CLINICAL AND COGNITIVE PHENOTYPING OF COPY NUMBER VARIANTS PATHOGENIC FOR NEURODEVELOPMENTAL DISORDERS FROM A MULTI-ANCESTRY BIOBANK.

Abstract

Rare copy number variants (CNVs) are pathogenic for neurodevelopmental disorders (NDDs) and effect neurocognitive impairment. In aggregate, NDD CNVs may present in up to 2% of population cohorts with implications for neuropsychiatric disease risk and cognitive health. However, analyses of NDD CNVs in biobanks or population cohorts have been hindered by limited clinical or cognitive phenotypes, and a lack of ancestral diversity. In the current proof-of-concept study, NDD CNV carriers were recontacted from BioMe, a multi-ancestry biobank derived from the Mount Sinai healthcare system, to enable 'deep phenotyping' beyond electronic health record outcomes. From BioMe biobank, 892 adult participants were recontacted, including 335 harboring NDD CNVs, 217 with schizophrenia and 340 neurotypical controls as comparators. Clinical and cognitive assessments were administered to each recruited participant. Seventy-three participants completed study assessments (mean age=48.8 years; 66% female; 36% African, 26% European, 34% Hispanic), or 8% of the recontacted subset, including 30 NDD CNV carriers across 15 loci. Among NDD CNV carriers, assessments indicated 40% with mood and anxiety disorders, 30% with learning disorders, and 13% with a history of special education. NDD CNV carriers were significantly cognitively impaired compared to controls on digit span backwards (Beta=-1.76, FDR=0.04) and digit span sequencing (Beta=-2.01, FDR=0.04). Feasibility of "recall-by-genotype" from a multi-ancestry biobank was established for NDD CNV carriers, along with comparator groups. The current study corroborated past reports of NDD CNVs effects of cognitive impairment, while elucidating clinical phenotypes for recalled individuals. Future "recall-by-genotype" studies may further facilitate clinical characterization of disease-relevant genomic variants.