelated to the rearrangement [17].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

Prognosis is dominated by the degree of ID and the language impairment: about 40% of patients do not acquire spoken language and more than 70% walk, on average at 2–3 years [1]; in the Okur cohort, more than half of the patients with invdupdel(8p) were still not walking and/or not saying first words at the time of the study, and the mean Vineland adaptive behaviour score was 52 [7]. Severity increases with the size of the duplication, and mosaic forms or forms with a small duplication may be mild [7, 8, 36]. Epilepsy is usually controllable: 20 patients in the Okur cohort no longer needed antiepileptic drugs, and at the Colorado centre nine of 14 became seizure-free and only one was refractory [7, 25]. Heart defects tend to be minor and to close spontaneously (73%) [7]. Progressive spasticity, scoliosis and feeding difficulties are the main sources of morbidity during growth [1]. There are no data on life expectancy and no adult series: the maximum age in the Okur cohort was 27.2 years and the PNDS notes the scarcity of data in adolescents and adults [1, 7]. Most published cases have no life-threatening malformations, but a newborn with severe polyvalvular dysplasia who died on the 12th day has been described [49]. In families with transmission, adult carriers had mild ID or their own educational and occupational path [1, 8].

11.2 Initial work-up

After diagnosis, the initial work-up looks for the frequent forms of involvement and is adapted to age and to the investigations already performed [1].

Table 11.1. Initial work-up according to the PNDS [1]

11.3 Surveillance

Coordination of follow-up provides for a visit to a reference or competence centre twice a year in the first 2–3 years and then annually in childhood, adolescence and adulthood [1].

Table 11.2. Surveillance in invdupdel(8p)

The surveillance proposed by the Children's Hospital Colorado programme for 8p syndromes complements these recommendations, but its content was not consulted [23]. As for ophthalmology, the PNDS text recommends annual screening and the visit table sets systematic examinations in the neonatal period, at 9 months, 2.5 years and 6 years; the two schedules are not mutually exclusive, and the table defines the minimum examinations [1].

12. Summary and Final Considerations

invdupdel(8p) is a complex, recurrent chromosomal rearrangement that combines, on the same chromosome 8, a terminal deletion of about 6.7 Mb, an intermediate normal-copy segment and an inverted 8p duplication of variable size. It almost always forms de novo in maternal meiosis, through unequal recombination between the two 8p23.1 blocks of olfactory receptor and defensin gene repeats in a woman heterozygous for the polymorphic inversion that separates them, which is frequent in European and Japanese populations. The estimated incidence is 1 in 10,000 to 1 in 30,000 births, and the entity is the most frequent chromosomal rearrangement in patients with ID and corpus callosum anomaly. The clinical picture combines global delay predominantly affecting language and mild to severe ID, hypotonia progressing to lower limb spasticity, epilepsy in about a third to a half of patients, corpus callosum anomalies in two thirds, usually minor septal heart defects, scoliosis, feeding difficulties, GOR and constipation, refractive errors and cortical visual impairment, with non-specific dysmorphism. Severity increases with the size of the duplication, and mosaicism and small duplications are associated with mild forms, including adult carriers who transmit the rearrangement. Diagnosis is by CMA, which gives the coordinates, completed by karyotype and FISH, which show the inverted structure; the parents undergo karyotyping to exclude a paucisymptomatic carrier, and testing for the polymorphic inversion does not change counselling. The recurrence risk after a de novo case is very low; prenatal diagnosis may be offered, with the caveat of possible discrepancy between villi and fetus. There is no specific treatment: the 2022 French PNDS defines multidisciplinary management, with early rehabilitation and AAC, treatment of epilepsy, spasticity, sleep, GOR and constipation by the usual means, pain assessment with adapted scales and an age-based surveillance schedule. Recent research adds natural history data on epilepsy and vision and a first cell model of correction of the abnormal chromosome, as yet without clinical translation.

13. References

1. Heide S, Gerasimenko A, Dubern B, Valence S, Siffroi JP, Marchetti-Waternaux I, Reyes JM; Centre de Référence Déficiences Intellectuelles de Causes Rares, Filière DéfiScience. Protocole National de Diagnostic et de Soins (PNDS): syndrome de duplication/délétion inversée du bras court du chromosome 8. Saint-Denis: Haute Autorité de Santé; 2022 (text of July 2022; published 10 Oct 2022). https://www.has-sante.fr/jcms/p_3373679
2. Orphanet. 8p inverted duplication/deletion syndrome (ORPHA:96092) [Internet]. Paris: INSERM; data of 23 Jun 2026 [accessed 6 Nov 2026]. https://www.orpha.net/en/disease/detail/96092
3. Orphanet. 8p23.1 microdeletion syndrome (ORPHA:251071) [Internet]. Paris: INSERM; data of 23 Jun 2026 [accessed 6 Nov 2026]. https://www.orpha.net/en/disease/detail/251071
4. Orphanet. 8p23.1 duplication syndrome (ORPHA:251076) [Internet]. Paris: INSERM; data of 23 Jun 2026 [accessed 6 Nov 2026]. https://www.orpha.net/en/disease/detail/251076
5. Orphanet. Trisomy 8p syndrome (ORPHA:264450) [Internet]. Paris: INSERM; data of 23 Jun 2026 [accessed 6 Nov 2026]. https://www.orpha.net/en/disease/detail/264450
6. OMIM. #179613 Recombinant chromosome 8 syndrome [Internet]. Baltimore: Johns Hopkins University; updated 30 Mar 2020 [accessed 6 Nov 2026]. https://www.omim.org/entry/179613
7. Okur V, Hamm L, Kavus H, Mebane C, Robinson S, Levy B, Chung WK. Clinical and genomic characterization of 8p cytogenomic disorders. Genet Med. 2021;23(12):2342-2351. doi:10.1038/s41436-021-01270-2
8. Yang X, Hu R, Huang W, Lu J. Prenatal diagnosis and molecular cytogenetic characterization of 12 cases of chromosome 8 inverted duplication deletion syndrome. Orphanet J Rare Dis. 2025;20(1):421. doi:10.1186/s13023-025-03969-w
9. OMIM. %222400 Diaphragmatic hernia 2; DIH2 [Internet]. Baltimore: Johns Hopkins University; updated 1 Dec 2025 [accessed 6 Nov 2026]. https://www.omim.org/entry/222400
10. Barber JC, Rosenfeld JA, Foulds N, Laird S, Bateman MS, Thomas NS, et al. 8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients. Am J Med Genet A. 2013;161A(3):487-500. doi:10.1002/ajmg.a.35767
11. Giglio S, Broman KW, Matsumoto N, Calvari V, Gimelli G, Neumann T, et al. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet. 2001;68(4):874-883. doi:10.1086/319506
12. Vibert R, Mignot C, Keren B, Chantot-Bastaraud S, Portnoï MF, Nouguès MC, et al. Neurodevelopmental phenotype in 36 new patients with 8p inverted duplication-deletion: genotype-phenotype correlation for anomalies of the corpus callosum. Clin Genet. 2022;101(3):307-316. doi:10.1111/cge.14096
13. García-Santiago FA, Martínez-Glez V, Santos F, García-Miñaur S, Mansilla E, Meneses AG, et al. Analysis of invdupdel(8p) rearrangement: clinical, cytogenetic and molecular characterization. Am J Med Genet A. 2015;167A(5):1018-1025. doi:10.1002/ajmg.a.36879
14. ERN ITHACA — European Reference Network on Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders [Internet]. [accessed 6 Nov 2026]. https://ern-ithaca.eu
15. Shimokawa O, Kurosawa K, Ida T, Harada N, Kondoh T, Miyake N, et al. Molecular characterization of inv dup del(8p): analysis of five cases. Am J Med Genet A. 2004;128A(2):133-137. doi:10.1002/ajmg.a.30063
16. Guo WJ, Callif-Daley F, Zapata MC, Miller ME. Clinical and cytogenetic findings in seven cases of inverted duplication of 8p with evidence of a telomeric deletion using fluorescence in situ hybridization. Am J Med Genet. 1995;58(3):230-236. doi:10.1002/ajmg.1320580307
17. Lo Bianco M, Vecchio D, Timpanaro TA, Arena A, Macchiaiolo M, Bartuli A, et al. Deciphering the invdupdel(8p) genotype-phenotype correlation: our opinion. Brain Sci. 2020;10(7):451. doi:10.3390/brainsci10070451
18. Weleber RG, Verma RS, Kimberling WJ, Fieger HG, Lubs HA. Duplication-deficiency of the short arm of chromosome 8 following artificial insemination. Ann Genet. 1976;19(4):241-247.
19. Jensen PK, Junien C, Despoisse S, Bernsen A, Thelle T, Friedrich U, de la Chapelle A. Inverted tandem duplication of the short arm of chromosome 8: a non-random de novo structural aberration in man. Localization of the gene for glutathione reductase in subband 8p21.1. Ann Genet. 1982;25(4):207-211.
20. Feldman GL, Weiss L, Phelan MC, Schroer RJ, Van Dyke DL. Inverted duplication of 8p: ten new patients and review of the literature. Am J Med Genet. 1993;47(4):482-486. doi:10.1002/ajmg.1320470410
21. Minelli A, Floridia G, Rossi E, Clementi M, Tenconi R, Camurri L, et al. D8S7 is consistently deleted in inverted duplications of the short arm of chromosome 8 (inv dup 8p). Hum Genet. 1993;92(4):391-396. doi:10.1007/bf01247342
22. Floridia G, Piantanida M, Minelli A, Dellavecchia C, Bonaglia C, Rossi E, et al. The same molecular mechanism at the maternal meiosis I produces mono- and dicentric 8p duplications. Am J Hum Genet. 1996;58(4):785-796.
23. Santucci K, Malik KE, Angione K, Bennink D, Gerk A, Mancini D, Stringfellow M, Dinkel T, Demarest S, Miele AS, Saenz M. Chromosome 8p syndromes clinical presentation and management guidelines. Clin Genet. 2025;107(2):169-178. doi:10.1111/cge.14626
24. Yurchenko DA, Minzhenkova ME, Dadali EL, Markova ZG, Rudenskaya GE, Matyushchenko GN, et al. Clinical manifestations of various molecular cytogenetic variants of eight cases of «8p inverted duplication/deletion syndrome». Biomedicines. 2022;10(3):567. doi:10.3390/biomedicines10030567
25. Abbott M, Angione K, Stringfellow M, Malik K, Saenz M, Miele A, Syverson K, Maniar B, Borello J, Chaby L, Demarest S. Evaluation of epilepsy in 8p-related disorders. Epilepsy Res. 2026;220:107720. doi:10.1016/j.eplepsyres.2025.107720
26. Redaelli S, Conconi D, Sala E, Villa N, Crosti F, Roversi G, et al. Characterization of chromosomal breakpoints in 12 cases with 8p rearrangements defines a continuum of fragility of the region. Int J Mol Sci. 2022;23(6):3347. doi:10.3390/ijms23063347
27. Yu S, Fiedler S, Stegner A, Graf WD. Genomic profile of copy number variants on the short arm of human chromosome 8. Eur J Hum Genet. 2010;18(10):1114-1120. doi:10.1038/ejhg.2010.66
28. Buysse K, Antonacci F, Callewaert B, Loeys B, Fränkel U, Siu V, et al. Unusual 8p inverted duplication deletion with telomere capture from 8q. Eur J Med Genet. 2009;52(1):31-36. doi:10.1016/j.ejmg.2008.10.007
29. Yu S, Graf WD. Telomere capture as a frequent mechanism for stabilization of the terminal chromosomal deletion associated with inverted duplication. Cytogenet Genome Res. 2010;129(4):265-274. doi:10.1159/000315887
30. Kato T, Inagaki H, Miyai S, Suzuki F, Naru Y, Shinkai Y, et al. The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications. Hum Genet. 2020;139(11):1417-1427. doi:10.1007/s00439-020-02186-8
31. Brewer BJ, Dunham MJ, Raghuraman MK. A unifying model that explains the origins of human inverted copy number variants. PLoS Genet. 2024;20(1):e1011091. doi:10.1371/journal.pgen.1011091
32. Zuffardi O, Fichera M, Bonaglia MC. The embryo battle against adverse genomes: are de novo terminal deletions the rescue of unfavorable zygotic imbalances? Eur J Med Genet. 2022;65(8):104532. doi:10.1016/j.ejmg.2022.104532
33. Pramparo T, Giglio S, Gregato G, de Gregori M, Patricelli MG, Ciccone R, et al. Inverted duplications: how many of them are mosaic? Eur J Hum Genet. 2004;12(9):713-717. doi:10.1038/sj.ejhg.5201240
34. Soler A, Sánchez A, Carrió A, Badenas C, Milà M, Borrell A. Fetoplacental discrepancy involving structural abnormalities of chromosome 8 detected by prenatal diagnosis. Prenat Diagn. 2003;23(4):319-322. doi:10.1002/pd.590
35. Huynh MT, Riteau AS, Moradkhani K, Pichon O, Richard S, Joubert M, Bézieau S. Structural abnormalities of chromosome 8 and fetoplacental discrepancy: a second case report and review of fetal phenotype of 8p inverted duplication deletion syndrome. Eur J Med Genet. 2021;64(1):104118. doi:10.1016/j.ejmg.2020.104118
36. Hand M, Gray C, Glew G, Tsuchiya KD. Mild phenotype in a patient with mosaic del(8p)/inv dup del(8p). Am J Med Genet A. 2010;152A(11):2827-2831. doi:10.1002/ajmg.a.33669
37. Ciccone R, Mattina T, Giorda R, Bonaglia MC, Rocchi M, Pramparo T, Zuffardi O. Inversion polymorphisms and non-contiguous terminal deletions: the cause and the (unpredicted) effect of our genome architecture. J Med Genet. 2006;43(5):e19. doi:10.1136/jmg.2005.037671
38. Lee SN, Banda EC, Qiao L, Thompson SL, Singh K, Hagenson RA, et al. Chromosome engineering to correct a complex rearrangement on chromosome 8 reveals the effects of 8p syndrome on gene expression and neural differentiation. Genome Res. 2026;36(3):547-560. doi:10.1101/gr.280425.125
39. Ensembl GRCh37. Gene lookup (REST API) [Internet]. Hinxton: EMBL-EBI [accessed 6 Nov 2026]. https://grch37.rest.ensembl.org
40. OMIM. mimTitles.txt and mim2gene.txt [data files downloaded from OMIM]. Baltimore: Johns Hopkins University [accessed 6 Nov 2026]. https://www.omim.org/downloads
41. Firth HV, Hurst JA. Microcephaly. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 228–231.
42. GeneGuidance. GATA4 gene record [local database]. 2026 [accessed 6 Nov 2026].
43. Verstraeten A, Roos-Hesselink J, Loeys B. Bicuspid aortic valve. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 345–361.
44. Firth HV, Hurst JA. Deletions and duplications (including microdeletions and microduplications). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 660–665.
45. Tokutake H, Chiba S. A case report of respiratory syncytial virus-infected 8p inverted duplication deletion syndrome with low natural killer cell activity. Tohoku J Exp Med. 2022;257(4):347-352. doi:10.1620/tjem.2022.j052
46. Fisch GS, Davis R, Youngblom J, Gregg J. Genotype-phenotype association studies of chromosome 8p inverted duplication deletion syndrome. Behav Genet. 2011;41(3):373-380. doi:10.1007/s10519-011-9447-4
47. Yenamandra A, Perrone R, McLaughlin J, Mehta L. Inverted duplication/deletion of chromosome 8p: mild clinical phenotype. Am J Med Genet. 1999;82(1):91-93. doi:10.1002/(SICI)1096-8628(19990101)82:1<91::AID-AJMG19>3.0.CO;2-E
48. Abbott M, Angione K, Stringfellow M, Malik K, Saenz M, McCourt E, Silveira L, Miele A, Benke TA, Demarest S. Cortical visual impairment across a range of neurodevelopmental disorders: clinical characterization, diagnostic tool evaluation, and association with developmental outcomes. J Child Neurol. 2026;41(4):470-477. doi:10.1177/08830738251361698
49. Akkurt MO, Higgs A, Turan OT, Turan OM, Turan S. Prenatal diagnosis of inverted duplication deletion 8p syndrome mimicking trisomy 18. Am J Med Genet A. 2017;173(3):776-779. doi:10.1002/ajmg.a.38074
50. Joseph AM, Karas M, Joubran E, Ramadan YO, Fowler BA. Severe COVID-19 infection in an infant with 8p inverted duplication/deletion syndrome: is vaccination still a debate? Cureus. 2023;15(9):e45060. doi:10.7759/cureus.45060
51. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-764. doi:10.1016/j.ajhg.2010.04.006
52. Firth HV, Hurst JA. Intellectual disability. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 188–193.
53. Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(11):2029-2037. doi:10.1038/s41436-021-01242-6
54. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22(2):245-257. doi:10.1038/s41436-019-0686-8
55. Zhou C, Li H, Shi Y, He L, Duan H, Li J. Detection of an 8p23.1 inversion using high-resolution optical genome mapping. Matern Fetal Med. 2024;6(3):173-177. doi:10.1097/fm9.0000000000000238
56. Orphanet. Mosaic trisomy 8 syndrome (ORPHA:96061) [Internet]. Paris: INSERM; data of 23 Jun 2026 [accessed 6 Nov 2026]. https://www.orpha.net/en/disease/detail/96061
57. OMIM. genemap2.txt [OMIM data file, generated on 27 Feb 2017]. Baltimore: Johns Hopkins University. https://www.omim.org/downloads
58. U.S. Food and Drug Administration. KEPPRA (levetiracetam) tablets and oral solution, prescribing information. UCB; label effective 2026-01-28 (openFDA, set_id 3ca9df05-a506-4ec8-a4fe-320f1219ab21). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3ca9df05-a506-4ec8-a4fe-320f1219ab21
59. European Medicines Agency. Keppra (levetiracetam) — summary of product characteristics (EPAR). First authorisation: 29 Sep 2000. https://www.ema.europa.eu/en/medicines/human/EPAR/keppra
60. U.S. Food and Drug Administration. DEPAKOTE (divalproex sodium) delayed-release tablets, prescribing information. AbbVie; label effective 2026-03-31 (openFDA, set_id 08a65cf4-7749-4ceb-6895-8f4805e2b01f). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f
61. Braegger C, Campoy C, Colomb V, Decsi T, Domellof M, Fewtrell M, et al; ESPGHAN Committee on Nutrition. Vitamin D in the healthy European paediatric population. J Pediatr Gastroenterol Nutr. 2013;56(6):692-701. doi:10.1097/MPG.0b013e31828f3c05
62. U.S. Food and Drug Administration. BOTOX (onabotulinumtoxinA) for injection, prescribing information. Allergan; label effective 2023-11-18 (openFDA, set_id 33d066a9-34ff-4a1a-b38b-d10983df3300). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=33d066a9-34ff-4a1a-b38b-d10983df3300
63. European Medicines Agency. Slenyto (melatonin) prolonged-release tablets: EPAR — product information (summary of product characteristics), sections 4.1 and 4.2. EMEA/H/C/004425; first authorisation 20 Sep 2018; extension to neurogenetic disorders (II/0025) 26 Aug 2024; ADHD indication (II/0028) 17 Mar 2025; product information updated on 10 Jun 2026 [accessed 7 Nov 2026]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/slenyto
64. U.S. Food and Drug Administration. PRILOSEC (omeprazole magnesium) delayed-release oral suspension, prescribing information. Covis Pharma; label effective 2024-03-19 (openFDA, set_id b6761f84-53ac-4745-a8c8-1e5427d7e179). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b6761f84-53ac-4745-a8c8-1e5427d7e179
65. Norgine Limited. Movicol Paediatric Plain 6.9 g powder for oral solution — summary of product characteristics (revised 11 Mar 2025). electronic medicines compendium (emc), United Kingdom. https://www.medicines.org.uk/emc/product/52/smpc
66. Brünger T, Syverson K, Maniar B, Borello J, Demarest S, Chaby L, Lal D. Bridging genomic insight and clinical care in chromosome 8p disorders through a registry-driven passport [preprint]. medRxiv. 2025 Dec 6. doi:10.64898/2025.12.02.25340619
67. Firth HV, Hurst JA. Inversions. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 672–673.
68. Association La Maison 8p [Internet]. [accessed 6 Nov 2026]. http://www.lamaison8p.com
69. Valentin APAC — Association de Porteurs d'Anomalies Chromosomiques [Internet]. [accessed 6 Nov 2026]. https://www.valentin-apac.org
70. Unique — Rare Chromosome Disorder Support Group [Internet]. [accessed 6 Nov 2026]. https://www.rarechromo.org
71. Project 8p Foundation [Internet]. [accessed 6 Nov 2026]. https://www.project8p.org