An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder

J Cell Mol Med. 2021 Mar;25(5):2459-2470. doi: 10.1111/jcmm.16161. Epub 2021 Jan 21.


Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%-30%) presenting a rare large-effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD-associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole-exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion-transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 × 10-5 ). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low-level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large-effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders.

Keywords: NRXN1; ASD; mtDNA; penetrance; rare variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Autism Spectrum Disorder / diagnosis
  • Autism Spectrum Disorder / etiology*
  • Autism Spectrum Disorder / psychology
  • Calcium-Binding Proteins / genetics*
  • Comparative Genomic Hybridization
  • Computational Biology / methods
  • DNA Copy Number Variations
  • Exons
  • Female
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Genome, Mitochondrial
  • Genomics / methods
  • Heterozygote*
  • Humans
  • Infant
  • Male
  • Neural Cell Adhesion Molecules / genetics*
  • Penetrance*
  • Phenotype
  • Sequence Deletion*
  • Whole Exome Sequencing


  • Calcium-Binding Proteins
  • NRXN1 protein, human
  • Neural Cell Adhesion Molecules