ClinVar

Description

This deletion interval involves the 5' portion of NRXN1 (OMIM *600565) gene. Biallelic variation of NRXN1 can cause autosomal recessive Pitt-Hopkins-like syndrome-2 (OMIM 614325). Additionally, heterozygous deletion of NRXN1 has been reported in patients with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual disability, autism spectrum disorders, hypotonia and epilepsy, and disorders of speech and verbal expression. While some deletions occurred de novo/segregated with disease in families, others were inherited from asymptomatic parents, suggesting reduced penetrance and variable expressivity (see list of references at bottom). Despite this, and the occurrence of NRXN1 deletions in the general populations of the Database of Genomic Variants, a recent study suggests partial deletions near the 5' end (like the one identified here) have a higher penetrance for expression of neurodevelopmental phenotypes compared to those at the 3' end (Lowther et al. Genet Med. 2017 Jan;19(1):53-61. PMID: 27195815). Thus, the clinical significance of this copy number variant (CNV) is pathogenic.