Attention Deficit Hyperactivity Disorder — Genetic Basis

A neurodevelopmental disorder with a predominantly polygenic genetic architecture, with contributions from rare coding variants, copy number variants and monogenic and chromosomal syndromes in which inattention and hyperactivity are frequent manifestations.

Literature and regulatory information updated: 9 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical overview

Descriptions of children with inattention and restlessness predate the concept of a neurodevelopmental disorder by more than a century. The 2021 international consensus statement of the World Federation of ADHD (WFADHD) reconstructs this history: Melchior Adam Weikard described the condition in a German medical textbook in 1775, Alexander Crichton revisited it in 1798, Heinrich Hoffmann portrayed it in a children's book in 1845, and Bourneville and other French authors studied it between 1887 and 1901 [1]. The first description in a scientific journal was by George Still in 1902; Augusto Vidal Perera in Spain (1907) and Gonzalo Rodríguez-Lafora (1917) followed, the latter already considering a brain disease of probable genetic origin [1]. In 1932, Kramer and Pollnow proposed the term “hyperkinetic disorder”, which the World Health Organization would subsequently adopt; in 1937, Charles Bradley observed that amphetamine reduced symptoms; in the 1940s, the concept of “minimal brain dysfunction” became widespread; between 1956 and 1958, the first indications of persistence into adulthood emerged; and in the 1960s, the United States Food and Drug Administration (FDA) approved methylphenidate for behavioural disorders in children [1].

1.2. Milestones in genetic research

Genetic research has passed through four phases. The first, involving twin, family and adoption studies, established that familial aggregation is predominantly genetic, with mean heritability of 74% across 37 twin studies [4]. The second, the candidate gene era, focused on dopaminergic and serotonergic genes and produced meta-analyses between 2001 and 2009 showing associations of small effect, such as that of the 7-repeat allele of the variable number tandem repeat (VNTR) in exon 3 of DRD4 [22–24]. The third began in 2010 with the demonstration of an excess of rare, large copy number variants (CNVs) in British children with ADHD, published in The Lancet, whose authors concluded that ADHD “is not purely a social construct” [10]. The fourth, the era of genome-wide association studies (GWAS), yielded the first 12 robust loci in 2019, drawing on the Danish iPSYCH consortium (Lundbeck Foundation Initiative for Integrative Psychiatric Research) and the Psychiatric Genomics Consortium (PGC), and 27 loci in 2023 [2, 5]. In parallel, exome sequencing showed a burden of rare truncating variants similar to that in autism spectrum disorder (ASD) and identified MAP1A in 2019 [25], implicated KDM5B through de novo variants in trios in 2024 [8] and, in a study published online in November 2025, identified the first three genes reaching exome-wide significance for ADHD: MAP1A, ANO8 and ANK2 [7].

1.3. Nomenclature and definitions

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), defines three presentations (predominantly inattentive, predominantly hyperactive-impulsive and combined) and a residual category of other specified or unspecified disorder; the International Classification of Diseases, 10th revision (ICD-10), uses code F90 and the term “hyperkinetic disorder” [3]. Guideline NG87 of the United Kingdom's National Institute for Health and Care Excellence (NICE) accepts DSM-5 or ICD-11 criteria [14]. In Brazil, the usual term is “transtorno de déficit de atenção/hiperatividade”, with the same Portuguese acronym. OMIM records ADHD only as a multilocus susceptibility entry (143465), indicated by braces, corresponding to a complex trait rather than a Mendelian disease [12]; Orphanet has no entry for ADHD, which is not a rare disease.

1.4. Entities covered

This article addresses three aetiological situations that coexist within the same clinical diagnosis. Polygenic ADHD, accounting for most cases, results from the accumulation of many common alleles of small effect and environmental factors, with no common variant being necessary or sufficient [1, 4]. ADHD associated with rare variants of moderate effect includes truncating or severely deleterious missense variants in constrained genes, present in approximately 1 in every 5 people with ADHD, and recurrent CNVs, whose penetrance for ADHD is incomplete [7, 26]. Syndromic ADHD refers to situations in which inattention and hyperactivity form part of a monogenic, chromosomal or metabolic syndrome with other manifestations, such as neurofibromatosis type 1, Williams syndrome, sex chromosome aneuploidies or X-linked adrenoleukodystrophy [4, 27–29]. Intellectual disability, autism spectrum disorder, fragile X syndrome, the 22q11.2 deletion and duplication syndromes, 16p11.2 microdeletion and microduplication, neurofibromatosis type 1 and KBG syndrome are described here only in their relationship to ADHD.

2. Molecular Genetics and Pathophysiology

2.1. Heritability: twins, families and adoption

In a study of 894 probands with ADHD and 1,135 siblings aged 5 to 17 years, the risk of ADHD in siblings of probands was 9 times that observed in siblings of controls [4]. Adoption studies attribute this aggregation to genetic factors, because biological relatives of children with ADHD have more ADHD than adoptive relatives, whose risk is similar to that of controls [4]. Mean heritability across 37 twin studies, using diagnostic or symptom measures, is 74%; in a study combining monozygotic and dizygotic twins, siblings and half-siblings, it reached approximately 80%; studies using categorical diagnoses place it between 77% and 88% [4]. The estimate is similar in men and women and for the dimensions of inattention and hyperactivity-impulsivity [4]. Studies conducted in the United States, Europe, Scandinavia and Australia converge on this finding [1].

The informant changes the estimate. With parent or teacher assessments, heritability is between 70% and 80%; with self-assessment in adolescence or adulthood, it falls below 50%, and to 30–40% when each twin is assessed by a different observer; in adults with a clinical diagnosis it is 72%, and a composite of self-report and parental report yields approximately 80% [4]. These data indicate that heritability remains stable from childhood into adulthood and that there are stable genetic components and dynamic components associated with onset, persistence and remission [4]. In a study of 16,366 Swedish twins, the genetic link between the extreme and subthreshold variation in DSM-IV symptoms was strong, supporting the model of ADHD as the extreme of a continuous distribution [4]. Heritability below 100% implies that environmental factors contribute to risk; these factors are not shared by siblings [2, 4].

Genetic overlap with other disorders is extensive. A general genetic factor explains up to 45% of covariance between externalising symptoms, internalising symptoms and phobias, and 31% of covariance in neurodevelopmental symptoms; in registry-based diagnoses, between 10% and 36% of liability [4]. The genetic correlation between ADHD and ASD exceeds 0.50; the intelligence quotient (IQ) of young people with ADHD is, on average, 9 points lower; and, in Swedish registers, 91% of the correlation between liability to ADHD and to ID was attributed to genetic factors [4]. There are also links with asthma, obesity and epilepsy, and familial overlap with autoimmune diseases, hypospadias and ID [1, 4].

2.2. The candidate gene era and its current interpretation

Linkage studies produced a single genome-wide significant result in meta-analysis, on chromosome 16 (64–83 Mb) [4]. In multigenerational families from an isolated population in Colombia, Arcos-Burgos and colleagues found linkage to 4q13.2, 5q33.3, 8q11.23, 11q22 and 17p11, and one of these regions implicated LPHN3 (now ADGRL3) [4]. ADGRL3 encodes a G protein-coupled receptor of the latrophilin subfamily, involved in cell adhesion and signal transduction; GeneGuidance records no clinical curation associating it with ADHD [30]. A pericentric inversion of chromosome 3 cosegregating with ADHD in a family pointed to SLC9A9 [4].

Candidate gene meta-analyses identified associations of small effect. Faraone and colleagues (2001) concluded that the association between the 7-repeat allele of the VNTR in exon 3 of DRD4 and ADHD was “small but real”, without publication bias [22]. Li and colleagues (2006), using European and Asian studies published up to October 2005, estimated an odds ratio (OR) of 1.34 (95% confidence interval [95% CI] 1.23–1.45; P=2×10⁻¹²) for the 7-repeat allele of DRD4, 1.68 (1.17–2.41) for the 5-repeat allele and 1.34 (1.21–1.49) for the 148-base-pair allele of DRD5; the 4-repeat allele of DRD4 (OR 0.90) and the 136-base-pair allele of DRD5 (OR 0.57) showed a protective effect, and the 480-base-pair (10-repeat) allele of DAT1 had no significant association (OR 1.04; 0.98–1.11) [23]. The meta-analysis by Gizer and colleagues (2009) found significant associations for DAT1, DRD4, DRD5, 5HTT, HTR1B and SNAP25, with significant between-study heterogeneity for DAT1, DRD4, DRD5, DBH, ADRA2A, 5HTT, TPH2, MAOA and SNAP25 [24]. In adults, the review by Faraone and Larsson adds BAIAP2; all these associations have ORs below 1.5 [4]. For the 40-base-pair VNTR in the 3′ untranslated region of SLC6A3, the 10-repeat allele was associated with ADHD in young people and the 9-repeat allele in adults [4]. WFADHD still regards ANKK1, DAT1, LRP5, LRP6, SNAP25, ADGRL3, DRD4 and BAIAP2 as uncertain until genome-wide validation [1].

The DRD4 data illustrate the limitations of this approach. A null allele, with a nonsense variant in exon 1, has a population frequency of approximately 2%, is distributed similarly in controls and patients with schizophrenia, bipolar disorder and Tourette syndrome, and a man homozygous for this allele had no major psychiatric illness [31]. GeneGuidance concludes that there is no established Mendelian gene–disease relationship for DRD4 (no ClinGen or GenCC assertion), that a germline loss-of-function variant in DRD4 has no established pathological significance and that the 7-repeat allele is a low-effect risk factor, “without diagnostic or predictive value for an individual” [12]. In GWAS, of the 9 classic candidate genes tested, only SLC9A9 showed a weak association (P=3.4×10⁻⁴), and no genome-wide significant locus overlaps a classic candidate [2].

The SLC6A3 gene (5p15.33; OMIM 126455) encodes the dopamine transporter (DAT), a sodium- and chloride-dependent presynaptic transporter that also transports noradrenaline and is inhibited by methylphenidate, amphetamine and cocaine [32, 33]. Biallelic loss-of-function variants cause dopamine transporter deficiency syndrome (DTDS), with autosomal recessive inheritance and infantile-onset parkinsonism-dystonia [34, 35]. Heterozygous loss-of-function variants have rarely been identified in people with ADHD, bipolar disorder and ASD, but heterozygous parents of patients with DTDS do not have an increased incidence of these disorders or of early-onset parkinsonism [35]. In an adult man with early-onset parkinsonism and ADHD, Hansen and colleagues described the DAT-Ile312Phe (published protein designation, = NM_001044.5:c.934A>T p.(Ile312Phe)) and DAT-Asp421Asn (= NM_001044.5:c.1261G>A p.(Asp421Asn)) variants, presumed to be de novo; both reduce dopamine uptake with preserved membrane localisation, and Asp421Asn impairs the second sodium-binding site, causing anomalous dopamine efflux and cation leak [33, 36]. Taken together, these data indicate that rare DAT missense variants may contribute to ADHD in a small number of people, without the common SLC6A3 genotype having clinical utility.

2.3. Genome-wide association studies

The 2019 GWAS included 20,183 cases and 35,191 controls from 12 cohorts: Danish iPSYCH (14,584 cases and 22,492 controls, with cases from the Psychiatric Central Research Register coded as ICD-10 F90.0) and 11 European, North American and one Chinese PGC cohorts [2]. It identified 12 independent genome-wide significant loci (P <5×10⁻⁸), with ORs for risk alleles between 1.077 and 1.198 [2]. Heritability explained by single nucleotide polymorphisms (h²SNP), on the liability scale and assuming a prevalence of 5%, was 0.216 (standard error [SE] 0.014), and 88% of inflation in test statistics reflected polygenicity [2]. The signal was concentrated in conserved regions (P=8.49×10⁻¹⁰), central nervous system regulatory elements (2.44-fold enrichment) and 2,932 constrained genes (P=2.6×10⁻⁴) [2]. Replication in deCODE (Iceland), 23andMe (self-report) and population symptom scales (EAGLE/QIMR, 17,666 children younger than 13 years and 2,798 adolescents) showed 72–82% concordance in direction of effect; the genetic correlation (rg) with population scales was 0.970, not different from 1, and with 23andMe was 0.653 [2].

Source: Demontis et al., 2019 [2].

Annotation of these loci pointed to genes involved in neural development: FOXP2 participates in synapse formation and speech and language acquisition (comorbidity between ADHD and specific language or learning disorders is 7–11%); SORCS3 encodes a transmembrane receptor involved in plasticity and is associated with depression; DUSP6 is a phosphatase regulating synaptic dopamine; SEMA6D is also associated with educational attainment; the chromosome 1 locus includes ST3GAL3, whose missense variants cause autosomal recessive ID, and PTPRF; and the chromosome 5 locus includes LINC00461, TMEM161B and MEF2C-AS1, near MEF2C, associated with severe ID [2]. Several of these genes have their own Mendelian disorders (FOXP2-related speech and language disorder, MEF2C haploinsufficiency syndrome, ST3GAL3-related epileptic encephalopathy and recessive ID, DUSP6-related hypogonadotrophic hypogonadism), but no GeneGuidance curation associates them with ADHD, and the GWAS signal reflects common regulatory variants of small effect [37].

The 2023 GWAS expanded the sample to 38,691 cases and 186,843 controls of European ancestry (effective sample size 51,568): iPSYCH (25,895 cases and 37,148 controls), deCODE (8,281 and 137,993) and 10 PGC cohorts (4,515 and 11,702) [5]. It identified 27 genome-wide significant loci, 21 of them new, with 32 independent lead variants and 76 plausible risk genes, enriched in genes expressed during early brain development (post-conception week 19; P=0.0008) [5]. The strongest signals (P <5×10⁻¹⁴) are on chromosome 1 (PTPRF), chromosome 5 (downstream of MEF2C) and chromosome 11 (downstream of METTL15, new); six of the 12 loci from 2019 replicated at genome-wide significance and the remainder at P <8×10⁻⁴ [5]. h²SNP fell to 0.14 (SE 0.01): 0.23 in iPSYCH, 0.12 in PGC and 0.08 in deCODE, differences attributed to ascertainment and diagnostic heterogeneity in PGC cohorts and the smaller effective size of the Icelandic population; there was no difference between sexes, and the genetic correlation between cohorts was 0.82–0.93 [5].

Source: Demontis et al., 2023, table 1 (hg19 coordinates; OR per A1 allele) [5].

Transcriptome-wide association analysis (TWAS), using 924 dorsolateral prefrontal cortex samples from PsychENCODE, pointed to 23 genes, led by B4GALT2 (lower predicted expression in cases; P=7×10⁻¹¹) and PPP1R16A (P=1.4×10⁻⁸); gene-based analysis (MAGMA) identified 45 significant genes and enrichment in genes expressed in the brain, particularly the frontal cortex, in excitatory and inhibitory neurons and midbrain dopaminergic neurons (P=0.005) [5]. PTPRF, SORCS3 and DCC belong to the postsynaptic density, and FOXP1 (new) and FOXP2 are transcription factors whose rare penetrant variants cause speech disorders and ID [5]. MiXeR modelling estimates that approximately 7,300 common variants (standard deviation 324) explain 90% of ADHD h²SNP, fewer than in schizophrenia (9,600), depression (11,700), ASD (10,300) or bipolar disorder (8,600); between 84% and 98% of these variants are shared with other psychiatric disorders, and 79% overlap variants associated with lower educational attainment [5].

The 2023 GWAS found 56 significant genetic correlations, including educational attainment (rg −0.55), body mass index (0.27), smoking initiation (0.48), insomnia (0.46), age at first childbirth (−0.65), ASD (0.42), schizophrenia (0.17), major depression (0.31), cannabis use disorder (0.61) and poor self-rated health in UK Biobank (0.60) [5]. The 2019 study had already described correlations with intelligence (−0.41), childhood obesity (0.22), type 2 diabetes (0.18), lung cancer (0.39) and number of children (0.42) [2]. The 2023 authors note that the model distinguishing ADHD from ASD has limited support and should be interpreted cautiously [5].

The meta-analysis by van der Laan and colleagues, published online in September 2025, included 290,134 ADHD symptom measurements in 70,953 individuals, with multiple raters, ages and instruments; alone, it found no genome-wide significant variants, but, combined with the diagnostic GWAS, it identified 39 independent loci, 17 new, and 22 potential effector genes [6]. The polygenic score derived from the combined analysis outperformed symptom-only or diagnosis-only scores in three cohorts, reinforcing the interpretation of clinical ADHD as the extreme of a continuous liability indexed by symptoms [6].

2.4. Polygenic scores

A polygenic score (PGS, also termed a polygenic risk score) sums the effects of thousands of common alleles weighted by GWAS coefficients. In iPSYCH, the PGS was consistently higher in cases, with a dose–response relationship by decile, a mean maximum Nagelkerke R² of 5.5% in cross-validation and an OR of 1.56 (95% CI 1.53–1.60) per standard deviation [2]. In the Philadelphia Neurodevelopmental Cohort (4,973 individuals of European ancestry, aged 8–21 years), the PGS was negatively associated with seven cognitive measures, including the Wide Range Achievement Test 4 as a proxy for IQ (β −0.09; P=1.09×10⁻¹⁰), attention (β −0.08) and working memory (β −0.05) [5]. The ADHD PGS predicts symptoms in the population and diagnoses of ADHD, anxiety and depression, and is associated with general psychopathology, limiting its specificity [1, 38].

In a study of 150 children with ADHD without ASD or ID and 370 Boston controls, five PGS methods produced highly variable effects (the 12-variant PGS from 2019 had no relevant effect and PGS002746 from the PGS Catalog was not significant), and the PGS varied markedly with ancestry, with between-ancestry effect sizes of up to −1.65, precluding comparison between populations [38]. The authors concluded that PGS measurement lacks sufficient reliability or validity for use alone in clinical practice [38]. In a Danish cohort, the PGS identified more people at a risk of ADHD comparable to that of recurrent CNV carriers than CNVs themselves: between 19.9% and 42.4% of the population had PGS-related risk equal to or above that of carrier groups [26]. These results describe risk stratification in populations, not individual prediction.

2.5. Copy number variants

The foundational study by Williams and colleagues (2010) compared 410 white British children aged 5 to 17 years with ADHD or hyperkinetic disorder, without schizophrenia or autism, recruited from child psychiatry and community paediatric clinics, with 1,156 controls from the 1958 British birth cohort; the final analysis included 366 cases and 1,047 controls [10]. Large (>500 kb), rare (<1%) CNVs were more frequent in cases (0.156 versus 0.075 per individual; P=8.9×10⁻⁵), with a much higher rate in children with ID (0.424; P=2.0×10⁻⁶) and an excess also in those without ID (0.125; P=0.0077) [10]. There was an excess of 16p13.11 duplications (P=0.0008 after correction), replicated in 825 Icelandic cases compared with 35,243 controls (P=0.031); CNVs in cases overlapped loci already implicated in autism (P=0.0095) and schizophrenia (P=0.010) [10]. The review by Faraone and Larsson adds that large, rare CNVs have ORs above 1 in almost all studies, with enrichment in duplications, and cites the implication of PARK2 (PRKN) in 489 cases and 1,285 controls, CHRNA7 (15q13.3) duplications replicated in cohorts from the United Kingdom, United States, Canada and Italy, a 3 Mb 7p15.2–15.3 duplication including NPY in 99 children with severe ADHD, and CNVs in metabotropic glutamate receptor genes [4]. SHANK genes are implicated through rare CNVs in several neurodevelopmental disorders, including schizophrenia, ADHD and ID, suggesting common pathways with distinct phenotypes [39].

Gudmundsson and colleagues (2019) assessed 19 neuropsychiatric CNVs in 7,890 cases and 155,519 controls from Iceland and Norway; 14 were sufficiently frequent (>0.018%) for individual testing and 8 were associated with ADHD [9]. Overall, 2.15% of cases and 0.86% of controls were carriers (OR 2.43; 95% CI 2.05–2.87; P=1.6×10⁻²¹), with ORs of 2.30 in Iceland and 2.66 in Norway; the association remained after excluding cases with ASD or schizophrenia [9]. Six CNVs had no previous association with ADHD: 2p16.3 (NRXN1), distal 16p11.2, 16p12.1 and 17p12 deletions and 17q12 and 22q11.21 duplications [9]. In Iceland, some cases were identified through prescriptions for psychostimulants or atomoxetine, and CNV-associated risk was higher in diagnosed cases, who were younger, than in the medication-identified group [9]. Individually, these CNVs are rare, with population frequencies from 0.0027% to 0.25% [9].

Source: Gudmundsson et al., 2019, table 1 (Iceland and Norway; 7,890 cases and 155,519 controls; FDR, false discovery rate) [9].

Case–control studies overestimate risk through selection bias. In the iPSYCH2015 case-cohort study (people born in Denmark between 1981 and 2008 and followed until 2015; 92,531 hospital cases and a random subcohort of 50,625 people; ages 7.0 to 34.7 years), Vaez and colleagues studied 3,547 recurrent CNVs (rCNVs) at 27 autosomal loci [11]. Increases in ADHD risk were modest, with hazard ratios (HRs) from 1.4 (15q11.2) to 4.2 (17q12 deletion; 95% CI 1.2–13.9), and HRs above 1.5 in 21 of the 32 rCNVs tested; ADHD risk associated with the 22q11.2 deletion was significantly lower than in the largest case–control study, and seven rCNVs showed increased risk not previously detected [11]. Risks correlated across disorders (ADHD–ASD r=0.68; ADHD–schizophrenia r=0.75) and were proportional to locus size and gene constraint, rather than dosage type, deletion or duplication [11]. The GeneReviews chapter on 17q12 deletion cites the same population-based study with an HR of 4.24 (95% CI 1.29–13.92) for ADHD [40].

The follow-up study by the same group (JAMA Psychiatry, 2026) analysed 94,276 unrelated people of European ancestry from iPSYCH2015 (mean age at the end of follow-up 21.9 years; 53.7% male) and grouped the 27 rCNVs by impact, according to the sum of the inverse LOEUF of included genes: low (<10), moderate (10–25) and high (>25), with population frequencies of 1.4%, 0.55% and 0.35% [26]. Absolute ADHD risk at the end of follow-up increased from 3.0% in non-carriers to 6.3% in carriers of high-impact rCNVs (β per impact group 0.29; 95% CI 0.23–0.35) and from 2.1% in the lowest to 4.5% in the highest PGS quintile (β 0.28; 0.26–0.30) [26]. Effects were additive, without significant interaction overall, apart from a negative interaction between the 16p13.11 duplication and PGS (β −0.51; −0.86 to −0.16; P=0.006) [26]. Diagnoses were hospital-based, the cohort was young and exclusively of European ancestry; the authors suggest incorporating rCNV analysis into screening of high-risk populations as a research avenue, which does not constitute a recommendation for population screening [26].

2.6. Rare coding variants and de novo variants

Satterstrom and colleagues (2019) sequenced the exomes of approximately 8,000 children with ASD and/or ADHD and 5,000 iPSYCH controls and found a similar burden of rare protein-truncating variants (PTVs) in constrained genes in both disorders, both above controls; the combined analysis identified MAP1A as an exome-wide significant gene for childhood psychiatric disorders [25]. The study by Demontis and colleagues published in Nature (online on 12 November 2025; 2026 volume) doubled the sample: 8,895 Danish cases and 9,001 controls, also compared with 44,779 non-Finnish European individuals from gnomAD without a psychiatric diagnosis [7]. Among cases, 18.4% had ID, and analyses were repeated with and without this subgroup [7].

The burden of rare PTVs was increased across all genes (OR 1.06; 95% CI 1.04–1.08) and particularly in the 2,811 constrained genes with pLI ≥0.9 (OR 1.35; 1.26–1.45; P=1.52×10⁻¹⁷); severely deleterious missense variants (MPC >3) had an OR of 1.29 (1.09–1.54) and moderate missense variants (MPC 2–3) an OR of 1.11 (1.07–1.16), without an excess of synonymous variants [7]. Class I variants (PTVs and severely deleterious missense variants) in constrained genes were present in approximately 1 in every 5 people with ADHD, meaning that highly deleterious variants do not contribute to risk in most people; there was no sex difference in burden [7]. With 8,895 cases and 53,780 controls and an exome-wide threshold of P <3.07×10⁻⁶, three genes reached significance: MAP1A (P=1.02×10⁻⁶; OR 13.31), ANO8 (P=1.90×10⁻⁶; OR 15.31) and ANK2 (P=2.72×10⁻⁶; OR 5.55); MAP1A and ANO8 through PTVs alone, ANK2 through PTVs and moderate missense variants [7]. Of the top 20 genes, 16 are constrained and 9 were already implicated in ASD or developmental disorders; KDM5B had an OR of 2.93 (P=1.23×10⁻³), without exome-wide significance [7]. In a German clinical sample of persistent ADHD (1,078 cases and 1,738 controls), the class I burden in constrained genes replicated (OR 1.24; 1.07–1.45), without power for individual genes and without deleterious ANO8 variants [7]. No X chromosome gene was significant after correction [7].

Burden heritability, on the liability scale with a prevalence of 5%, was 2.5% (SE 0.7%) for class I variants and 0.1% for class II, and 1.43% for class I when ID was excluded, values comparable to schizophrenia (1.7%) and bipolar disorder (1.8%); the three genes explain 5.2% of class I burden heritability, indicating that many rare risk genes remain to be identified [7]. Approximately 50% of the MAP1A signal came from people with ADHD without schizophrenia, ID or ASD, and approximately 30% of the ANO8 signal; the ANK2 signal, a known autism risk gene, came predominantly from people with ASD or ID [7]. The class I and II burden in constrained genes was higher in ADHD with ID (n=1,654) than in ADHD without ID, which remained above controls; the C-alpha test showed no difference in the distribution of affected genes between ADHD without ASD (n=5,536) and ASD without ADHD (n=7,554), indicating substantial sharing of rare risk genes [7].

Rare and common variants add their effects. In people without class I variants, the PGS was associated with risk (OR for highest versus lowest quintile 6.52); with one or more class I variants, risk was higher in almost all quintiles, in a parallel pattern, and having at least one class I variant was equivalent to an approximately 20% increase in polygenic burden [7]. In the Boston genomic study, children with ADHD without an explanatory rare variant had a higher PGS than controls (d=0.36), and those with a rare variant had a PGS similar to controls (d=−0.036), which the authors interpret as distinct aetiological pathways to the same phenotype (equifinality) [38].

Olfson and colleagues (2024) sequenced the exomes of 152 trios with a child with ADHD; after quality control, they compared 147 trios with 780 control trios from the Simons Simplex Collection [8]. The rate of deleterious de novo variants (PTVs and missense variants with MPC >2) was higher in cases: rate ratio 1.67 (95% CI 1.08–2.53) for rare variants and 1.93 (1.24–2.97) for ultra-rare variants, without a difference in total de novo variants [8]. Twenty-four ultra-rare deleterious de novo variants occurred in 23 of the 147 probands (approximately 16%), against 51 in 50 of the 780 controls; KDM5B had two de novo PTVs in unrelated individuals and, combined with a case–control sample of 3,206 cases and 5,002 controls, became a high-confidence risk gene (FDR 0.04) [8]. KDM5B carriers had neither ASD nor ID; six of the 23 affected genes (FBXO11, KDM5B, STAG1, CTNNA2, EML6, PAK1) are risk genes for ASD or developmental delay, and the authors estimate that 1,057 genes (95% CI 219–2,791) contribute to ADHD risk [8].

2.7. Mechanisms and biology

The catecholaminergic hypothesis, supported by the efficacy of stimulants that inhibit DAT and the noradrenaline transporter, was the first pathophysiological model [7, 33]. Genomic data broaden it without confirming it as the sole core mechanism: GWAS loci do not overlap catecholaminergic candidate genes, and the review by Faraone and Larsson concludes that these results challenge the idea that the pathophysiological core is catecholaminergic, proposing the omnigenic model as a hypothesis [2, 4]. Common-variant genes are concentrated in prenatal expression and central nervous system regulatory elements, whereas rare risk genes are highly expressed in 11 of 12 stages of cortical development, from the prenatal period to adulthood (MAP1A more postnatally, ANO8 more prenatally) [5, 7].

Interactomes obtained by immunoprecipitation and mass spectrometry in neural progenitors and excitatory neurons derived from induced pluripotent stem cells (iPSCs) included 184 interactors for MAP1A, 35 for ANO8 and 158 for ANK2, enriched in rare risk genes for ASD and developmental disorders and without enrichment in common-variant genes [7]. Associated functions are binding to RNA and ribosomal proteins (MAP1A, which participates in microtubule assembly and whose sister gene MAP1B causes ID, autism and white matter deficits), cell junctions and synapses (ANO8), and the actin cytoskeleton (ANK2); ANK2 and ANO8 participate in membrane calcium transport, leading the authors to hypothesise a synaptic channelopathy [7]. Single-cell expression analysis associated rare risk genes with fetal midbrain dopaminergic neurons (P=9.99×10⁻⁴), GABAergic neurons and medial neuroblasts, with replication in iPSC-derived dopaminergic neurons from 215 donors [7]. Convergence with the GWAS, which also implicated midbrain dopaminergic neurons, suggests that the dopaminergic system contributes to risk, but as part of a broader network of cortical and synaptic development [5, 7].

Environmental factors associated with ADHD act predominantly during the fetal and early postnatal periods, and WFADHD calls them “correlates”, because many may reflect genetic confounding: the association with maternal smoking during pregnancy, exceeding 50%, disappears after adjustment for family history [1]. Prenatal valproate exposure was associated with an approximately 50% increase (913,000 Danish children, without an association for other antiepileptics), prematurity or very low birth weight with approximately 3 times the risk, with a gradient not explained by familial factors in 1.2 million Swedes, and high lead levels with an OR of approximately 4 [1]. Other reported associations include passive smoking (+60%), paracetamol in pregnancy (+33% in Taiwan, with a dose–response relationship in the Norwegian MoBa cohort), maternal phthalates (3-fold in the highest quintile, Norway), organophosphates, hypertension in pregnancy (+25%), pre-eclampsia (+15%), maternal obesity (approximately +60%), maternal vitamin D deficiency (+50%, Finland), previous miscarriages and deprivation or adversity, including out-of-home placement; air pollution findings are inconsistent and food colourings show a small increase, reported only by parents [1]. Maternal fever between weeks 9 and 12 of pregnancy was associated with increased ADHD in the study by Dreier and colleagues (2016), and the risk of autism associated with fever was lower with antipyretics [41].

2.8. Allelic disorders and normalisation of cited variants

Several genes implicated in ADHD have their own Mendelian disorders, which are not equivalent to ADHD. Biallelic SLC6A3 variants cause DTDS, and the atypical late-onset form begins with ADHD in childhood [35]; FOXP2, MEF2C and ST3GAL3 cause, respectively, speech and language disorder, MEF2C haploinsufficiency syndrome, and epileptic encephalopathy or recessive ID [37]; KDM5B is described in ID and developmental delay with frequently recessive inheritance, and heterozygous variants occur in developmental delay and ASD cohorts, suggesting pleiotropy and a dosage effect [8]. For DRD4, conversely, no Mendelian disease is established [12].

The variants cited in this article were normalised using VariantValidator (GRCh38, MANE Select transcripts) [42].

In the Boston study, the two variants found in controls were described by the authors as PLCB1 NM_015192.4:c.1250+1G>A and KCNQ5 NM_001160132.2:c.1277+2T>C (ClinVar 3019100) [38]. CYP2D6 alleles follow PharmVar star allele nomenclature and are not converted into HGVS (section 7.5) [17].

3. Clinical Spectrum and Manifestations by System

3.1. Symptom dimensions and presentations

ADHD is defined by symptoms of inattention and/or hyperactivity-impulsivity inappropriate to development, present for at least 6 months, in different settings, beginning in early or middle childhood and causing functional impairment, without another disorder better explaining them [1]. DSM-5 presentations (predominantly inattentive, predominantly hyperactive-impulsive and combined) describe the current symptom profile and may change over time [3]. Inattention is predominantly associated with academic impairment; hyperactivity-impulsivity is associated with peer rejection, aggression, risky driving and injuries [1]. Diagnosis is possible in people with high IQ, as shown in a cohort of more than 5,700 individuals [1].

3.2. Natural history by age

At preschool age, assessment is more difficult, and the 2019 American Academy of Pediatrics (AAP) guideline considers the evidence insufficient to diagnose and treat below 4 years of age [3]. At school age, the median age at diagnosis in the United States is 7 years, approximately one third are diagnosed before 6 years and more than half are initially diagnosed by a primary care clinician [3]. Hyperactivity-impulsivity symptoms decrease during adolescence, whereas inattention tends to persist [3]. Two thirds of young people retain disabling symptoms in adulthood [4, 5]; however, only approximately 1 in every 6 still meets all criteria at 25 years, and approximately half have residual impairment [1]. In adulthood and old age, the 2019 European consensus describes ADHD as frequently persistent, underdiagnosed and undertreated in many European countries [47].

3.3. Comorbidities and outcomes

Most children with ADHD, of both sexes, have another mental disorder; boys have more externalising disorders and girls more anxiety and depression [3]. Between 12% and 16% of people with ADHD have ASD and approximately 40% have depression, according to the studies cited in the 2023 GWAS [5], and specific language or learning disorders occur in 7–11% [2]. Other comorbidities to consider are oppositional defiant disorder, conduct disorder, substance use disorders, eating disorders, tics, sleep apnoea and epilepsy [1, 3]. In the British ALSPAC cohort (Avon, births in 1991–1992), ADHD diagnosed between 7 and 15 years was associated with not obtaining the GCSE secondary school leaving qualification (OR 4.97; 95% CI 2.51–9.83), depression at 24 years (OR 2.75), functional impairment (OR 3.34), not being in employment, education or training at 25 years (OR 5.70; 3.24–10.02) and receipt of welfare benefits (OR 2.86) [48]. In the Danish exome cohort, rare PTVs in constrained genes were associated, in people with ADHD, with completing only primary education (OR 1.24) and low socioeconomic status (OR 1.28); in a German clinical sample of adults (n=962), each ultra-rare class I variant in constrained genes was associated with 2.25 fewer IQ points [7].

3.4. ADHD in genetic, chromosomal and CNV-related syndromes

The review by Faraone and Larsson highlights the high frequency of ADHD in velocardiofacial syndrome (22q11.2), fragile X syndrome, Turner syndrome, tuberous sclerosis complex, neurofibromatosis, Klinefelter syndrome and Williams syndrome [4]. The following table brings together frequencies reported in GeneReviews chapters and reference textbooks. They come from ascertained clinical series with heterogeneous sizes and methods (parent surveys or DSM criteria), and are not comparable with one another or with population prevalence.

Other genes with documented ADHD in GeneReviews chapters are CSNK2A1 (Okur-Chung syndrome; approximately one fifth), MTOR (Smith-Kingsmore syndrome; 22%), HNRNPH2 (approximately 15%), GRIN2A (6/70), PUF60 (25%), SYNCRIP (25%), NR4A2 (8/24), GNB5 (3/5, with language delay and normal IQ), WAC (30–40%, with anxiety), KMT2B (7–10%), YY1 (Gabriele-de Vries syndrome; behavioural problems in 5/9) and TRIO (inattention in 79%, 22/28), as well as Xia-Gibbs syndrome, microcephalic osteodysplastic primordial dwarfism type II, CNOT1, Primrose syndrome and FOXP2-related speech and language disorder [103–119]. In spinocerebellar ataxia type 14, a French family had cognitive, attention and executive deficits in 13 of 18 members (72%) [120], and in hypokalaemic periodic paralysis without an identified variant, attention deficit disorder is among frequent findings [121]. In a boy with a de novo KCNC1 variant and epilepsy, ADHD persisted despite complete seizure control (section 10) [44].

3.5. ADHD in inherited metabolic diseases

Metabolic diseases merit particular attention because some are treatable and others are progressive.

Atypical late-onset DTDS exemplifies ADHD as the first manifestation of a monogenic neurological disease. By 2023, five individuals had been described, four with biallelic loss-of-function variants and one with a heterozygous dominant-negative SLC6A3 variant; they acquired walking and language, had ADHD manifestations in childhood and, in late childhood, adolescence or adulthood (up to the fourth decade), developed parkinsonism-dystonia with resting and action tremor, progressive bradykinesia, dysarthria, variable tone and dystonic posturing; the long-term prognosis is unknown [35]. Children with classic DTDS have lower residual transporter activity than those with the atypical form, and cerebrospinal fluid homovanillic acid is elevated [34, 35]. DTDS is ultra-rare, with fewer than 60 identified individuals [35].

4. Clinical Recognition and Red Flags

4.1. When to suspect ADHD

The AAP recommends that primary care clinicians initiate an ADHD assessment in any child or adolescent aged 4 to 18 years with academic or behavioural problems and symptoms of inattention, hyperactivity or impulsivity (grade B, strong recommendation) [3]. NICE identifies groups with increased prevalence, in whom the threshold for suspicion should be lower: those born prematurely; children in institutional or foster care; oppositional defiant or conduct disorder; mood disorders; a close relative with ADHD; epilepsy; other neurodevelopmental disorders (ASD, tics, ID, specific learning difficulties); adults with mental illness; substance misuse; people in the criminal justice system; and acquired brain injury [14]. NICE emphasises that ADHD is under-recognised in girls and women, who are less often referred, more often underdiagnosed and more often misdiagnosed, and advises against universal screening in schools [14]. In children with problems causing mild impairment, NICE allows watchful waiting for up to 10 weeks and ADHD-focused group parental support before diagnosis; if at least moderate impairment persists, the child is referred to secondary care, while severe impairment warrants direct referral [14]. Adults without a childhood diagnosis are referred to a specialist when symptoms began in childhood, persist, are not explained by another diagnosis and cause moderate or severe impairment [14].

Relative age matters: the youngest children in a class are diagnosed more often, an effect documented in 25 studies with more than 8 million participants, and repeating a school year generally brings no benefit [1, 3].

4.2. Signs suggesting an identifiable genetic or metabolic cause

Most people with ADHD do not have an identifiable monogenic or chromosomal cause, and WFADHD considers that rare causes help elucidate aetiology but do not serve to diagnose the disorder [1]. Some signs, however, shift the probability towards an identifiable cause and justify medical genetics assessment:

4.3. Emergency warning signs

Some situations require prompt action. Loss of academic, motor or language skills in a child with recent ADHD departs from the course of ADHD and requires neurological and metabolic investigation, because cerebral adrenoleukodystrophy progresses within a few years [29, 129]. Suicidal ideation requires immediate assessment: the meta-analysis cited by WFADHD shows suicide attempts to be 2 times and completed suicide more than 6 times as frequent in ADHD, and atomoxetine and centanafadine have boxed warnings for suicidal thoughts and behaviours in paediatric patients [1, 16, 19]. An acute psychotic or manic episode requires stopping ADHD medication [14], and in CNVs carrying psychosis risk, such as 3q29 deletion or 22q11.2 deletion, surveillance for psychotic symptoms forms part of follow-up [54, 59]. Exertional syncope, sudden-onset palpitations and a family history of sudden death before 40 years require cardiology advice before starting or continuing medication [14].

4.4. Newborn screening

There is no newborn screening for ADHD. In metabolic diseases associated with ADHD, early treatment does not completely eliminate the behavioural phenotype: children with phenylketonuria treated from the neonatal period retain hyperactivity, mannerisms and anxiety, and in maple syrup urine disease managed with diet the cumulative incidence of ADHD exceeds 50% [122, 125].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

The diagnosis of ADHD is clinical. NICE requires it to be made by a specialist (psychiatrist, paediatrician or other trained professional), with a full clinical and psychosocial assessment, developmental and psychiatric history, observer reports and mental state examination; criteria are those of DSM-5 or ICD-11, with at least moderate impairment in two or more settings, without excluding the diagnosis because of ASD or uncertainty about age at onset [14]. Rating scales, such as Conners or the Strengths and Difficulties Questionnaire, are adjuncts and are insufficient for diagnosis; since 2024, NICE has accepted QbTest as an option from 6 to 17 years [14]. The AAP recommends DSM-5 criteria, with symptoms and impairment in more than one setting, information from parents, teachers and others and exclusion of alternative causes (grade B, strong), and states that neuropsychological tests do not improve diagnostic accuracy in most cases [3]. In preschool children, it recommends interview, observation and scales completed by parents and educators, and parent training in behaviour management (PTBM) before assigning the diagnosis; in adolescents, information from at least two teachers or other sources and manifestations before 12 years [3]. WFADHD reiterates that diagnosis is not made by scales, neuropsychological tests or imaging, and that comorbidities do not exclude it [1].

Assessment includes needs, comorbidities, social and educational circumstances and physical health; in children, parental mental health is also assessed [14]. The AAP recommends screening at least for emotional and behavioural comorbidities (anxiety, depression, oppositional defiant disorder, conduct disorder, substance use), developmental comorbidities (learning, language, ASD) and physical comorbidities (tics, sleep apnoea), including seizures, developmental coordination disorder and sleep disorders (grade B, strong) [3]. An AAP note is particularly relevant to syndromic forms: DSM-5 does not require symptoms to exceed expectations for developmental age, only chronological age, which may lead to diagnostic errors in children with developmental disorders [3]. In children with ID, inattention and hyperactivity should be judged against mental age, as proposed by the autism differential diagnosis framework in SGRT [136]. The AAP refers more complex cases to the 2020 Society for Developmental and Behavioral Pediatrics (SDBP) guideline on “complex ADHD”, defined by age (under 4 years or presentation after 12), comorbidities, moderate to severe functional impairment, diagnostic uncertainty or inadequate treatment response, which recommends integrated, interprofessional assessment and treatment [3, 137]. Syndromic ADHD frequently meets these criteria.

5.2. Genetic aetiological investigation: indications

None of the clinical ADHD guidelines consulted recommends genetic testing. NICE NG87 does not mention karyotyping, microarray or exome sequencing, and the 2019 AAP guideline does not mention microarray or fragile X testing [3, 14]. WFADHD states that rare monogenic and chromosomal causes help elucidate ADHD causes but are not useful for diagnosing it [1]. Indications therefore derive from guidelines on ID and congenital anomalies: the 2021 American College of Medical Genetics and Genomics (ACMG) guideline, developed using GRADE methodology, strongly recommends considering exome or genome sequencing as a first- or second-line test in paediatric patients with congenital anomalies beginning before 1 year or developmental delay or ID beginning before 18 years [15]. This guideline does not include isolated ADHD. The ALSPAC authors summarise British guidance for psychiatrists: routine genetic testing in ID, but not in ADHD or ASD, except with comorbidities, dysmorphism or an unusual medical presentation [48].

5.3. Test yield in ADHD

Data on diagnostic yield in ADHD without ID are scarce. In the Boston genomic study (40× genome sequencing, 150 children aged 4 to 17 years with ADHD without ASD or ID and 370 controls), rare variants potentially explaining ADHD were found in 13% (19/150): 7% (11/150) likely pathogenic, 4% (6/150) loss-of-function variants in neurodevelopmental genes with a less established association and 1% (2/150) potentially deleterious missense variants [38]. In controls, the article abstract reports 2 of 370 (0.5%), whereas the results text gives 2% and a relative risk of 26, an internal inconsistency in the article itself; the curated set includes variants of uncertain significance (VUS) and is not equivalent to clinical diagnostic yield [38]. Variants were concentrated in genes for histone modification (P=0.03) and histone H3 methyltransferase activity (P=0.013) [38]. These figures come from a small research study and do not establish a diagnostic rate applicable to clinical practice.

5.4. Test limitations

No genetic test establishes or excludes the diagnosis of ADHD. Candidate gene genotypes, such as the 7-repeat DRD4 allele, have no individual diagnostic or predictive value [12]. The PGS explains approximately 5.5% of variance, varies with ancestry and lacks sufficient reliability or validity for standalone clinical use [2, 38]. Exome sequencing detects coding and splice-junction variants, but its sensitivity for small CNVs, deep intronic variants, repeat expansions (such as FMR1) and low-level mosaicism is limited; a negative result does not exclude a genetic cause, and the trio study by Olfson and colleagues analysed only the coding region [8]. In multigene panels, included genes and sensitivity vary between laboratories [35]. CYP2D6 tests do not detect rare or de novo variants, and untested alleles are reported as *1 by default [17].

5.5. Variant interpretation in a polygenic trait

Rare variants found in people with ADHD require cautious interpretation. CNV penetrance for ADHD is incomplete (absolute risk of 6.3% in high-impact rCNV carriers, against 3.0% in non-carriers) [26]; class I variants in constrained genes are present in approximately 1 in every 5 people with ADHD and also in controls [7]; and families with rare functional variants show incomplete segregation, as with SORCS2 c.2104C>T, whose carriers include a person without a diagnosis (section 10) [43]. Such a variant should be described as a risk factor or VUS, rather than a Mendelian cause of ADHD, except when part of a well-established syndrome. The report should state the gene, versioned transcript (preferably MANE Select), DNA- and protein-level HGVS nomenclature, zygosity, origin (de novo or inherited, when known) and classification according to ACMG and Association for Molecular Pathology (ACMG/AMP) criteria, with the associated disease [42, 44]. Classification of de novo variants as likely pathogenic predominantly on criterion PS2, when in silico predictors disagree, warrants caution, as in the KCNC1 case described in section 10 [44]. In CNV carriers, parental assessment sometimes reveals undiagnosed disorders: in 3q29 deletion, a transmitting parent assessed with a comprehensive protocol had schizoaffective disorder, ADHD, panic disorder, social anxiety, executive deficits and adaptive delays, all previously unknown [59].

5.6. Practical algorithm

The diagnostic pathway begins with clinical confirmation of ADHD according to DSM-5 or ICD-11, with information from several settings and comorbidity screening [3, 14]. This is followed by a systematic search for red flags for an identifiable cause (ID, global delay, dysmorphism, congenital anomalies, epilepsy, ASD, loss of skills, neurological signs, café-au-lait macules, relevant prenatal exposure) (section 4.2). Without these signs, genetic testing is not recommended and counselling rests on empirical risks (section 8). When they are present, testing is chosen according to guidance for the associated condition: exome or genome sequencing in ID or congenital anomalies, targeted testing when the syndrome is recognisable, metabolic and neurological investigation with regression [15, 29]. CYP2D6 genotyping may be considered when atomoxetine is planned or being used [18, 19].

5.7. Prenatal and preimplantation diagnosis

There is no prenatal or preimplantation diagnosis for polygenic ADHD; the PGS is not valid for individual prediction and varies with ancestry [26, 38]. In syndromic forms with a known familial variant or CNV, prenatal and preimplantation options are those of the underlying syndrome; for incompletely penetrant CNVs, counselling should explain that detecting the CNV does not predict the phenotype [11, 26].

6. Differential Diagnosis

The differential diagnosis of ADHD has two levels: conditions mimicking or coexisting with symptoms, and genetic, metabolic and environmental causes of ADHD-like symptoms. The AAP lists substance use (cannabis can mimic ADHD), depression, anxiety, trauma and post-traumatic stress disorder, learning and language difficulties, ASD, tics, sleep apnoea, seizures, developmental coordination disorder and sleep disorders as mimics or comorbidities to screen for, as well as malingering to obtain stimulants in adolescents [3]. WFADHD adds that, rarely, ADHD-like symptoms result from extreme early deprivation, early traumatic brain injury or a single genetic abnormality [1].

Distinguishing ADHD from ASD is the most difficult task, because the two disorders share common variants (rg 0.42) and rare risk genes, and frequently coexist [5, 7]. Current guidelines allow simultaneous diagnosis, and NICE explicitly states that ASD does not exclude ADHD [14]. In children with ID, the relevant question is whether inattention and hyperactivity exceed expectations for mental age, because DSM-5 does not require this comparison [3, 136]. Cerebral adrenoleukodystrophy is the differential with the greatest consequences, because an initial ADHD-like presentation, sometimes responding to stimulants, can delay diagnosis of a progressive disease [29, 129]. Prenatal exposures act as phenocopies: in utero exposure to antiepileptics was associated with an approximately 4-fold higher risk of neurodevelopmental disorders, including ADHD and autism, and in the Cochrane review cited by the Oxford Desk Reference, IQ was lower in the valproate-exposed group, with greater risk above 800 mg/day, without a difference for carbamazepine [134]. A relationship between temporal lobe arachnoid cysts and ADHD has been described, and bilateral temporal cysts should prompt investigation for glutaric aciduria type 1 [133].

7. Treatments and Risk Management Strategies

7.1. General principles

Knowledge of ADHD genetic architecture has not yet produced treatments directed at the cause, and treatment of polygenic ADHD, ADHD associated with rare variants and syndromic ADHD rests on the same interventions, with adjustments dictated by the underlying syndrome (section 7.8). The AAP recommends managing ADHD as a chronic disease, according to the medical home model, because people with ADHD, treated or untreated, have a higher risk of early death, suicide, psychiatric comorbidity (particularly substance use), lower educational attainment and incarceration, and treatment discontinuation is associated with road traffic accidents, criminality, depression and injuries (grade B, strong) [3]. NICE calls for a holistic, shared treatment plan considering severity, sleep, goals, resilience and comorbidities, discussing benefits and risks of pharmacological and non-pharmacological interventions, and including healthy lifestyle and exercise [14].

7.2. Non-pharmacological interventions

Below 5 years, NICE recommends an ADHD-focused group parent-training programme as first line; if significant impairment persists, it seeks advice from a specialist service, preferably tertiary, and does not recommend medication without a second specialist opinion [14]. From 4 years to the sixth birthday, the AAP recommends PTBM and/or classroom behavioural interventions as first line (grade A, strong) [3]. From 6 to 12 years, the AAP recommends combining medication with PTBM and/or classroom behavioural interventions, preferably both, and formal educational interventions (grade A, strong) [3]. In children aged 5 years or older, NICE recommends ADHD-focused information and parental support, parent training when there are oppositional or conduct symptoms, and cognitive behavioural therapy (CBT) for young people who have benefited from medication but retain impairment, focused on social skills, problem solving, self-control, active listening and expression of feelings [14]. In adults, NICE proposes non-pharmacological treatment when medication is declined, poorly tolerated or ineffective, or in combination, with at least a structured supportive psychological intervention focused on ADHD and regular follow-up, which may include CBT [14].

Regarding diet, NICE recommends a balanced diet and exercise, advises against general elimination of colourings and additives and does not recommend fatty acid supplements; when a food appears clearly associated with symptoms, it suggests a food diary and referral to a dietitian, and the few-food diet lacks long-term evidence [14]. The MTA (Multimodal Treatment Study of ADHD), cited by the AAP, did not show superiority of combined medication and behavioural treatment over medication alone for core symptoms, although a secondary analysis found an effect of d=0.28, with greater benefit in comorbid anxiety and low socioeconomic status, lower doses and greater satisfaction; at 36 months there were no between-group differences [3].

7.3. Pharmacological algorithms and divergence between guidelines

Sources: NICE NG87 [14]; AAP [3].

NICE recommends preferring once-daily modified-release stimulants for adherence, stigma, storage and diversion risk; immediate release serves titration and flexibility, and morning modified release may be combined with immediate release at another time; in patients at risk of misuse, immediate-release forms or forms easily injected or insufflated are avoided [14]. Titration involves recording symptoms, impairment and adverse effects at every change, according to the British National Formulary, and proceeds more slowly, with more frequent monitoring, in people with ASD, tics, ID, mental illnesses and physical illnesses such as heart disease, epilepsy or brain injury [14]. The AAP considers that mg/kg dosing is not useful and recommends weekly titration, or every 3 days in urgent situations [3]. With comorbid anxiety, tics or ASD, choices are the same; during an acute psychotic or manic episode, medication is stopped and may be restarted after resolution [14].

Expected efficacy differs between classes. Effect size is approximately 1.0 for stimulants and approximately 0.7 for non-stimulants [3]. Approximately 40% of children respond to both methylphenidate and amphetamines and approximately 40% to only one, without the clinical presentation predicting response; with titration through four doses, more than 70% respond to methylphenidate and more than 90% respond to a psychostimulant when both classes are tested [3]. In the network meta-analysis cited by WFADHD, amphetamines produced large improvements at all ages, methylphenidate large improvements in young people and moderate improvements in adults, extended-release guanfacine moderate improvements in children and atomoxetine moderate improvements at all ages [1]. Methylphenidate was effective in children with borderline intellectual functioning or ID (8 studies, 423 children), relevant to syndromic ADHD, and stimulants reduced anxiety by 14% compared with placebo, as well as aggression and opposition [1].

7.4. Drugs, label dosing and adverse effects

The following doses are those in the consulted labels: the US label (FDA) and, where available, the European summary of product characteristics (SmPC), centralised or Portuguese national (Concerta®, Elvanse®, generic atomoxetine), or the United Kingdom SmPC for dexamfetamine, which is not authorised in Portugal; where the labels diverge, both dosing schedules are given [139–142]. NICE refers titration to the national formulary [14]. In Brazil, the approved formulations and doses are set out in the national package inserts (bulas), which were not among the sources consulted.

Dexamfetamine and extended-release clonidine are mentioned in the guidelines (dexamfetamine in the NICE sequence; extended-release clonidine with sufficient but weaker evidence in the AAP and FDA approval as an adjunct), and the doses in the table are those of the US and British labels [3, 14, 142, 147, 148]. In NICE, dexamfetamine is licensed from 6 to 17 years when response to methylphenidate is inadequate, and indications at 5 years are off-label [14, 142]. The US label for Zenzedi® includes the 3- to 5-year age range, which falls outside the conditions of the European label.

Stimulant adverse effects include appetite loss, abdominal pain, headache and sleep disturbance [3]. In WFADHD, methylphenidate was associated with a 50% increase in abdominal pain and a decrease in appetite more than 3 times greater than placebo, and stimulants reduced total sleep time and delayed sleep onset [1]. In the MTA, growth velocity decreased, with a reduction of 1–2 cm in predicted adult height, especially with higher, consistent doses, attenuated by the third year but without catch-up; in WFADHD, mean height delay was approximately 2 cm over 1–2 years, sometimes attenuated or reversible [1, 3]. Heart rate increases by a mean of 1–2 beats per minute and blood pressure by 1–4 mmHg, with larger increases in 5–15% of patients; sudden death is extremely rare and no increase compared with untreated patients has been demonstrated [3]. In a Danish study of more than 700,000 people, stimulants were associated with more than twice as many cardiovascular events, mainly hypertension, which are rare; in a meta-analysis, methylphenidate did not increase death, myocardial infarction or stroke [1]. Hallucinations or psychotic symptoms rarely occur; however, in Hong Kong and Swedish studies, methylphenidate was not associated with psychosis, and psychosis incidence was 36% and 18% lower in the year after initiation [1, 3]. In preschool children, stimulants may cause mood lability and dysphoria [3]. All stimulant labels have boxed warnings for abuse, misuse and addiction, and non-medical use, particularly among university students and by non-oral routes, is a public health problem [1, 143, 144].

Atomoxetine increases heart rate and blood pressure, may cause initial somnolence and gastrointestinal symptoms, particularly with rapid titration, decreased appetite and, very rarely, hepatitis, and has an FDA boxed warning for suicidal ideation; growth delay in the first 1–2 years catches up at 2–3 years [3]. The label lists contraindications (monoamine oxidase inhibitors [MAOIs] within the preceding 14 days, narrow-angle glaucoma, phaeochromocytoma, severe cardiovascular disorders that would deteriorate with blood pressure increases of 15–20 mmHg or heart rate increases of 20 beats per minute) and warnings for severe liver injury, psychosis or mania, aggression, urinary retention and priapism [19]. In adults, atomoxetine was associated with 40% more discontinuations due to adverse effects [1]. Extended-release guanfacine and clonidine decrease heart rate and blood pressure and cause somnolence, dry mouth, dizziness, irritability, headache, bradycardia, hypotension and abdominal pain; withdrawal should be gradual to avoid rebound hypertension, and in the Intuniv® maintenance study, 7 of 158 patients (4.4%) had blood pressure above the 95th percentile after switching to placebo [3, 146]. Centanafadine has boxed warnings for suicidal ideation and behaviour in paediatric patients (suicide attempt in 0.7%, 2/304, versus 0/153 with placebo in the study of 6- to 12-year-olds; ideation in 0.8%, 5/620, in the open-label extension) and for abuse; the most frequent adverse effects were rash and decreased appetite in children, and headache, decreased appetite, insomnia, nausea, dry mouth and diarrhoea in adults; it contains tartrazine and is metabolised predominantly by monoamine oxidase A [16].

Before starting medication, NICE recommends confirming criteria, assessing mental and social health (including misuse or diversion risk), medical history and medication, recording height and weight on centiles, pulse and blood pressure with an appropriate cuff, and undertaking a cardiovascular assessment; an electrocardiogram (ECG) is not required before stimulants, atomoxetine or guanfacine unless specifically indicated or medication with cardiac risk is being taken [14]. Cardiology advice is sought for congenital heart disease or cardiac surgery, sudden death in a first-degree relative before 40 years suggestive of cardiac disease, disproportionate exertional dyspnoea, syncope on exertion or with fright or noise, rapid regular palpitations with sudden onset and offset, cardiac chest pain, signs of heart failure, murmur or hypertensive blood pressure; in a child with blood pressure persistently above the 95th percentile for age and height, referral is to paediatric hypertension services [14]. The AAP calls for additional assessment when there are cardiac symptoms, a family history of sudden death, Wolff-Parkinson-White syndrome, hypertrophic cardiomyopathy or long QT syndrome, and ECG and possible paediatric cardiology assessment when risk factors are present [3].

7.5. Pharmacogenetics

The only gene–drug interaction with guideline recommendations in ADHD is CYP2D6 with atomoxetine. CYP2D6 has more than 100 alleles catalogued in PharmVar: normal-function alleles (*1, *2, *35), decreased-function alleles (*9, *10, *17, *29, *41) and no-function alleles (*3 to *6, with *5 being the gene deletion), as well as duplications [17]. The activity score classifies phenotypes as poor metaboliser (0), intermediate (0.5), normal (1.0–2.0) and ultrarapid (>2); for atomoxetine, a score of 1.0 is classified by the Clinical Pharmacogenetics Implementation Consortium (CPIC) as normal or intermediate because of controversy [17]. Strong CYP2D6 inhibitors (bupropion, fluoxetine, paroxetine) convert the patient into a phenotypic poor metaboliser, for fluoxetine for up to 2–3 months after discontinuation [17].

In poor metabolisers, the atomoxetine area under the curve is approximately 10 times and peak concentration approximately 5 times higher than in other phenotypes, and half-life increases from 5.2 to 21.6 hours [4, 19]. These patients show greater symptom improvement and fewer discontinuations for lack of efficacy, but more adverse effects, such as increased heart rate and diastolic blood pressure, dry mouth, blurred vision, sleep changes, loss of weight and appetite, constipation, tremor, syncope, urinary retention and sexual dysfunction [17]. The 2022 label stated that approximately 7% of the Caucasian population are poor metabolisers and described, in paediatrics, a mean heart rate increase of 5.0 beats per minute in extensive metabolisers and 9.4 in poor metabolisers, and, with 2 or more years of treatment, losses of 2.4 kg and 1.1 cm compared with predicted values in poor versus 0.2 kg and 0.4 cm in extensive metabolisers [150]. Genotype alone does not explain response: in 6 trials (n=618), 47% had a beneficial response, 13% a minimal response and 40% no response, and poor metabolisers constitute 5–10% of the population [17].

The three sources diverge in strategy. CPIC proposes plasma measurement and escalation towards approximately 400 ng/mL, with concentrations of 200–1,000 ng/mL considered therapeutic [17]; DPWG emphasises not increasing the dose in poor metabolisers and reducing it with adverse effects [18]; and the FDA recommends considering genetic testing and slower titration, with the same doses [19]. In practice, genotype guides titration speed and adverse-effect monitoring, and plasma measurement, when available, allows dose individualisation according to CPIC.

For the remaining drugs, pharmacogenetics has no established clinical utility. DPWG identified no gene–drug interaction between CYP2D6 or COMT and methylphenidate, or between CYP2D6 and clonidine, and proposes clonidine as an alternative in variant metabolisers [18]. The meta-analysis by Myer and colleagues (36 studies, 3,647 young people treated with methylphenidate), cited by Faraone and Larsson, found small-effect associations with ADRA2A rs1800544 (OR 1.69), COMT rs4680 (OR 1.40), SLC6A2 rs5569 (OR 1.73) and rs28386840 (OR 2.93), the 4-repeat DRD4 VNTR (OR 1.66) and the 10-repeat SLC6A3 VNTR (OR 0.74), without established clinical utility; results for CES1, CYP2D6 and CYP3A4 and methylphenidate are inconsistent [4]. The 20 SLC6A2 polymorphisms associated with atomoxetine response in one study did not replicate and are not recommended [17]. The AAP does not recommend commercial pharmacogenetic tools to choose the drug or dose, because tested variants have been little studied, results are inconsistent, effects small and cost high, and lists three requirements for recommending them: replicated associations with response, a change in clinical decision-making with better outcomes or lower cost, and acceptable operational characteristics [3].

Polygenic scores do not predict response either. In the first meta-analysis of PGS and methylphenidate response, with 1,000 cases from Norway, Brazil and Spain in real-world settings, none of the seven PGSs (ADHD, ASD, bipolar disorder, educational attainment, depression, neuroticism, schizophrenia) was associated with clinically significant response [152]. In iPSYCH, 39% of 18,362 people starting stimulants discontinued in the first year (29.4% below 16 years and 57.1% from 16 years); discontinuation h²SNP was 0.06, a single locus (SLC5A12) reached significance only below 16 years, without replication, and the ADHD PGS was not associated with discontinuation [153].

7.6. Comparative regulatory status

7.7. Clinical trials

Differences between trials of different drugs cannot be compared indirectly, because scales (ADHD-RS-5, AISRS, Conners), populations and durations differ. The methylphenidate trial in NF1 is the first randomised trial to show short-term benefit in this syndrome, but was small, did not reach its planned size and measured a parent-reported endpoint over 4 weeks [156]. In the centanafadine trials, 140 mg equivalent doses were not effective in children and adolescents, and adult studies used a formulation different from the approved one [16]. Mean scale reductions should be read alongside improvement in the placebo group, which was substantial (−10.8 and −14.2 points). The within-individual registry studies cited by WFADHD (better school grades, less criminality, injury, accidents, depression, suicidal events and mortality during medication periods) are observational and subject to residual confounding despite their design [1].

7.8. Syndromic ADHD: adjustments and precautions

NICE calls for slower titration and more frequent monitoring in people with ID, ASD, tics, epilepsy or heart disease, conditions frequent in syndromic ADHD [14].

7.9. Developments in the past twelve months

The ClinicalTrials.gov records consulted on 9 October 2026 showed the solriamfetol FOCUS-2 (NCT07717879) and FOCUS-3 (NCT07717892) trials and their open-label paediatric extension (NCT07773883) recruiting, as well as centanafadine trials in adults (NCT07759154) and paediatric patients (NCT07086313, NCT07087327). The adult solriamfetol FOCUS trial (NCT05972044) ended in February 2025 without registered results; NCT06973577 (ADHD with anxiety) ended in April 2026; HLD200 in children aged 4–5 years (NCT06431256) and NRCT-101SR (NCT06215144) were terminated early; and CTx-1301 (dexmethylphenidate; NCT05924594) was suspended. These records do not constitute efficacy results. Outside the twelve-month window, but in force, the 2025 FDA safety communication on weight loss with extended-release stimulants below 6 years led to a uniform limitation of use being included in labels (section 9.3) [154], and the combined symptom and diagnosis GWAS was published in September 2025 [6]. Preclinically, the SORCS2 p.(Arg702Trp) variant abolished BDNF signalling in a dominant-negative manner in neurons, and mice lacking Sorcs2 had hyperactivity normalised by amphetamine [43].

7.10. Adults, transition and deprescribing

The AAP recommends planning transition to adult care from 14 years, focusing on the 2 years before the end of secondary school [3]. In adolescents, substance use should be assessed before prescribing medication, diversion monitored, non-stimulants considered when there is misuse risk, and medication coverage ensured during driving [3]. The 2019 European consensus on adult ADHD, developed by 63 experts from the European Network Adult ADHD and the European Psychiatric Association, emphasises persistence into adulthood and old age, underdiagnosis and undertreatment in many European countries, and the need for research on gender differences and older people [47]. The American Society of Clinical Psychopharmacology (ASCP) Delphi consensus, with 45 international experts, proposes considering stimulant deprescribing in adults when reassessment shows misdiagnosis (unless another condition responds to stimulants), when cognitive complaints have another more likely aetiology, when there is no cognitive benefit, when medical or psychiatric comorbidities worsen, or when there are unmanageable adverse effects, misuse or an untreated substance use disorder other than cannabis; regular cannabis use alone almost reached consensus as an insufficient reason [163].

7.11. Pregnancy, lactation and perioperative care

In an analysis of 1.8 million pregnancies in the USA and 2.5 million in the Nordic countries (Huybrechts, 2018), methylphenidate exposure, but not amphetamine exposure, was associated with an increase in cardiac malformations from 12.9 to 16.5 per 1,000 [1]. Atomoxetine and centanafadine labels refer to the National Pregnancy Registry for ADHD Medications, and human atomoxetine data are insufficient to establish risk [16, 19, 165]. Women with epilepsy planning pregnancy should receive preconception counselling about the neurodevelopmental risk of valproate, including ADHD [1, 134]. The consulted sources contain no specific recommendations on breastfeeding or perioperative management of ADHD drugs, apart from the warning not to stop guanfacine and clonidine abruptly because of rebound hypertension risk, and the contraindication to combining atomoxetine or centanafadine with MAOIs [3, 16, 19, 145].

7.12. Agents to avoid and interactions

MAOIs are contraindicated with atomoxetine and centanafadine, and centanafadine additionally requires avoiding alcohol until 2 hours after dosing and monitoring CYP1A2 substrates [16, 19]. Strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, bupropion) increase atomoxetine exposure and justify slow titration [17, 150]. Guanfacine requires adjustment with CYP3A4/5 inhibitors and inducers [146]. In DTDS, antidopaminergic drugs worsen the movement disorder [35], and in heritable pulmonary arterial hypertension, stimulants should be avoided or discussed with a specialist [161].

8. Reproductive Options and Family Counselling

8.1. Polygenic ADHD: empirical risks

In ADHD without an identified cause, counselling rests on empirical risks. Siblings of probands with ADHD have approximately 9 times the risk of siblings of controls (894 probands and 1,135 siblings), and heritability of approximately 74% is similar in both sexes [4]. With a prevalence of 5.9% in young people [1], this relative risk translates into a high recurrence probability, but consulted sources do not provide a validated estimate of absolute risk for siblings or offspring according to the number of affected relatives. Genetic architecture is shared with ASD, depression and schizophrenia (84–98% of common variants shared with other psychiatric disorders), so relatives' risk is not specific to ADHD and extends to other neurodevelopmental and psychiatric disorders [4, 5]. Non-shared environmental factors contribute to risk, and some environmental associations, such as maternal smoking, are explained by familial factors [1, 2].

8.2. Polygenic scores, candidate genes and consumer tests

There is no validated estimate of individual risk from PGS. The PGS explains approximately 5.5% of variance, varies with ancestry and lacks sufficient reliability or validity for standalone clinical use; candidate gene genotypes, such as the 7-repeat DRD4 allele, have no individual predictive value [2, 12, 38]. In the Danish cohort, absolute ADHD risk was 2.1% in the lowest and 4.5% in the highest PGS quintile, showing that even the highest PGS leaves the vast majority of people without a diagnosis [26]. For these reasons, PGS should not be used for prediction in embryos, fetuses or children, or for reproductive decisions.

8.3. CNVs and rare variants

In recurrent CNV carriers, ADHD risk is real but modest: absolute risk of 6.3% in high-impact rCNV carriers, against 3.0% in non-carriers, modulated by PGS [26], and HRs between 1.4 and 4.2 according to locus [11]. The same CNVs increase the risk of ASD, ID and schizophrenia, with risks correlated across disorders [11]. A CNV inherited from an apparently healthy parent does not exclude expressivity in that parent, as shown by the transmitting parent of a 3q29 deletion with several undiagnosed disorders [59]. Counselling about specific CNVs (22q11.2, 16p11.2, 15q13.3, 1q21.1) follows the recommendations specific to each CNV. Rare variants of moderate effect show incomplete penetrance and variable expressivity, as in the family with SORCS2 p.(Arg702Trp), including a carrier without a diagnosis, and in KDM5B carriers [8, 43]. Heterozygous parents of patients with DTDS have no reported increase in ADHD, bipolar disorder, ASD or early-onset parkinsonism, which helps reassure carriers of SLC6A3 loss-of-function variants [35].

8.4. Syndromic ADHD

When ADHD forms part of a monogenic or chromosomal syndrome, recurrence risk is that of the syndrome: 50% for offspring in autosomal dominant diseases (NF1, Legius syndrome, tuberous sclerosis complex, inherited deletions and duplications), 25% for siblings in autosomal recessive diseases (DTDS, phenylketonuria, maple syrup urine disease), sex-dependent risks in X-linked conditions (fragile X syndrome, X-linked adrenoleukodystrophy, creatine transporter deficiency), and low but non-zero risk owing to possible germline mosaicism when the variant arose de novo. For neurofibromatosis type 1, intellectual disability, fragile X syndrome, the 22q11.2 deletion and duplication syndromes and 16p11.2 microdeletion and microduplication, cascade testing, prenatal diagnosis and preimplantation genetic testing apply. In maternal phenylketonuria, 22% of exposed offspring were receiving ADHD medication, making preconception metabolic control a preventive measure [124]. Sex chromosome aneuploidies are generally sporadic; many are detected as incidental prenatal findings, and more than 85% of 47,XYY males are never diagnosed [52].

8.5. Prenatal exposures and prevention

Preconception counselling includes review of antiepileptics, because prenatal valproate exposure was associated with an approximately 50% increase in ADHD in a Danish cohort of 913,000 children, without an association for other antiepileptics [1], and antiepileptic exposure overall with an approximately 4-fold higher risk of neurodevelopmental disorders [134]. Avoiding alcohol in pregnancy prevents fetal alcohol spectrum disorder [135]. For the remaining described exposures (paracetamol, phthalates, maternal obesity, fever at weeks 9–12), associations are observational and may reflect genetic confounding [1, 41].

8.6. Counselling minors and communication

As no validated predictive test exists for polygenic ADHD, the issue of predictive testing in minors arises only in syndromic forms, where it follows the syndrome's rules. Communication of genetic research results should explain that a risk variant or incompletely penetrant CNV does not determine diagnosis, that ADHD is treatable regardless of cause and that high heritability does not mean an absence of environmental influence [4, 26]. Patient and family associations, such as ADHD Europe and ABDA, are resources for families (section 9.5) [166, 167].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Prevalence estimates depend on design. The most restricted meta-analysis cited by WFADHD (19 studies, more than 55,000 participants) estimates 5.9% of young people; a meta-analysis of 135 studies (approximately 250,000 young people; Polanczyk, 2014) found no differences between North America, Europe, Asia, Africa, South America and Oceania, or an increase in prevalence over three decades, and attributes increased diagnoses in the USA and Sweden to administrative and clinical practices [1]. The meta-analysis cited by the AAP estimates 7.2% in children, with 8.7–15.5% in community samples [3]. In adults, estimates are 2.5% (6 studies, more than 5,300 people) and 2.8% (20 studies in 13 countries, more than 26,000 people); in people aged 50 or older, 1.5% by scales, but only 0.2% by clinical diagnosis and 0.02% treated [1]. The male:female ratio is approximately 2:1 in young people [1].

In the United States, the 2016 national survey found 9.4% of children aged 2 to 17 years ever diagnosed (2.4% at 2–5 years) and 8.4% with current ADHD (5.4 million); of these, almost two thirds were receiving medication, approximately half had received behavioural treatment in the previous year and approximately one quarter had no treatment [3]. The 2025 FDA page reports 7 million children aged 3 to 17 years (11.4%) with an ADHD diagnosis, 15% of boys and 8% of girls [154]. These figures measure parent-reported diagnoses rather than prevalence according to criteria applied to a population sample, explaining the difference from the 5.9% in meta-analyses. In Black US young people, a meta-analysis of 19 studies (more than 150,000 participants) estimated 14% [1].

9.2. Europe, founder populations and ancestry

ADHD genetics has been built predominantly on European samples. Danish iPSYCH is the largest source of cases for GWAS and exome studies, with registered hospital diagnoses; Iceland (deCODE) contributed a population of smaller effective size, reflected in lower h²SNP (0.08); and Norway, Germany, the Netherlands and the United Kingdom contributed clinical and population cohorts [5, 7, 9, 43, 48]. In an isolated Colombian population, multigenerational families enabled identification of linkage regions, one including ADGRL3 [4]. The 2019 GWAS included a Chinese cohort, but the 2023 and 2026 studies are exclusively of European ancestry, as are the gnomAD controls used in the exome study [2, 5, 7]. The PGS varies greatly with ancestry, and results cannot be transferred to non-European populations [38].

9.3. Special populations

In children younger than 6 years, the FDA revised labels for all extended-release stimulants to warn of clinically significant weight loss (a fall of at least 10% in weight percentile) and other adverse effects: these drugs are not approved below 6 years, younger children have higher plasma exposure at the same dose, and the FDA concludes that benefits may not outweigh risks at this age [154]. The date of this communication (30 June 2025) comes from secondary sources, and the April 2026 lisdexamfetamine and OROS methylphenidate labels already include the limitation of use [143, 144, 154]. Girls and women are under-recognised [14]. People with ID, ASD or epilepsy require slower titration [14], and methylphenidate is effective in borderline intellectual functioning and ID [1]. In older people, the contrast between scale-based and clinical diagnosis prevalence suggests underdiagnosis or symptom overlap with other conditions [1].

9.4. Portugal and Brazil

The consulted sources contain no epidemiological data from Portugal. From Brazil, the meta-analysis of PGS and methylphenidate response included a Brazilian cohort [152], and the Associação Brasileira do Déficit de Atenção (ABDA) is the reference association [167]. The absence of these data from the consulted sources does not mean there are no published studies.

9.5. Reference networks and associations

There is no European Reference Network (ERN) for polygenic ADHD. Syndromic, monogenic and CNV-related forms fall within ERN ITHACA, the European reference network for rare malformation syndromes, intellectual disability and other rare neurodevelopmental disorders [20]. EUNETHYDIS is the European scientific network dedicated to ADHD [21]. ADHD Europe federates European patient associations [166]; in the USA, CHADD (Children and Adults with ADHD) supports patients and families and APSARD (American Professional Society of ADHD and Related Disorders) brings together professionals [168, 169]; in Brazil, ABDA [167]. The National Pregnancy Registry for ADHD Medications collects pregnancy exposure data [165]. No Portuguese association with an active website was identified in the consulted sources.

10. Illustrative Clinical Case

10.1. Norwegian family with persistent ADHD and a rare SORCS2 variant

In the national ADHD in Norwegian Adults study, Kaas and colleagues sequenced the exomes of 21 families with multiple cases of persistent ADHD [43]. In a family with three members with ADHD, three people were heterozygous for an exon 16 SORCS2 variant, NM_020777.3:c.2104C>T, p.(Arg702Trp) (GRCh38 NC_000004.12:g.7714354C>T; GRCh37 NC_000004.11:g.7716081C>T) [42, 43]. Two of the three carriers had ADHD and the third had no diagnosis; clinical information across four generations suggested a high familial ADHD burden, but no clear Mendelian segregation pattern [43]. Brain magnetic resonance imaging at 3 T in the second-generation carrier with ADHD showed no pathological changes, only mild asymmetry of the external cerebrospinal fluid space, a partially empty sella and some enlarged perivascular spaces [43]. Figure 1 of the article, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC12916480/figure/Fig1/, shows the pedigree (panel A; black, persistent ADHD; half-filled, unassessed with ADHD signs), the heterozygous variant electropherogram (B), the T1 magnetic resonance image (C), the cross-species alignment around residue Arg702 (D) and the three-dimensional structure of the Vps10p domain (E) [43].

Residue Arg702 lies in the 10CC module of the Vps10p domain, with five conserved disulphide bonds [43]. In functional studies, the variant caused endoplasmic reticulum retention, aberrant post-translational processing, increased ectodomain shedding and reduced ligand binding; it formed heterodimers with normal SorCS2 and SorCS3 and abolished brain-derived neurotrophic factor (BDNF) signalling in a dominant-negative manner, in neurons lacking Sorcs2 and in iPSC-derived glutamatergic neurons [43]. Mice lacking Sorcs2 had hyperactivity normalised by amphetamine [43]. However, in the Bergen (597 cases and 433 controls) and German and Dutch IMpACT cohorts (1,078 cases and 1,738 controls), the 38 low-frequency SORCS2 missense variants in cases and the 65 in controls showed no excess of deleterious variants in ADHD (P=0.55), and other variants (p.Ser484Ile in cases and controls; p.Arg631Cys and p.Arg666Cys only in cases) also abolished the BDNF response in vitro [43].

The authors allow for incomplete penetrance, suggest that the variant manifests only against a polygenic and environmental background, and acknowledge limited confidence in the association [43]. The case illustrates interpretation of a rare variant in a polygenic trait: convincing functional data, incomplete segregation and absence of population enrichment mean that, for clinical use, the variant is equivalent to a VUS or a risk factor rather than a Mendelian cause. This is a research study; sequencing families with ADHD is not guideline-recommended practice (section 5.2).

10.2. Inattentive ADHD in a boy with a de novo KCNC1 variant and epilepsy

Huang and colleagues described a boy, the third of four siblings, born at term in February 2012, with normal psychomotor development (walking at 13 months, appropriate language) and a maternal aunt with febrile seizures [44]. He had a febrile seizure at 19 months, generalised tonic-clonic seizures at 20 months and, before 2 years, paroxysmal bruxism and sudden falls; EEG showed epileptiform discharges and, at 2 years, he started valproate (0.2 g/day, adjusted to weight and drug levels), with complete seizure remission for more than 3 years [44]. In 2022, predominantly inattentive ADHD was diagnosed, with below-average school performance in the 6th year [44]. At 13 years (July 2025), motor skills and social interaction were appropriate, Raven's matrices scored 48 points (75th–80th percentile), height was 147 cm (2nd percentile; −2.08 standard deviations) and weight 35.5 kg (6th percentile), interpreted as idiopathic short stature; strength and reflexes were normal and ataxia tests negative despite mild gait instability; annual EEG retained epileptiform abnormalities, magnetic resonance imaging at 1.5 T showed a mega cisterna magna with normal cerebellar volume and cortex, and electromyography was normal [44]. There was no progression over 3 years of follow-up [44].

Trio sequencing, confirmed by Sanger sequencing, identified the heterozygous de novo variant NM_001112741.2(KCNC1):c.1147C>T, p.(His383Tyr) (GRCh38 NC_000011.10:g.17772241C>T), absent from gnomAD, which the authors classified as likely pathogenic (PS2, PM2_supporting, PP2); the gene-associated OMIM disease is progressive myoclonic epilepsy type 7 (616187, autosomal dominant) [42, 44]. In silico predictors disagreed (SIFT tolerated, PolyPhen-2 benign, CADD 6.898, REVEL 0.463, MutationTaster pathogenic), so classification rests predominantly on de novo occurrence [44]. Figure 3 of the article, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC12954995/figure/Fig3/, shows the pedigree (II-3, proband) and family Sanger sequencing [44]. In the review of 54 cases with KCNC1 variants, transmembrane variants were associated with myoclonic epilepsy with ataxia and non-transmembrane variants with developmental encephalopathies [44]. The authors emphasise the dissociation between seizure control and persistent ADHD, suggesting distinct mechanisms, and advocate early genetic testing in neurological patients with EEG abnormalities [44]. This conclusion applies to epilepsy; it does not extend to isolated ADHD, for which guidelines do not recommend genetic testing [3, 14].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Two thirds of young people with ADHD retain disabling symptoms in adulthood, although only approximately 1 in every 6 retains all criteria at 25 years [1, 4]. In Denmark (approximately 2 million people), ADHD was associated with a small increase in premature death, predominantly from accidents and greater with comorbidity; in Taiwan (2.2 million), there was no increase in natural death, but suicide and homicide were 2 times and unintentional injuries 30% more frequent; in another Danish cohort (2.9 million), suicide attempts or deaths were 4 times more frequent, and more than 10 times with another disorder; in a meta-analysis, suicide attempts were 2 times, ideation more than 3 times and completed suicide more than 6 times more frequent [1].

Treatment is associated with better outcomes in within-individual registry studies: better grades and secondary school completion (Sweden, more than 650,000 people), one third less criminality in men and 40% less in women (Sweden), 30–40% fewer injuries in adolescents (Denmark), more than 70% fewer traumatic brain injuries (Sweden), 38% fewer road traffic accidents in men (USA, 2.3 million), more than 40% less depression at 3 years, 20% fewer suicidal events with stimulants (no effect with non-stimulants), more than 30% less substance misuse, 30% less teenage pregnancy (Taiwan) and one fifth lower all-cause mortality with methylphenidate (Taiwan, 68,000) [1]. Discontinuation is frequent: 39% in the first year in iPSYCH and 35–61% in a cited multinational study [153].

Genetic markers have limited prognostic value. In the ALSPAC cohort (8,414 people with CNV data; 2.3% with neurodevelopmental CNVs and 8.7% with large, rare CNVs), there was no evidence that CNVs modified educational, employment or mental health outcomes associated with ADHD in young adulthood, although confidence intervals were wide [48]. Rare deleterious variants in constrained genes are associated with lower educational attainment, lower socioeconomic status and lower IQ, but these data describe groups and do not allow individual prognosis [7]. In syndromic ADHD, prognosis is that of the syndrome: in cerebral adrenoleukodystrophy, duration from neurological onset to death was 1.9 ± 2 years in 167 patients [129]; in 47,XYY males, a Danish study of 161 men showed moderately increased conviction risk, similar to controls after socioeconomic adjustment, with lower IQ as the main risk factor [52]; and 47,XXX women in a US survey (n=11) had poorer adjustment and more work and relationship problems than their sisters, but were mostly self-sufficient [51]. In 22q11.2 deletion, surveillance should anticipate the transition from childhood ADHD to psychosis risk in emerging adulthood [54].

11.2. Surveillance

NICE also recommends adherence support with visual reminders, routines, written or pictorial instructions and parental supervision of children's medication, and annual review includes preferences, benefit throughout the day, adverse effects, school or work impact, the effect of missed doses and comorbidities [14].

12. Summary and Final Considerations

ADHD is a common neurodevelopmental disorder (5.9% of young people and 2.5–2.8% of adults), with heritability of approximately 74% and a layered genetic architecture [1, 4]. The main layer is polygenic: thousands of common variants of small effect, approximately 7,300 of which explain 90% of h²SNP, distributed across loci such as the 27 from the 2023 GWAS, largely shared with ASD, depression and schizophrenia and enriched in genes expressed in the developing brain [5]. The second layer comprises rare variants of moderate effect: recurrent CNVs that double absolute risk in high-impact carriers, and truncating or deleterious missense variants in constrained genes, present in approximately one fifth of people with ADHD, with MAP1A, ANO8 and ANK2 as the first genes reaching exome-wide significance [7, 26]. The two layers add their effects [7]. The third layer comprises genetic, chromosomal and metabolic syndromes in which ADHD is a frequent manifestation, such as NF1, Williams syndrome, sex chromosome aneuploidies, 22q11.2 and 16p11.2 CNVs, fragile X syndrome and X-linked adrenoleukodystrophy [4, 27–29].

For clinical practice, three conclusions follow from these data. First, ADHD diagnosis is clinical, and in isolated ADHD there is no indication for genetic testing; PGS and candidate genes have no individual diagnostic or predictive value [3, 12, 14, 38]. Second, ID, global delay, congenital anomalies, dysmorphism, epilepsy, regression or neurological signs change the approach and justify targeted genetic and metabolic investigation, with exome or genome sequencing as a first- or second-line test in ID and congenital anomalies [15, 29, 35]. Third, treatment follows general guidelines, with adjustments in syndromes (cardiology in Williams syndrome, psychosis surveillance in 3q29 and 22q11.2 deletions, avoidance of antidopaminergics in DTDS), and actionable pharmacogenetics is limited to CYP2D6 and atomoxetine, where the FDA label revised in 2026, CPIC and DPWG diverge in strategy but converge on caution in poor metabolisers [17–19, 28, 35, 59]. FDA approval of centanafadine in July 2026 broadens options in the United States, without a European equivalent to date [16]. Family counselling rests on empirical risks, with approximately 9-fold higher risk in siblings, and should explain that identified risk variants have incomplete penetrance and do not determine diagnosis [4, 26, 43].

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