In contrast to rare copy number variants (CNVs) causing classical syndromes such as Smith-Magenis syndrome and Williams syndrome, recent studies have identified a class of rare CNVs associated with the risk of developing a wide variety of neurodevelopmental and neuropsychiatric features. Individuals affected by these variants often have carrier parents who are apparently unaffected or manifest only subclinical neuropsychiatric features. This makes genetic diagnosis, counseling and management of individuals affected by such CNVs difficult. Several identified CNVs of this category, including 16p11.2 deletion, 1q21.1 deletion, 15q13.3 deletion and 16p12.1 deletion, collectively account for about 20 percent of individuals with neurodevelopmental disorders. Although these CNVs confer higher risk for a disorder, alone they are not sufficient for the manifestation of the disorder. It is therefore essential to consider additional genetic factors that may account for the observed variability in manifestation of these disorders.

Santhosh Girirajan and his colleagues previously identified a microdeletion at 16p12.1 associated with a range of neurodevelopmental phenotypes, including developmental delay¹. Girirajan proposes to study the 16p12.1 deletion as a paradigm for understanding how complex disease genetics leads to disease phenotypes. Girirajan’s team will perform an in-depth study of high-risk families carrying the 16p12.1 deletion. The researchers plan to evaluate the genomes of 50 families with at least one individual carrying the deletion to identify second-hit CNVs, single nucleotide variants, and small insertions and deletions. They also plan to perform deep clinical evaluation to quantify measures of neurodevelopmental function.

Variants in cis and trans to the 16p12.1 deletion will be prioritized for functional relevance and clinical significance. The researchers will also integrate genotypic and phenotypic data to identify phenotype-specific genes or loci contributing to the variability observed in individuals with the deletion. By providing a detailed assessment of the phenotypic variability associated with 16p12.1 deletion, this proposal will help to identify generalizable principles that contribute to the variability of phenotypes in other complex genetic disorders. Such findings will be valuable for understanding how other rare CNVs contribute to the heterogeneity of autism.