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

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.

SUBMITTER: Naseer MI

PROVIDER: S-EPMC6572970 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Naseer Muhammad Imran MI Rasool Mahmood M Abdulkareem Angham Abdulrahman AA Chaudhary Adeel G AG Zaidi Syed Kashif SK Al-Qahtani Mohammad H MH

Pakistan journal of medical sciences 20190101 3

<h4>Objective</h4>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.<h4>Methods</h4>Whole exo ...[more]

PMID: 31258591

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Project description:Developmental glaucoma, a subset of glaucoma, is associated with trabeculodysgenesis and/or anterior segment dysgenesis. It is one of the major causes of childhood blindness. Understanding its genetic background is important to diagnose, and identify potential therapeutic targets, of this disease. The present study aimed to detect the molecular origin of developmental glaucoma in a Chinese pedigree and its association with glaucomatous phenotypes. A three‑generation pedigree with developmental glaucoma was analyzed in the current study; a thorough ocular examination was performed on the proband and other individuals in the family. Genomic DNA was extracted from the peripheral blood of each individual, and possible disease‑causing genes were screened for mutations using a candidate gene panel. Exons and adjacent regions of the target genes were captured and enriched by probe hybridization. The enriched genes were sequenced on an Illumina high‑throughput sequencer. Variations were verified in other family members using Sanger sequencing. Disease causing mutations were analyzed by comparing the sequences and the structures of wild‑type and mutated cytochrome P450 family 1 subfamily B member 1 (CYP1B1) proteins using PyMOL software. The proband was diagnosed with developmental glaucoma and his parents and other relatives were asymptomatic. Novel compound heterozygous mutations, c.3G>A (p.M1I) and c.1310C>T (p.P437L), in CYP1B1 were detected in the proband, with the former inherited from his father and the latter from his mother. The c.3G>A (p.M1I) change is a novel mutation that disrupts the ATG start codon in exon one of CYP1B1 and therefore interferes with the translation start site. In conclusion, the findings of the present study suggested that the aforementioned compound heterozygous mutations in CYP1B1 may have caused developmental glaucoma in this Chinese family. The c.3G>A mutation in CYP1B1 is a novel mutation, and this study expands the gene mutation spectrum of CYP1B1.

Dataset Information

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

Publications

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

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