Novel splice‐site mutation in <scp><i>WDR</i></scp><i>62</i> revealed by whole‐exome sequencing in a <scp>S</scp>udanese family with primary microcephaly

Bastaki, Fatma; Mohamed, Madiha; Nair, Pratibha; Saif, Fatima; Tawfiq, Nafisa; Gururaj, Aithala; El-Halik, Majdi; Al-Ali, Mahmoud Taleb; Hamzeh, Abdul Rezzak

doi:10.1111/cga.12144

Cited by 14 publications

(11 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When mutations in WDR62 were initially discovered15, it became apparent that they cause a form of microcephaly invariably accompanied by a wide spectrum of additional and diverse cortical abnormalities, including pachygyria, thickened cortex, lissencephaly, and polymicrogyria, which were traditionally thought to be distinct, suggesting they can have a unified underlying genetic causation. More than 30 missense, nonsense, frameshift or splice site mutations mapping throughout the gene have been reported in patients around the world (refs 15, 16, 17,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and our unpublished findings). Like many other MCPH-associated proteins, WDR62 has been implicated in spindle maintenance, mitotic progression and maintenance of the neural progenitor pool333435 and further shown to associate with c-Jun N-terminal kinase (JNK) and Aurora kinase A333436373839.…”

mentioning

confidence: 56%

Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly

Sgourdou

Mishra-Gorur

Saotome

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase. Expression of WDR62 is closely correlated with components of the chromosome passenger complex (CPC), a key regulator of mitosis. Wild type WDR62, but not disease-associated mutant forms, interacts with the CPC core enzyme Aurora kinase B and staining of CPC components at centromeres is altered in patient-derived fibroblasts. Our findings demonstrate critical and diverse functions of WDR62 in neocortical development and provide insight into the mechanisms by which its disruption leads to a plethora of structural abnormalities.

show abstract

mentioning

confidence: 56%

Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly

Sgourdou

Mishra-Gorur

Saotome

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Val1402GlyfsTer12; Q470X; Gly1280AlafsTer21; 2083delA; 2472_2473delAG; c.390G>A; c.2527dupG; p.R438H; p.D955Afs*112). 8 , 9 , 34 , 35 , 38 – 40 The frameshift mutations reported by Murdock et al were reported to cause nonsense-mediated mRNA decay and loss of function. 34 However, the effect of the missense variant detected here remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

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

Naseer

Rasool

Sogaty

et al. 2017

Annals of Saudi Medicine

View full text Add to dashboard Cite

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.

show abstract

“…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).…”

Section: Introductionmentioning

confidence: 90%

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

et al. 2019

View full text Add to dashboard Cite

Autosomal recessive primary microcephaly (MCPH) is a group of rare neurodevelopmental diseases with severe microcephaly at birth. One type of the disorder, MCPH2, is caused by biallelic mutations in the WDR62 gene, which encodes the WD repeatcontaining protein 62. Patients with WDR62 mutation may have a wide range of malformations of cortical development in addition to congenital microcephaly. We describe two patients, a boy and a girl, with severe congenital microcephaly, global developmental delay, epilepsy, and failure to thrive. MRI showed hemispherical asymmetry, diffuse pachygyria, thick gray matter, indistinct gray-white matter junction, and corpus callosum and white matter hypoplasia. Whole exome sequencing revealed the same novel homozygous missense mutation, c.668T>C, p.Phe223Ser in exon 6 of the WDR62 gene. The healthy parents were heterozygous for this mutation. The mutation affects a highly conserved region in one of the WD repeats of the WDR62 protein. Haplotype analysis showed genetic relatedness between the families of the patients. Our findings expand the spectrum of mutations randomly distributed in the WDR62 gene. A review is also provided of the brain malformations described in WDR62 mutations in association with congenital microcephaly.

show abstract

Novel splice‐site mutation in WDR62 revealed by whole‐exome sequencing in a Sudanese family with primary microcephaly

Cited by 14 publications

References 10 publications

Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly

Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly

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

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

Contact Info

Product

Resources

About