Case Report-An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions

Abstract

Background: Heterozygous, large-scale deletions at 14q24.3-31.1 affecting the neurexin-3 gene have been associated with neurodevelopmental disorders such as autism. Both "de novo" occurrences and inheritance from a healthy parent suggest incomplete penetrance and expressivity, especially in autism spectrum disorder. NRXN3 encodes neurexin-3, a neuronal cell surface protein involved in cell recognition and adhesion, as well as mediating intracellular signaling. NRXN3 is expressed in two distinct isoforms (alpha and beta) generated by alternative promoters and splicing. MM/Results: Using exome sequencing, we identified a monoallelic frameshift variant c.159_160del (p.Gln54AlafsTer50) in the NRXN3 beta isoform (NM_001272020.2) in a 5-year-old girl with developmental delay, autism spectrum disorder, and behavioral issues. This variant was inherited from her mother, who did not have any medical complaints.

Discussion: This is the first detailed report of a loss-of-function variant in NRXN3 causing an identical phenotype, as reported for heterozygous large-scale deletions in the same genomic region, thereby confirming NRXN3 as a novel gene for neurodevelopmental disorders with autism.

Keywords: NRXN3; autism; neurodevelopmental disorder; novel disease.

Figure 1

Results of Sanger sequencing and schematic presentation of NRXN3 gene organization. (A): Sanger sequencing of the affected patient and the parents. (B): Schematic presentation of the NRXN3 gene organization showing the two promoters used for generation of long α- and short β-NRXN3 isoforms adapted from Hishimoto et al. (2007) [61]. The NRXN3 LoF variant affects exon β1. The p.Gln54AlafsTer50 variant should cause a complete loss of all NRXN3 β-isoforms in the patient.