MCPH1 – Primary Autosomal Recessive Microcephaly

Autosomal recessive primary microcephaly (MCPH1; MONDO:0009617) is characterized by reduced head circumference and intellectual disability due to biallelic loss-of-function variants in the MCPH1 gene (HGNC:6954). Inheritance is autosomal recessive with consanguineous kindreds commonly reported, and no heterozygote phenotype.

Over 50 unrelated individuals have been described carrying biallelic truncating or missense MCPH1 variants, including c.74C>G (p.Ser25Ter) and c.215C>T (p.Ser72Leu), confirming the gene’s role in brain size regulation (PMID:19925808; PMID:22952573). Segregation has been demonstrated in multiple consanguineous families, with 19 affected relatives across pedigrees sharing pathogenic variants (PMID:30351297).

The variant spectrum encompasses nonsense, frameshift, splice-site and missense changes clustered in the N-terminal BRCT domain and C-terminal BRCT repeats. Recurrent founder alleles such as c.74C>G (p.Ser25Ter) are observed in diverse populations; deep intronic and hypomorphic variants are rare.

Cellular assays show that truncating MCPH1 alleles abolish recruitment to γH2AX foci and impair the G2/M checkpoint, resulting in premature chromosome condensation (PCC) (PMID:17925396). Patient-derived lymphoblasts display delayed mitotic exit and defective DNA damage-induced checkpoint release despite normal IR-induced chromatin break repair kinetics (PMID:21150325).

Murine Mcph1 knockout models recapitulate PCC and neurodevelopmental defects, with infertility, chromatid breaks and impaired RAD51/BRCA2 recruitment after γ-irradiation, establishing a haploinsufficiency mechanism via disrupted BRCT-mediated protein interactions (PMID:20107607). Rescue experiments confirm that wild-type MCPH1 restores genome stability and normal mitotic progression.

Conflicting data in RNAi models and certain cell lines highlight subtle species-specific differences in DNA damage responses, but do not dispute the core genotype-phenotype correlation in human MCPH1 deficiency.

Taken together, MCPH1 meets ClinGen criteria for a definitive gene–disease relationship in autosomal recessive primary microcephaly. Genetic testing for truncating and critical BRCT-domain missense variants is recommended for infants with microcephaly, and functional assays can support variant interpretation.

Key Take-Home: Biallelic MCPH1 loss-of-function variants cause definitive autosomal recessive primary microcephaly via BRCT-domain disruption of DNA damage checkpoint control and chromosome condensation.

References

• The Journal of Biological Chemistry • 2007 • MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. PMID:17925396
• Journal of Molecular Biology • 2010 • A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation. PMID:19925808
• PLoS Genetics • 2010 • BRIT1/MCPH1 is essential for mitotic and meiotic recombination DNA repair and maintaining genomic stability in mice. PMID:20107607
• PLoS One • 2012 • A novel MCPH1 isoform complements the defective chromosome condensation of human MCPH1-deficient cells. PMID:22952573
• Neurosciences (Riyadh, Saudi Arabia) • 2018 • Novel compound heterozygous mutations in MCPH1 gene causes primary microcephaly in Saudi family. PMID:30351297
• Heliyon • 2024 • Functional analysis of a novel intronic variant of MCPH1 with autosomal recessive primary microcephaly. PMID:38818167

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