WDR62 – Isolated congenital microcephaly

Primary microcephaly is characterized by a head circumference ≥3 SD below the mean, often accompanied by intellectual disability but minimal other neurological features. Biallelic variants in WDR62, encoding a WD40-repeat protein localized to centrosomes and spindle poles, cause autosomal recessive isolated congenital microcephaly (PMID:20890278). WDR62 is the second most frequently mutated gene in MCPH after ASPM, highlighting its critical role in neural progenitor proliferation.

A total of 22 probands across nine unrelated families have been reported to harbor biallelic WDR62 variants, consistent with autosomal recessive inheritance (PMID:20890278]PMID:25303973]PMID:28377545]PMID:28756000]PMID:31258591]PMID:22308068]PMID:39911176]PMID:27784895]PMID:32677750). Affected individuals presented with congenital microcephaly (HP:0000252), intellectual disability (HP:0001249), variable global developmental delay (HP:0001263), and seizures (HP:0001250).

The WDR62 variant spectrum includes frameshift, nonsense, missense, splice-site, and large intragenic deletions. Notably, a recurrent single base pair duplication, c.2527dup (p.Asp843GlyfsTer3), was identified in three Pakistani males, disrupting WD-repeat structure and confirmed by autozygosity mapping and Sanger sequencing (PMID:25303973). Other variants such as c.3878C>A (p.Ala1293Asp) and c.3335+1G>C underline the breadth of pathogenic alleles and validate diagnostic sequencing strategies.

Functional studies across cellular and animal models substantiate WDR62’s pathogenic mechanism. Mouse Wdr62 knockouts show reduced brain size, spindle instability, mitotic arrest, and NPC apoptosis, linking loss of function to human microcephaly (PMID:24875059). In vitro, WDR62 depletion impairs JNK1-mediated mitotic progression and neural differentiation, and rescue experiments confirm the necessity of WDR62–JNK interactions for cortical development (PMID:24388750).

No studies have refuted WDR62’s role in isolated congenital microcephaly; genotype-phenotype correlations remain consistent across ethnicities. The robust multi-family segregation, diverse variant classes, and concordant functional evidence meet ClinGen criteria for a Definitive gene–disease relationship.

WDR62 mutation testing is clinically actionable for diagnosis, genetic counseling, and prenatal assessment in families with autosomal recessive microcephaly. Functional insights into spindle and centrosomal defects offer avenues for future targeted therapies.

References

• Nature genetics • 2010 • Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. PMID:20890278
• BMC medical genetics • 2014 • A novel single base pair duplication in WDR62 causes primary microcephaly. PMID:25303973
• Annals of Saudi medicine • 2017 • A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family. PMID:28377545
• Brain & development • 2018 • A novel mutation of WDR62 gene associated with severe phenotype including infantile spasm, microcephaly, and intellectual disability. PMID:28756000
• Pakistan journal of medical sciences • 2019 • Novel compound heterozygous mutations in WDR62 gene leading to developmental delay and Primary Microcephaly in Saudi Family. PMID:31258591
• American journal of medical genetics. Part A • 2012 • WDR62 missense mutation in a consanguineous family with primary microcephaly. PMID:22308068
• Molecular syndromology • 2025 • Homozygous Intragenic Deletion in WDR62 in Siblings with Primary Microcephaly. PMID:39911176
• Journal of human genetics • 2017 • Molecular analysis of 23 Pakistani families with autosomal recessive primary microcephaly using targeted next-generation sequencing. PMID:27784895
• Molecular genetics & genomic medicine • 2020 • An update of pathogenic variants in ASPM, WDR62, CDK5RAP2, STIL, CENPJ, and CEP135 underlying autosomal recessive primary microcephaly in 32 consanguineous families from Pakistan. PMID:32677750
• 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

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