A novel non sense mutation in WDR62 causes autosomal recessive primary microcephaly: a case report

Abstract

BackgroundAutosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development characterized by a reduced head circumference at birth with no remarkable anomalies of brain architecture and variable degrees of intellectual impairment. Clinical and genetic heterogeneity in genetic disorders represent a major diagnostic challenge.Case presentationTwo patients, 11 and 9 years old, born from consanguineous parents, were referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of MCPH was made, based on reduced head circumference without brain architecture abnormalities. The two patients were subject to the whole-exome sequencing, which allowed to diagnose a novel homozygous mutation c.1027C > T; p.Gln343* in exon 8 of WDR62, a gene already known to be related to MCPH. Sanger sequencing confirmed the segregation of the mutation in the family.ConclusionOur data expends the spectrum of mutations in WDR62 gene, proves the efficiency and cost-effectiveness of whole exome sequencing for the molecular diagnosis of genetically heterogeneous disorders such MCPH. Exome sequencing led to the rapid and cost-effective identification of a novel homozygous mutation in WDR62 gene, thereby facilitating genetic counseling.

Further Delineation of Phenotype and Genotype of Primary Microcephaly Syndrome with Cortical Malformations Associated with Mutations in the WDR62 Gene

“…Most of the reported cases come from countries that allow marriage between relatives. Complex heterozygotes were found only in 11 cases and their clinical picture did not differ significantly from those in which homozygotes were found [ 6 , 8 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

Primary microcephaly with an unstable genome

“…The WDR62 gene contains 32 exons and is located in the MCPH2 candidate region on chromosome 19q13.12. It encodes a 1523-amino acid protein with multiple WD40 repeats, which are ~ 40-amino acid-long structural motifs that normally end in a tryptophan-aspartic acid dipeptide (Cherkaoui Jaouad et al 2018). A WDR62 null was identified as the second most common cause of MCPH due to the discovery of homozygous missense and frame-shifting mutations in seven MCPH Arab, Pakistani and Caucasian families (Adeline K. Nicholas et al 2010).…”

The Spindle-Associated Microcephaly Protein, WDR62, Is Required for Neurogenesis and Development of the Hippocampus

“…Previous studies have identified numerous (>35) patient mutations in WDR62 that are causative of primary microcephaly ( Shohayeb et al, 2017 ; Cherkaoui Jaouad et al, 2018 ; Yi et al, 2019 ). These mutations variously disrupt mRNA stability, splicing or result in the severe truncation WDR62 to trigger nonsense-mediated decay, and lost expression ( Xu et al, 2014 ; Shohayeb et al, 2017 , 2019 ) highlighting that WDR62 expression is required for normal brain growth.…”