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We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as obsessive-compulsive disorder (R=0.31-0.49, p

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.

Autism spectrum disorders are classified as neurodevelopmental disorders characterised by diminished social communication and interaction. The core symptoms typically coexist with other medical conditions such as intellectual disability. The involvement of rare copy number variations of varying expressivity and penetrance as risk factors in autism spectrum disorders/intellectual disability phenotypes has been highlighted in large series. The DLGAP2 gene, whose glutamatergic postsynaptic density product may play a role in synaptogenesis and plasticity, has been identified as a novel candidate on the basis of 2 de novo duplications in sporadic non-syndromic autism spectrum disorders/intellectual disability males. It has also been suggested that increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia spectrum disorders. Based on these results and after fine phenotyping of another patient with a de novo duplication involving DLGAP2 and presenting with autism spectrum disorder intersecting early-onset schizophrenia spectrum disorder, we gathered an international series of 9 cases (6 families) via international data sharing. Four sporadic males presented with autism spectrum disorders and one had other neurodevelopmental disorders. A family with 4 females displayed intellectual disability (2/4) and specific learning disorder (2/4). This study supports the hypothesis that rare copy number variations encompassing DLGAP2 with incomplete penetrance and variable expressivity could predispose to a broad range of early-onset neurodevelopmental disorders trajectories including autism spectrum disorders/intellectual disability, highlighting the existence of common predisposing factors to these overlapping phenotypic spectrums.

We report the first case of inherited ring chromosome 8 syndrome without loss of subtelomeric sequences. The proband is a 6 1/2-year-old boy with short stature, microcephaly, mild mental retardation, and behavioral problems including hyperactivity and attention deficit. His mother presented the same physical features but intelligence was normal. Family history also revealed an uncle and a grandmother, with short stature and microcephaly. Moderate mental retardation was reported in the uncle. Karyotypes and fluorescence in situ hybridization (FISH) analyses were performed on peripheral blood lymphocytes for both child and mother. The child’s karyotype was reported as 46,XY,r(8)(p23q24.3)[24]/45,XY,–8[2] and the mother’s karyotype 46,XX,r(8)(p23q24.3)[22]/45,XX,–8[2]/47,XX,r(8)(p23q24.3), +r(8)(p23q24.3)[1]. FISH studies showed no deletion of subtelomeric sequences for both child and mother indicating that no or little chromosomal euchromatic material has been deleted. These findings indicate that ring chromosome 8 without loss of subtelomeric sequences can be inherited and that carriers in a same family present with cognitive function ranging from mild mental retardation to normal intelligence.