Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes

Marc Woodbury-Smith, Rob Nicolson, Mehdi Zarrei, Ryan K. C. Yuen, Susan Walker, Jennifer Howe, Mohammed Uddin, Ny Hoang, Janet A. Buchanan, Christina Chrysler, Ann Thompson, Peter Szatmari, Stephen W. Scherer

Autism Spectrum Disorder (ASD) is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to ASD, showing de novo and inherited unbalanced copy number variants (CNVs) and smaller insertions and deletions (indels), more complex structural variants (SVs), as well as single nucleotide variants (SNVs) deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two CNV microdeletions, which affect regions of NRXN1 and MBD5 - each well-established in association with risk of ASD and other neurodevelopmental disorders. Although each CNV would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks.