Novel Missense CNTNAP2 Variant Identified in Two Consanguineous Pakistani Families With Developmental Delay, Epilepsy, Intellectual Disability, and Aggressive Behavior.

Autor:	Badshah N; Institute of Biotechnology and Genetic Engineering, University of Agriculture Peshawar, Peshawar, Pakistan.; Department of Human Genetics, Emory University, Atlanta, GA, United States., Mattison KA; Department of Human Genetics, Emory University, Atlanta, GA, United States.; Genetics and Molecular Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA, United States., Ahmad S; Institute of Biotechnology and Genetic Engineering, University of Agriculture Peshawar, Peshawar, Pakistan., Chopra P; Department of Human Genetics, Emory University, Atlanta, GA, United States., Johnston HR; Department of Human Genetics, Emory University, Atlanta, GA, United States., Ahmad S; Department of Animal Health, University of Agriculture Peshawar, Peshawar, Pakistan., Khan SH; Institute of Biotechnology and Genetic Engineering, University of Agriculture Peshawar, Peshawar, Pakistan., Sarwar MT; Department of Molecular Biology and Genetics, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan., Cutler DJ; Department of Human Genetics, Emory University, Atlanta, GA, United States., Taylor M; Department of Pediatric Neurology, Leeds Teaching Hospital NHS Trust, Leeds, United Kingdom., Vadlamani G; Department of Pediatric Neurology, Leeds Teaching Hospital NHS Trust, Leeds, United Kingdom., Zwick ME; Department of Human Genetics, Emory University, Atlanta, GA, United States., Escayg A; Department of Human Genetics, Emory University, Atlanta, GA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in neurology [Front Neurol] 2022 Jul 14; Vol. 13, pp. 918022. Date of Electronic Publication: 2022 Jul 14 (Print Publication: 2022).
DOI:	10.3389/fneur.2022.918022
Abstrakt:	We report the genetic analysis of two consanguineous pedigrees of Pakistani ancestry in which two siblings in each family exhibited developmental delay, epilepsy, intellectual disability and aggressive behavior. Whole-genome sequencing was performed in Family 1, and we identified ~80,000 variants located in regions of homozygosity. Of these, 615 variants had a minor allele frequency ≤ 0.001, and 21 variants had CADD scores ≥ 15. Four homozygous exonic variants were identified in both affected siblings: PDZD7 (c.1348_1350delGAG, p.Glu450del), ALG6 (c.1033G>C, p.Glu345Gln), RBM20 (c.1587C>G, p.Ser529Arg), and CNTNAP2 (c.785G>A, p.Gly228Arg). Sanger sequencing revealed co-segregation of the PDZD7, RBM20 , and CNTNAP2 variants with disease in Family 1. Pathogenic variants in PDZD7 and RBM20 are associated with autosomal recessive non-syndromic hearing loss and autosomal dominant dilated cardiomyopathy, respectively, suggesting that these variants are unlikely likely to contribute to the clinical presentation. Gene panel analysis was performed on the two affected siblings in Family 2, and they were found to also be homozygous for the p.Gly228Arg CNTNAP2 variant. Together these families provide a LOD score 2.9 toward p.Gly228Arg CNTNAP2 being a completely penetrant recessive cause of this disease. The clinical presentation of the affected siblings in both families is also consistent with previous reports from individuals with homozygous CNTNAP2 variants where at least one allele was a nonsense variant, frameshift or small deletion. Our data suggests that homozygous CNTNAP2 missense variants can also contribute to disease, thereby expanding the genetic landscape of CNTNAP2 dysfunction. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Badshah, Mattison, Ahmad, Chopra, Johnston, Ahmad, Khan, Sarwar, Cutler, Taylor, Vadlamani, Zwick and Escayg.)
Databáze:	MEDLINE
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