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SM Journal of Neurological Disorders and Stroke

WES Analysis Reveals a Nonsense Mutation in ASPM Gene Leading to Primary Microcephaly in a Saudi Arabian Family

[ ISSN : 3067-9982 ]

Abstract
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Received: 26-May-2016

Accepted: 09-Aug-2016

Published: 12-Aug-2016

Research Article | Volume 2 - Issue 1 | Article DOI :

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Nuha Alrayes¹², Saleem Ahmed²³, Hussein Sheikh Ali Mohamoud¹², Jumana Yousuf Al-Aama¹², Kate Everett², Jamal Nasir², and Musharraf Jelani¹⁴*

¹Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Saudi Arabia
²Cell Sciences and Genetics Research Centre, St. George’s University of London (SGUL), United Kingdom
³Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Saudi Arabia
?Biochemistry Department, Medical Genetics and Molecular Biology Unit, Institute of Basic Medical Sciences, Khyber Medical University, Pakistan

Corresponding Author:

Musharraf Jelani, Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Saudi Arabia and Medical Genetics and Molecular Biology Unit, Biochemistry Department, Institute of Basic Medical Sciences, Khyber Medical University, Pakistan

Keywords

Autosomal recessive primary microcephaly; ASPM gene; Nonsense mutation; SNP microarray; Whole exome sequencing; Molecular diagnostics

Abstract

Autosomal Recessive Primary Microcephaly (MCPH) is one of the most common hereditary neurological disorders in Saudi Arabia. Frequent consanguineous unions, due to isolated tribal set ups and large family sizes, is considered the primary reason for this high prevalence. In our study we ascertained a consanguineous family living in the South-Western region of the Kingdom. The patients were characterized by primary microcephaly, moderate intellectual disability and developmental delays. For genetic analysis we performed SNP array Based Comparative Genome Hybridization (aCGH) and analyzed the data for homozygosity mapping alongside Whole Exome Sequencing (WES). Three putative causal variants in regions of extended homozygosity on chromosome 1q31, chromosome 5p13.2 and chromosome 5p13.3 were identified: respectively, a nonsense variant in the ASPM gene (NM_018136; c.8903G>A; p.Trp2968*); a missense variant in SPEF2 (NM_024867; c.1262G>A; p.Arg421His); and a missense variant in PDZD2 (NM_178140; c.2153C>A; p.Thr718Asn) were found potential candidates for the disease phenotype in this family. Sanger sequencing determined that the variants in SPEF2 and PDZD2 did not co-segregate with the disease phenotype. However, the nonsense variant in ASPM does co-segregate with disease in this family. Our study concludes WES as a successful molecular diagnostic tool in this highly inbred population.

Citation

Alrayes N, Ahmeda S, Mohamoud HSA, Al-Aama JY, Everett K, Nasir J, et al. WES Analysis Reveals a Nonsense Mutation in ASPM Gene Leading to Primary Microcephaly in a Saudi Arabian Family. SM J Neurol Disord Stroke. 2016; 2(1): 1008.