Novel compound heterozygous mutations in WDR62 gene leading to developmental delay and Primary Microcephaly in Saudi Family.

Muhammad Imran Naseer,Syed Kashif Zaidi,Mahmood Rasool,Angham Abdulrahman Abdulkareem,Adeel G Chaudhary,Mohammad H Al-Qahtani

doi:10.12669/pjms.35.3.36

Abstract

Objective:Primary microcephaly (MCPH) is a rare autosomal recessive disorder characterized by impaired congenital reduction of brain size along with head circumference and intellectual disability. MCPH is a heterogeneous disorder and more than twenty four genes associated with this disease have been identified so far. The objective of this study was to find out the novel genes or mutations leading to the genetic defect in a Saudi family with primary microcephaly.Methods:Whole exome sequencing was carried out to find the novel mutation and the results was further validated using Sanger sequencing analysis. This study was done in the Center of excellence in Genomic Medicine and Research, King Abdulaziz University under KACST project during 2017 and 2018.Results:We report a novel compound heterozygous mutations c.797C>T in exon 7 and c.1102G>A in exon 9 of the WD repeat domain 62 (WDR62) (OMIM 604317) gene in two affected siblings in Saudi family with intellectual disability, speech impediments walking difficulty along with primary microcephaly. Two rare, missense variants were detected in heterozygous state in the WDR62 gene in these two affected individuals from the heterozygous parents.Conclusions:A compound heterozygous mutations c.797C>T in exon 7 and c.1102G> A in exon 9 of the WDR62 gene was identified. WDR62 gene is very important gene and mutation can lead to neuro developmental defects, brain malformations, reduced brain and head size. These results should be taken into consideration during prognostic discussions and mutation spectrum with affected patients and their families in the Saudi population.

Highlights

The autosomal recessive form of primary microcephaly (MCPH) is a rare genetic disorder that is characterized by head circumference less than three standard deviation below the mean from age and sex associated with mild to severe intellectual disability.[1]
We have reported in our recent study a missense mutation in exon 30 of WDR62changing alanine to aspartate in the protein leading to the typical microcephaly 2 (MCPH2) phenotype.[4]
Compound Heterozygous Mutations in WD repeat domain 62 (WDR62) Identified through Exome Sequencing: Whole exome sequencing revealed two rare, missense variants detected in heterozygous state in the WDR62 gene of this patient

Summary

Introduction

The autosomal recessive form of primary microcephaly (MCPH) is a rare genetic disorder that is characterized by head circumference less than three standard deviation below the mean from age and sex associated with mild to severe intellectual disability.[1]. Pak J Med Sci May - June 2019 Vol 35 No 3 www.pjms.org.pk 764 spindle microtubule assembly (ASPM) OMIM 608716 genes accounting for more than half of all mutations; and WDR62 gene around 10% of all reported cases related to primary microcephaly.[2]. WD repeat domain 62 genes (WDR62 – GenBank Accession NM_005682.5) are known to play important role in cerebral cortical development and any mutations in this gene lead to cortical malformations, mental retardation and primary microcephaly. G > T (p.Glu 805 X) in the WDR62 gene responsible for the mitotic centrosomal protein WDR62, in a microcephaly family from Japanese.[3] We have reported in our recent study a missense mutation in exon 30 of WDR62changing alanine to aspartate in the protein leading to the typical MCPH2 phenotype.[4] Whereas new homozygous splicing variantc.3335+1G>C in the WDR62 gene reported recently.[5]

Methods

Results

Conclusion