Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

Genet Med. 2019 Apr;21(4):816-825. doi: 10.1038/s41436-018-0266-3. Epub 2018 Sep 7.


Purpose: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants.

Methods: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants.

Results: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes.

Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

Keywords: 16p11.2 deletion; CNV; autism; modifier; phenotypic variability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autistic Disorder / genetics*
  • Autistic Disorder / physiopathology
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Chromosomes, Human, Pair 16 / genetics
  • Cognition / physiology
  • Cytoskeletal Proteins
  • DNA Copy Number Variations / genetics
  • Female
  • Gene Expression Regulation / genetics
  • Genetic Background
  • Genetic Carrier Screening*
  • Humans
  • Male
  • Methyltransferases / genetics*
  • Nerve Tissue Proteins / genetics*
  • Neural Cell Adhesion Molecules
  • Parents
  • Pedigree
  • Phenotype
  • Proteins / genetics*
  • Sequence Deletion / genetics
  • Siblings
  • Transcription Factors


  • AUTS2 protein, human
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal
  • Cytoskeletal Proteins
  • NRXN1 protein, human
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules
  • Proteins
  • Transcription Factors
  • Methyltransferases
  • SETD5 protein, human