Gonadal Mosaicism as a Rare Inheritance Pattern in Recessive Genodermatoses: Report of Two Cases with Pseudoxanthoma Elasticum and Literature Review.

Germline mosaicism in autosomal recessive disorders is considered a rare disease mechanism with important consequences for diagnosis and patient counseling. In this report, we present two families with PXE in which paternal germline mosaicism for an ABCC6 whole-gene deletion was observed. The first family further illustrates the clinical challenges in PXE, with a typical PXE retinopathy in an apparently heterozygous carrier parent. A systematic review of the literature on gonadal mosaicism in autosomal recessive genodermatoses revealed 16 additional patients. As in most reported families, segregation analysis data are not mentioned, and this may still be an underrepresentation. Though rare, the possibility of germline mosaicism emphasizes the need for variant verification in parents and sibs of a newly diagnosed proband, as it has significant implications for genetic counseling and management.

HRAS-related epidermal nevus syndromes: Expansion of the spectrum with first branchial arch defects.

Epidermal nevus syndrome (ENS) comprises a heterogeneous group of neurocutaneous syndromes associated with the presence of epidermal nevi and variable extracutaneous manifestations. Postzygotic activating HRAS pathogenic variants were previously identified in nevus sebaceous (NS), keratinocytic epidermal nevus (KEN), and different ENS, including Schimmelpenning-Feuerstein-Mims and cutaneous-skeletal-hypophosphatasia syndrome (CSHS). Skeletal involvement in HRAS-related ENS ranges from localized bone dysplasia in association with KEN to fractures and limb deformities in CSHS. We describe the first association of HRAS-related ENS and auricular atresia, thereby expanding the disease spectrum with first branchial arch defects if affected by the mosaic variant. In addition, this report illustrates the first concurrent presence of verrucous EN, NS, and nevus comedonicus (NC), indicating the possibility of mosaic HRAS variation as an underlying cause of NC. Overall, this report extends the pleiotropy of conditions associated with mosaic pathogenic variants in HRAS affecting ectodermal and mesodermal progenitor cells.

C-terminal frameshift variant of TDP-43 with pronounced aggregation-propensity causes rimmed vacuole myopathy but not ALS/FTD.

Neuronal TDP-43-positive inclusions are neuropathological hallmark lesions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathogenic missense variants in TARDBP, the gene encoding TDP-43, can cause ALS and cluster in the C-terminal prion-like domain (PrLD), where they modulate the liquid condensation and aggregation properties of the protein. TDP-43-positive inclusions are also found in rimmed vacuole myopathies, including sporadic inclusion body myositis, but myopathy-causing TDP-43 variants have not been reported. Using genome-wide linkage analysis and whole exome sequencing in an extended five-generation family with an autosomal dominant rimmed vacuole myopathy, we identified a conclusively linked frameshift mutation in TDP-43 producing a C-terminally altered PrLD (TDP-43p.Trp385IlefsTer10) (maximum multipoint LOD-score 3.61). Patient-derived muscle biopsies showed TDP-43-positive sarcoplasmic inclusions, accumulation of autophagosomes and transcriptomes with abnormally spliced sarcomeric genes (including TTN and NEB) and increased expression of muscle regeneration genes. In vitro phase separation assays demonstrated that TDP-43Trp385IlefsTer10 does not form liquid-like condensates and readily forms solid-like fibrils indicating increased aggregation propensity compared to wild-type TDP-43. In Drosophila TDP-43p.Trp385IlefsTer10 behaved as a partial loss-of-function allele as it was able to rescue the TBPH (fly ortholog of TARDBP) neurodevelopmental lethal null phenotype while showing strongly reduced toxic gain-of-function properties upon overexpression. Accordingly, TDP-43p.Trp385IlefsTer10 showed reduced toxicity in a primary rat neuron disease model. Together, these genetic, pathological, in vitro and in vivo results demonstrate that TDP-43p.Trp385IlefsTer10 is an aggregation-prone partial loss-of-function variant that causes autosomal dominant vacuolar myopathy but not ALS/FTD. Our study genetically links TDP-43 proteinopathy to myodegeneration, and reveals a tissue-specific role of the PrLD in directing pathology.

Clinical and subclinical findings in heterozygous ABCC6 carriers: results from a Belgian cohort and clinical practice guidelines.

BACKGROUND: Biallelic pathogenic variants in the ATP-binding cassette subfamily C member 6 (ABCC6) gene cause pseudoxanthoma elasticum, a multisystemic ectopic calcification disorder, while heterozygous ABCC6 variants are associated with an increased risk of cardiovascular and cerebrovascular disease. As the prevalence of pathogenic ABCC6 variants in the general population is estimated at ~1%, identifying additional ABCC6-related (sub)clinical manifestations in heterozygous carriers is of the utmost importance to reduce this burden of disease. Here, we present a large Belgian cohort of heterozygous ABCC6 carriers with comprehensive clinical, biochemical and imaging data. Based on these results, we formulate clinical practice guidelines regarding screening, preventive measures and follow-up of ABCC6 carriers. METHODS: The phenotype of 56 individuals carrying heterozygous pathogenic ABCC6 variants was assessed using clinical (eg, detailed ophthalmological examinations), biochemical, imaging (eg, cardiovascular and abdominal ultrasound) and genetic data. Clinical practice guidelines were then drawn up. RESULTS: We found that ABCC6 heterozygosity is associated with distinct retinal alterations ('comet-like') (24%), high prevalence of hypercholesterolaemia (>75%) and diastolic dysfunction (33%), accelerated lower limb atherosclerosis and medial vascular disease, abdominal organ calcification (26%) and testicular microlithiasis (28%), though with highly variable expression. CONCLUSION: In this study, we delineated the multisystemic ABCC6 heterozygosity phenotype characterised by retinal alterations, aberrant lipid metabolism, diastolic dysfunction and increased vascular, abdominal and testicular calcifications. Our clinical practice guidelines aimed to improve early diagnosis, treatment and follow-up of ABCC6-related health problems.

The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.

ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G>A (p.Val787Ile) and c.1171A>G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A>G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling.

Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons.

While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.

Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases.

Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC contributes to significant morbidity and mortality and is considered a major health problem for which no effective treatments currently exist. In recent years, growing emphasis has been placed on the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of EC. Impaired mitochondrial respiration and increased levels of reactive oxygen species can be directly linked to key molecular pathways involved in EC such as adenosine triphosphate homeostasis, DNA damage signaling, and apoptosis. While EC is mainly encountered in common diseases such as diabetes mellitus and chronic kidney disease, studies in rare hereditary EC disorders such as pseudoxanthoma elasticum or Hutchinson-Gilford progeria syndrome have been instrumental in identifying the precise etiopathogenetic mechanisms leading to EC. In this narrative review, we describe the current state of the art regarding the role of mitochondrial dysfunction and oxidative stress in hereditary EC diseases. In-depth knowledge of aberrant mitochondrial metabolism and its local and systemic consequences will benefit the research into novel therapies for both rare and common EC disorders.

Minocycline Counteracts Ectopic Calcification in a Murine Model of Pseudoxanthoma Elasticum: A Proof-of-Concept Study.

Pseudoxanthoma elasticum (PXE) is an intractable Mendelian disease characterized by ectopic calcification in skin, eyes and blood vessels. Recently, increased activation of the DNA damage response (DDR) was shown to be involved in PXE pathogenesis, while the DDR/PARP1 inhibitor minocycline was found to attenuate aberrant mineralization in PXE cells and zebrafish. In this proof-of-concept study, we evaluated the anticalcifying properties of minocycline in Abcc6-/- mice, an established mammalian PXE model. Abcc6-/- mice received oral minocycline supplementation (40 mg/kg/day) from 12 to 36 weeks of age and were compared to untreated Abcc6-/- and Abcc6+/+ siblings. Ectopic calcification was evaluated using X-ray microtomography with three-dimensional reconstruction of calcium deposits in muzzle skin and Yasue's calcium staining. Immunohistochemistry for the key DDR marker H2AX was also performed. Following minocycline treatment, ectopic calcification in Abcc6-/- mice was significantly reduced (-43.4%, p < 0.0001) compared to untreated Abcc6-/- littermates. H2AX immunostaining revealed activation of the DDR at sites of aberrant mineralization in untreated Abcc6-/- animals. In conclusion, we validated the anticalcifying effect of minocycline in Abcc6-/- mice for the first time. Considering its favorable safety profile in humans and low cost as a generic drug, minocycline may be a promising therapeutic compound for PXE patients.

Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc.

PURPOSE: Pseudoxanthoma elasticum (PXE) is a heritable disorder affecting elastic fibers in the skin, eyes, and cardiovascular system. It is caused by biallelic pathogenic variants in the ABCC6 gene. To date, over 300 ABCC6 variants are associated with PXE, more than half being missense variants. Correct variant interpretation is essential for establishing a direct link between the variant and the patient's phenotype and has important implications for diagnosis and treatment. METHODS: We used a systematic approach for interpretation of 271 previously reported and 15 novel ABCC6 missense variants, based on the semiquantitative classification system Sherloc. RESULTS: Only 35% of variants were very likely to contribute directly to disease, in contrast to reported interpretations in ClinVar, while 59% of variants are currently of uncertain significance (VUS). Subclasses were created to distinguish VUS that are leaning toward likely benign or pathogenic, increasing the number of (likely) pathogenic ABCC6 missense variants to 47%. CONCLUSION: Besides highlighting discrepancies between the Sherloc, American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP), ClinVar, and Leiden Open Variation Database (LOVD) classification, our results emphasize the need for segregation analysis, functional assays, and detailed evidence sharing in variant databases to reach a confident interpretation of ABCC6 missense variants and subsequent appropriate genetic and preconceptual counseling.

Phenotypic spectrum of the RBM10-mediated intellectual disability and congenital malformation syndrome beyond classic TARP syndrome features.

Pathogenic variants in the RBM10 gene cause a rare X-linked disorder described as TARP (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left vena cava superior) syndrome. We report two novel patients with truncating RBM10 variants in view of the literature, presenting a total of 26 patients from 15 unrelated families. Our results illustrate the highly pleiotropic nature of RBM10 pathogenic variants, beyond the classic TARP syndrome features. Major clinical characteristics include severe developmental delay, failure to thrive, brain malformations, neurological symptoms, respiratory issues, and facial dysmorphism. Minor features are growth retardation, cardiac, gastrointestinal, limb, and skeletal abnormalities. Additional recurrent features include genital and renal abnormalities as well as hearing and visual impairment. Thus, RBM10 loss of function variants typically cause an intellectual disability and congenital malformation syndrome that requires assessment of multiple organ systems at diagnosis and for which provided clinical features might simplify diagnostic assessment. Furthermore, evidence for an RBM10-related genotype-phenotype correlation is emerging, which can be important for prognosis.

Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers-Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix.

PURPOSE: To date, heterozygous or homozygous COL12A1 variants have been reported in 13 patients presenting with a clinical phenotype overlapping with collagen VI-related myopathies and Ehlers-Danlos syndrome (EDS). The small number of reported patients limits thorough investigation of this newly identified syndrome, currently coined as myopathic EDS. METHODS: DNA from 78 genetically unresolved patients fulfilling the clinical criteria for myopathic EDS was sequenced using a next-generation panel of COL12A1, COL6A1, COL6A2, and COL6A3. RESULTS: Among this cohort, we identified four pathogenic heterozygous in-frame exon skipping (∆) defects in COL12A1, clustering to the thrombospondin N-terminal region and the adjacent collagenous domain (Δ52, Δ53, Δ54, and Δ56 respectively), one heterozygous COL12A1 arginine-to-cysteine substitution of unclear significance (p.(Arg1863Cys)), and compound heterozygous pathogenic COL6A1 variants (c.[98-6G>A];[301C>T]) in one proband. Variant-specific intracellular accumulation of collagen XII chains, extracellular overmodification of the long isoform and near-absence of the short isoform of collagen XII, and extracellular decrease of decorin and tenascin-X were observed for the COL12A1 variants. In contrast, the COL6A1 variants abolished collagen VI and V deposition and increased tenascin-X levels. CONCLUSION: Our data further support the significant clinical overlap between myopathic EDS and collagen VI-related myopathies, and emphasize the variant-specific consequences of collagen XII defects.

VEGFA variants as prognostic markers for the retinopathy in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive ectopic mineralization disorder, characterized by skin, eye and cardiovascular symptoms. The most devastating ocular complication is choroidal neovascularization, which is thought to be mediated by vascular endothelial growth factor (VEGF) signaling, a molecule encoded by the VEGFA gene. As early detection and treatment is essential to preserve vision, prioritization of patients at risk is crucial, but impossible because of wide phenotypic variability and a lack of genotype-phenotype correlations for PXE. This study aimed to validate the previously suggested association of five single nucleotide VEGFA variants (rs13207351, rs833061, rs699947, rs25648 and rs1413711) with a severe PXE retinopathy in an independent cohort. Direct Sanger sequencing was performed in 100 PXE patients, with a mild (56) or severe (44) PXE retinopathy. The inclusion criteria for severe retinopathy were a unilateral best-corrected visual acuity of <5/10 and/or the need for anti-angiogenic treatment. We found a significant association of three of five variants and borderline missed significance for one. These data further suggest the VEGFA gene to be a modifier gene for the PXE retinopathy. Hereby, we provide the necessary evidence to implement these variants in ocular risk stratification and individualized patient follow-up.

Nonlinear optical microscopy is a novel tool for the analysis of cutaneous alterations in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by mutations of the ABCC6 gene that leads to decreased serum levels of inorganic pyrophosphate (PPi) anti-mineralization factor. The occurrence of severe complications among PXE patients highlights the importance of early diagnosis so that prompt multidisciplinary care can be provided to patients. We aimed to examine dermal connective tissue with nonlinear optical (NLO) techniques, as collagen emits second-harmonic generation (SHG) signal, while elastin can be excited by two-photon excitation fluorescence (TPF). We performed molecular genetic analysis, ophthalmological and cardiovascular assessment, plasma PPi measurement, conventional histopathological examination, and ex vivo SHG and TPF imaging in five patients with PXE and five age- and gender-matched healthy controls. Pathological mutations including one new variant were found in the ABCC6 gene in all PXE patients and their plasma PPi level was significantly lower compared with controls. Degradation and mineralization of elastin fibers and extensive calcium deposition in the mid-dermis was visualized and quantified together with the alterations of the collagen structure in PXE. Our data suggests that NLO provides high-resolution imaging of the specific histopathological features of PXE-affected skin. In vivo NLO may be a promising tool in the assessment of PXE, promoting early diagnosis and follow-up.

Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis.

DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis.

The Role of Vitamin K and Its Related Compounds in Mendelian and Acquired Ectopic Mineralization Disorders.

Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders.

The Genetics of Soft Connective Tissue Disorders.

Over the last few years, the field of hereditary connective tissue disorders has changed tremendously. This review highlights exciting insights into three prototypic disorders affecting the soft connective tissue: Ehlers-Danlos syndrome, pseudoxanthoma elasticum, and cutis laxa. For each of these disorders, the identification and characterization of several novel but related conditions or subtypes have widened the phenotypic spectrum. In parallel, the vast underlying molecular network connecting these phenotypes is progressively being uncovered. Identification and characterization (both clinical and molecular) of new phenotypes within the connective tissue disorder spectrum are often key to further unraveling the pathways involved in connective tissue biology and delineating the clinical spectrum and pathophysiology of the disorders. Although difficult challenges remain, recent findings have expanded our pathophysiological understanding and may lead to targeted therapies in the near future.

The Belgian MicroArray Prenatal (BEMAPRE) database: A systematic nationwide repository of fetal genomic aberrations.

OBJECTIVE: With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs. METHODS: The Belgian MicroArray Prenatal (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016. RESULTS: In this three-year period, 13 266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs, 31.5% would have remained undetected with non-invasive prenatal test as the first-tier test. CONCLUSION: The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype-phenotype correlation.

FOXP1-related intellectual disability syndrome: a recognisable entity.

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

Delineating the psychiatric and behavioral phenotype of recurrent 2q13 deletions and duplications.

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.