Two Novel Mutations (c.883-4_890del and c.1684C>G) of WDR62 Gene Associated With Autosomal Recessive Primary Microcephaly: A Case Report

Abstract

Background: Autosomal recessive primary microcephaly (Microcephaly Primary Hereditary, MCPH) is a rare disorder, affecting 1 in 10,000 children in areas where consanguineous marriages are common. WDR62 gene mutations are the second most common cause of MCPH. Herein, we report a case of primary microcephaly caused by two novel WDR62 mutations, which is, to our knowledge, the first such case report in East Asia.Case presentation: A 6-year-old girl visited our outpatient clinic as a result of microcephaly and delayed development. The patient was born at 36 weeks 4 days through cesarean section. Her birth weight was 1.8 kg (<1st percentile), and she was noted to have microcephaly (head circumference at birth was 28 cm, <−3SD). On examination, delayed speech development and microcephaly with an occipitofrontal head circumference of 43.5 cm (<−3SD) were noted. The patient's gross and fine motor development was normal. Her intelligence quotient was 43 (<0.1 percentile), the same as a 27-month-old child, and her social intelligence quotient was 76.92. Brain imaging revealed simplified gyral patterns of the cerebral cortex; however, laboratory findings, including organic acids, were normal. Multiplex ligation-dependent probe amplification technique for microdeletion syndrome and chromosomal microarray, showed no abnormality. Clinical exome sequencing test revealed two novel heterozygous variants in the WDR62 gene at two different sites: in the boundary of intron 7 and exon 8 (NM_001083961.1: c.883-4_890del) and in exon 13 (NM_001083961.1: c.1684C>G). The patient's parents were identified as heterozygous carriers for each variation.Conclusion: We report on two novel heterozygous mutations in East Asia. Our data expand the understanding of WDR62 mutations.

An update of pathogenic variants in ASPM, WDR62, CDK5RAP2, STIL, CENPJ, and CEP135 underlying autosomal recessive primary microcephaly in 32 consanguineous families from Pakistan

“…Our data also supported the notion that WDR62 (MIM# 613583) is the second most frequently mutated gene (14%) of MCPH (Zaqout et al, 2017), because we have found a nearly similar number of MCPH families (15.62%) with mutations in this gene. After a thorough literature review of WDR62 mutations by Poulton and colleagues (Poulton et al, 2014), summarizing a total of 24 mutations, 29 new mutations were published thereafter (Kvarnung et al, 2018; Yi et al, 2019; Zombor et al, 2019). The novel missense mutation reported in our study increased the total number of identified mutations to 54 (Figure 1 and Table ).…”

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 ].…”

“…Delayed psychomotor development was observed in most children, although in some the motor development was normal in the first months of life [ 28 , 34 ]. Hypotonia was described only in 9 out of 30 [30%] and spasticity or hyperreflexia in 16 out of 44 patients [37%].…”

Neurological outcome in WDR62 primary microcephaly

“…Taken individually, 44 out of 60 patients were able to walk independently, and 44 out of 59 patients were able to talk with simple sentences. Objective evaluation of cognitive abilities was only reported for 3 out of 137 patients, for one of whom IQ was assessed using the Korean-Leiter International Performance Scale -Revised test 12 and for two of whom a developmental quotient was calculated from VABS. 1,13…”