A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family

Abstract

BACKGROUNDPrimary microcephaly (MCPH) is a rare developmental defect characterized by impaired cognitive functions, retarded neurodevelopment and reduced brain size. It is genetically heterogeneous and more than 17 genes so far have been identified that are associated with this disease.OBJECTIVETo study the genetic defect in a consanguineous Saudi family with primary microcephaly.DESIGNCross-sectional clinical genetics study of a Saudi family.SETTINGMedical genomics research center.PATIENTS AND METHODSBlood samples collected from six members of a family of healthy consanguineous parents were analyzed by whole exome sequencing to identify the underlying pathogenic mutations in two members of the family (23-year-old female and 7-year-old male) who presented with primary microcephaly, intellectual disability, delayed psychomotor development and walking difficulty, speech impediments and seizures.MAIN OUTCOME MEASURE(S)Detection of mutation in the WD repeat domain 62 (WDR62) gene in a family segregating autosomal recessive primary microcephaly.RESULTSThe exome variant analysis identified a novel missense mutation (c.3878C>A) in WDR62 gene in exon 30 resulting in amino acid change from alanine to aspartate (p.Ala1293Asp). Further validation in the affected patients and healthy members of family and 100 unrelated healthy persons as controls confirmed it to be pathogenic.CONCLUSIONSFunctional impairment of the WDR62 gene can lead to severe neurodevelopmental defects, brain malformations and reduced head size. A missense mutation of exon 30 changed alanine to aspartate in the WDR62 protein leading to the typical MCPH phenotype.LIMITATIONSMutation was identified in a single family.

A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature

“…Over 40 pathogenic mutations in WDR62 have already been published. In addition to microcephaly, a wide range of cortical malformations was also described in these patients (Bacino et al 2012;Banerjee et al 2016;Bastaki et al 2016;Bhat et al 2011;Farag et al 2013;Sajid Hussain et al 2013;Kousar et al 2011;McDonell et al 2014;Memon et al 2013;Miyamoto et al 2017;Murdock et al 2011;Najmabadi et al 2011;Nardello et al 2018;Naseer et al 2017;Poulton et al 2014;Rupp et al 2014;Wang et al 2017).…”

A case report of microcephaly and refractory West syndrome associated with WDR62 mutation

“…Mutations in the WDR62 can cause severe cerebral cortical abnormalities, including microcephaly, cerebral gyrus hypertrophy with cortical thickening and dysplasia of corpus callosum [6,8,9], all inherited in an autosomal recessive. A number of neurobehavioral abnormalities have been reported, including psychomotor developmental delay, seizure, aggression and irritability [9][10][11]. In addition, some case reports claimed that WDR62 mutation can also cause skin changes [12].…”

Comprehensive review on the molecular genetics of autosomal recessive primary microcephaly (MCPH)

“…The majority of mutations found in WDR62 revealed that these are responsible for approximately 10% of cases of microcephaly. Homozygous or heterozygous mutations in WDR62 both cause MCPH with or without cortical malformations (Naseer et al, 2017). Patients with these mutations have a head circumference ranging from normal to severe.…”