Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression

• Published in: Genetics in medicine Vol. 19; no. 1; pp. 53 - 61
• Main Authors: Lowther, Chelsea, Speevak, Marsha, Armour, Christine M., Goh, Elaine S., Graham, Gail E., Li, Chumei, Zeesman, Susan, Nowaczyk, Malgorzata J.M., Schultz, Lee-Anne, Morra, Antonella, Nicolson, Rob, Bikangaga, Peter, Samdup, Dawa, Zaazou, Mostafa, Boyd, Kerry, Jung, Jack H., Siu, Victoria, Rajguru, Manjulata, Goobie, Sharan, Tarnopolsky, Mark A., Prasad, Chitra, Dick, Paul T., Hussain, Asmaa S., Walinga, Margreet, Reijenga, Renske G., Gazzellone, Matthew, Lionel, Anath C., Marshall, Christian R., Scherer, Stephen W., Stavropoulos, Dimitri J., McCready, Elizabeth, Bassett, Anne S.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.01.2017; Nature Publishing Group US; Elsevier Limited
• Subjects: 631/1647/2017/2079; 631/208/2489; 631/208/457/649; 692/699/375/366; Biomedicine; Calcium-Binding Proteins; Cell Adhesion Molecules, Neuronal - genetics; Child; copy-number variation; DNA Copy Number Variations; Exons - genetics; Female; Genetic Predisposition to Disease; Genotype; genotype–phenotype; Human Genetics; Humans; Introns - genetics; Laboratory Medicine; Male; Microarray Analysis; Nerve Tissue Proteins - genetics; Neural Cell Adhesion Molecules; Neurodevelopmental Disorders - epidemiology; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - physiopathology; NRXN1; original-research-article; Penetrance; Phenotype; Sequence Deletion; variable expression; genotype–phenotype; variable expression; NRXN1; copy-number variation; penetrance
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/gim.2016.54

The purpose of the current study was to assess the penetrance of NRXN1 deletions. We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions. We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91–22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3ʹ end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5ʹ NRXN1 deletion (OR = 7.47; 95% CI: 2.36–23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035). The results support the importance of exons near the 5ʹ end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.