Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

Abstract

There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant 1. However, patients with the same genetic defect can have different clinical presentation 2–4, and some individuals carrying known disease-causing variants can appear unaffected 5. What explains these differences? Here, we show in a cohort of 6,987 children with heterogeneous severe neurodevelopmental disorders expected to be almost entirely monogenic that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, decreased intelligence, and risk of schizophrenia. We found that common variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in disorders typically considered to be monogenic.

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual

“…To date, many researchers have worked to reveal interactions between genetic variants and disease phenotypes. Recently, COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-020-0755-1 ARTICLE COMMUNICATIONS BIOLOGY | (2020) 3:33 | https://doi.org/10.1038/s42003-020-0755-1 | www.nature.com/commsbio genome-wide quantification analyses have shown that rare mutations are found in normal tissue, whereas risk variants from neurodevelopmental disorder patients are common genetic variants, implying that non-rare genetic variants may cause genetic disease in some patients [50][51][52][53][54][55] . In this study, we showed that correction of the ATP7A M1311V mutation can rescue the function of MNs derived from cells of one ALS patient of Ashkenazi Jewish descent.…”

Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes

“…Current research suggests that genetic effects can overlap between syndromes that have traditionally been considered as clinically distinct. Similarly, genetic overlaps are reported between Mendelian forms of disease and more complex forms of disorder [23][24][25] . These changes in the field led us to apply an alternative approach to the investigation of molecular mechanisms underlying hearing and language within the current study.…”

Treatment-resistant psychotic symptoms and the 15q11.2 BP1–BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature

“…Factors that can disrupt neurodevelopment are not fully delineated, but a significant proportion of neurodevelopmental risk is attributed to copy number variants (CNVs) 5,6 . CNVs are structural mutations that occur when genomic regions are duplicated or deleted compared to the reference genome 7 . Several large, rare CNVs have been robustly associated with increased risk for neurodevelopmental disorders (NDDs) including intellectual disability (ID), developmental delay (DD), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and multiple congenital anomalies 8,9 .…”