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

Abstract

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.

A case report of microcephaly and refractory West syndrome associated with WDR62 mutation

“…b: ictal EEG, epileptic spasm occurred with irregular high amplitude slow waves followed by short fast activities during the EEG recording Discussion WDR62 is located in chromosome 19q13.12, composing of 32 exons, encodes 1523 amino acids, and the protein contains multiple WD40 repeats [6,7]. Mutations in the WDR62 can cause severe cerebral cortical abnormalities, including microcephaly, cerebral gyrus hypertrophy with cortical thickening and dysplasia of corpus callosum [6,8,9], all inherited in an autosomal recessive. A number of neurobehavioral abnormalities have been reported, including psychomotor developmental delay, seizure, aggression and irritability [9][10][11].…”

“…Mutations in the WDR62 can cause severe cerebral cortical abnormalities, including microcephaly, cerebral gyrus hypertrophy with cortical thickening and dysplasia of corpus callosum [6,8,9], all inherited in an autosomal recessive. A number of neurobehavioral abnormalities have been reported, including psychomotor developmental delay, seizure, aggression and irritability [9][10][11]. In addition, some case reports claimed that WDR62 mutation can also cause skin changes [12].…”

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

“…Microcephaly is a condition characterized by a head circumference measuring at least three standard deviations below the mean for a given population, gender, and age (1). Primary microcephaly is a congenital developmental defect in which the cerebral cortex may be thickened or disorganized and in which the gyral pattern may be normal or simplified (1–5). Autosomal recessive (AR) primary microcephaly (Microcephaly Primary Hereditary, MCPH) is a rare form of primary microcephaly, characterized by a marked reduction in brain size, and intellectual disability, which affects 1 in 30,000 children in Japan (6) and 1 in 10,000 children in areas where consanguineous marriages are common (1, 4).…”

“…MCPH has previously been described as a genetically heterogeneous disorder influenced by mutations in at least 20 genes including ( MCPH1, WDR62, CDK5RAP2, KNL1, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6, MFSD2A, ANKLE2, CIT, AGMO, RTTN , and PGAP2 ) (2, 7). However, mutations in two particular genes are thought to be primarily responsible, with ASPM mutations being observed in over half of cases (1, 7, 8), and WDR62 mutations accounting for around 10% of MCPH cases (3, 5, 7, 8).…”

“…WDR62 is known to encode the WD repeat-containing protein 62, playing a significant role in neuronal progenitor cell proliferation and spindle formation (2, 5, 9, 10). Children with WDR62 mutations often present with intellectual disability alongside delayed development of speech and language skills and prominent microcephaly (2–5, 10, 11), whereas some also present with seizures (2, 3, 5, 11). Mutations in this gene are also reported to cause a range of other cortical malformations including polymicrogyria, pachygyria with cortical thickening, lissencephaly, schizencephaly, corpus callosum hypoplasia, simplified gyral patterns, cerebral hypoplasia, and band heterotopias (2–5, 11).…”