We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a deletion or point mutation. This first series reporting the phenotype ascribed to mutation in highlights the importance of data sharing in the field of rare disorders.

BackgroundIntragenic NRXN1 deletions are susceptibility variants for neurodevelopmental disorders; however, their clinical interpretation is often unclear. Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided.MethodsThe literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives, and was used for clinical hypothesis testing. Exact breakpoint determination was performed for 43 in-house deletions.ResultsThe prevalence of exonic NRXN1 deletions in controls was ~1/3000 as compared with ~1/800 in patients with neurodevelopmental/neuropsychiatric disorders. The differential distribution of deletions across the gene between controls and probands allowed to distinguish distinct areas within the gene. Exon 6–24 deletions appeared only twice in over 100000 control individuals, had an estimated penetrance for neurodevelopmental disorders of 32.43%, a de novo rate of 50% and segregated mainly with intellectual disability (ID) and schizophrenia. In contrast, exon 1–5 deletions appeared in 20 control individuals, had an estimated penetrance of 12.59%, a de novo rate of 32.5% and were reported with a broad range of neurodevelopmental phenotypes. Exact breakpoint determination revealed six recurrent intron 5 deletions.ConclusionExon 6–24 deletions have a high penetrance and are mainly associated with ID and schizophrenia. In contrast, the actual contribution of exon 1–5 deletions to a neurodevelopmental/neuropsychiatric disorder in an individual patient and family remains very difficult to assess. To enhance the clinical interpretation, this study provides practical considerations for counselling and an interactive table for comparing a deletion of interest with the available literature data.

The prevalence of autism spectrum disorder (ASD) has increased considerably in the past decades. The primary care paediatrician plays an important role not only in the early recognition of ASD but also in its chronic management. Paediatricians need to be comfortable with the global care of children with ASD. The diagnostic assessment of children with ASD comprises the medical investigations to identify associated or underlying medical conditions. The most important associated conditions are seizures, feeding and gastrointestinal problems, sleep disturbances and dental abnormalities. The care of ASD patients is very demanding since along with the purely medical issues there are challenging behavioural and psychiatric conditions that need consideration and professional skills.

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