The genetic epidemiology of the form of microcephaly ascribed to mutation at the WDR62 locus

Stark, Alan E.

doi:10.21037/atm.2016.07.08

Cited by 5 publications

(4 citation statements)

References 14 publications

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“…Mutations in WDR62 have been associated with primary microcephaly 2 (MCPH2), with or without cortical malformations 14,16,17. This is a disease characterized by microcephaly associated with other manifestation and showing a wide phenotypic variability 18.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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. doi: https://doi.org/10.12669/pjms.35.3.36 How to cite this:Naseer MI, Rasool M, Abdulkareem AA, Chaudhary AG, Zaidi SK, Al-Qahtani MH. Novel compound heterozygous mutations in WDR62 gene leading to developmental delay and Primary Microcephaly in Saudi Family. Pak J Med Sci. 2019;35(3):---------. doi: https://doi.org/10.12669/pjms.35.3.36 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“… 32 Mutations in this gene have been associated with microcephaly 2, primary, autosomal recessive, with or without cortical malformations (MCPH2). 7 – 9 , 33 – 36 This is a disease characterized by microcephaly associated with other manifestations and shows wide phenotypic variability. 37 Associated features include moderate to severe mental retardation, and various types of cortical malformations in most patients.…”

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

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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.

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“…The human WDR62 ( WD repeat domain 62 ) gene is localized in the 19q13.12 region and encodes a 1523 amino acid protein that is localized in the cytoplasm and centrosome . WDR62 plays important roles in cell cycle progression, spindle maintenance, and cell proliferation, and germline mutations of the WDR62 gene cause primary microcephaly, which is characterized by a rare neurodevelopmental disease with severe microcephaly at birth . In human malignancies, the overexpression of WDR62 protein has been recently reported in gastric cancer and ovarian cancer; however, whether abnormal WDR62 expression is present in other types of cancers, including LAC, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…neurodevelopmental disease with severe microcephaly at birth. [4][5][6][7][8][9][10] In human malignancies, the overexpression of WDR62 protein has been recently reported in gastric cancer and ovarian cancer 8,11 ; however, whether abnormal WDR62 expression is present in other types of cancers, including LAC, remains unclear. Given this situation, we first examined whether WDR62 is aberrantly expressed in LAC in the present study.…”

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WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma

Shinmura

Kato

Kawanishi

et al. 2017

Molecular Carcinogenesis

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Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.0432, Wilcoxon matched pairs test). An immunohistochemical analysis for LAC (n = 237) showed that WDR62 proteins were also significantly overexpressed in LAC (P < 0.0001, Mann-Whitney U test). A Kaplan-Meier analysis demonstrated that patients with LAC who exhibit WDR62 overexpression have a short overall survival (P = 0.0378, log-rank test), and a multivariate analysis revealed that WDR62 overexpression was an independent predictor of a poor survival outcome among LAC patients (hazard ratio, 2.032; 95% confidence interval, 1.071-3.777; P = 0.0305). Next, we examined the functional effect of WDR62 overexpression on the lung cancer cell line H1299. WDR62-overexpressing lung cancer cells exhibited an increase in cell growth. Moreover, the concurrent overexpression of WDR62 and TPX2, a WDR62-interacting protein that is also overexpressed in LAC, induced centrosome amplification in the lung cells. Finally, we disclosed that the concurrent overexpression of WDR62 and TPX2 is common in diverse human cancers, using data from the Cancer Genome Atlas. These results suggested that WDR62 overexpression is associated with a poor prognosis in patients with LAC and leads to an increase in the malignant potential of lung cells.

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The genetic epidemiology of the form of microcephaly ascribed to mutation at the WDR62 locus

Cited by 5 publications

References 14 publications

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

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

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

WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma

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