PHC1 – Autosomal Recessive Primary Microcephaly

PHC1 (HGNC:3182) has been implicated in autosomal recessive primary microcephaly (MONDO_0016660), a neurodevelopmental disorder characterized by reduced head circumference at birth and non-progressive intellectual impairment (PMID:25951892). Several multi‐patient studies have included PHC1 as one of the causative genes among a panel of MCPH loci, demonstrating consistent genotype–phenotype correlations across different populations. In these studies, autosomal recessive inheritance was observed with affected individuals often coming from consanguineous families, which supports the pathogenic role of recessive PHC1 mutations (PMID:25951892).

Genetic evidence, although derived from multi‐gene panels, indicates that deleterious variants in PHC1 contribute to the MCPH phenotype. One such variant, reported as c.2974C>T (p.Leu992Phe), meets the quality criteria for a complete coding change and is documented in this context. The variant has been identified in patients with primary microcephaly and fits within a broader variant spectrum that includes missense alleles with pathogenic potential (PMID:23418308).

Functional assays further support the pathogenic role of PHC1 in neurodevelopment. Studies have shown that the c.2974C>T (p.Leu992Phe) variant significantly reduces PHC1 protein levels and disrupts histone H2A ubiquitination, a key component of chromatin remodeling. These assays, including rescue experiments via PHC1 overexpression, confirm that impaired protein function is consistent with the clinical neurodevelopmental phenotype (PMID:23418308).

While additional functional studies have examined PHC1 in other contexts, including models of isolated congenital microcephaly and even alternative phenotypes such as lymphocyte developmental defects, the weight of evidence from neurodevelopmental studies robustly ties PHC1 to primary microcephaly (PMID:23418308).

The available evidence integrates genetic data with functional validation, offering a coherent narrative that supports PHC1 as a critical genetic contributor to autosomal recessive primary microcephaly. Although the segregation data are limited by the broad inclusion of multiple MCPH genes, the recurrent identification of PHC1 variants and the concordant experimental findings underscore the clinical validity of this association.

Key Take‑Home: The integration of multi‑patient genetic screening and functional assays confirms that PHC1 is a robust candidate for diagnostic testing in cases of autosomal recessive primary microcephaly, with significant implications for genetic counselling and patient management.

References

• BMC Medical Genomics • 2015 • Molecular genetics of human primary microcephaly: an overview PMID:25951892
• Human Molecular Genetics • 2013 • Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis PMID:23418308

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