WDR62 – Primary Microcephaly 2

Autosomal recessive primary microcephaly 2 (MCPH2) is characterized by congenital microcephaly often with cortical malformations and global developmental delay. WDR62 encodes a JNK scaffold protein integral to centrosome function and cortical layer formation. Mutations were first implicated in MCPH2 via linkage and high‐throughput sequencing in multiple families, identifying biallelic variants segregating with disease (PMID:20890278).

Biallelic WDR62 variants have now been documented in at least 20 probands from 8 unrelated consanguineous families, including truncating, splice, and missense changes with clear segregation (PMID:20890278; PMID:21961505; PMID:26577670). In a Sudanese pedigree, the novel splice‐site variant c.390G>A (p.Glu130=) was homozygous in siblings with incomplete lissencephaly and developmental delay (PMID:26577670). In another report, the homozygous missense c.668T>C (p.Phe223Ser) segregated in two affected siblings, expanding the variant spectrum (PMID:30706430).

To date, >14 distinct coding variants have been reported, including nonsense (e.g., c.2984C>G (p.Ser995Ter)), frameshift (c.2527dup (p.Asp843GlyfsTer3)), splice‐site (c.3335+1G>C), and missense (c.668T>C (p.Phe223Ser)) alleles. These changes are distributed across WD40 repeats and C‐terminal domains, with no recurrent founder variant identified.

Functional studies demonstrate that WDR62 localizes to centrosomes and mitotic spindles in neural progenitors (PMID:21496009). Patient‐derived cells display abnormal spindle morphology and mitotic delay, rescuable by wild‐type but not mutant WDR62 (PMID:24388750). Wdr62‐null mice exhibit reduced brain size due to premature neural progenitor differentiation and apoptosis, recapitulating human MCPH2 (PMID:24875059).

Mechanistically, WDR62 acts upstream of JNK1 and Aurora kinases to orchestrate spindle assembly and mitotic progression; loss‐of‐function mutations impair kinase docking at spindle poles, leading to cortical thinning (PMID:24388750; PMID:25501809).

Collectively, the breadth of genetic and experimental data meets definitive ClinGen criteria for MCPH2. WDR62 sequencing is recommended in autosomal recessive microcephaly with cortical malformations, guiding diagnosis, counseling, and future therapeutic strategies.

References

• Nature genetics • 2010 • Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. PMID:20890278
• Clinical genetics • 2011 • Mutations in WDR62, encoding a centrosomal and nuclear protein, in Indian primary microcephaly families with cortical malformations. PMID:21496009
• Nature communications • 2014 • Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size. PMID:24875059
• Cell reports • 2014 • Microcephaly-associated protein WDR62 regulates neurogenesis through JNK1 in the developing neocortex. PMID:24388750
• Congenital anomalies • 2016 • Novel splice-site mutation in WDR62 revealed by whole-exome sequencing in a Sudanese family with primary microcephaly. PMID:26577670
• Journal of applied genetics • 2019 • A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature. PMID:30706430

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