MCPH1 – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH; MONDO_0016660) is a congenital neurodevelopmental disorder defined by non‐progressive microcephaly (head circumference ≥4 SD below age and sex means) and intellectual disability in the absence of other major malformations. The first gene identified for MCPH, MCPH1 (HGNC:6954; Gene), encodes microcephalin, a centrosomal and DNA damage–response protein with three BRCT domains. Truncating and missense variants in MCPH1 disrupt cell‐cycle regulation and chromosome condensation, leading to reduced neuronal progenitor proliferation.

Genetic evidence includes a homozygous missense variant c.80C>G (p.Thr27Arg) in the N‐terminal BRCT domain identified in a patient with mild MCPH and 3–4% prophase‐like cells, versus >10% in truncating cases ([PMID:16211557]). A splice‐acceptor mutation c.322-2A>T causing r.322_336del15 (p.Arg108_Gln112del5) was found in two affected siblings with discordant cognitive outcomes ([PMID:26192461]). Chromosomal microarray in a Hispanic family revealed a 250 kb deletion of exons 1–8 segregating with microcephaly in two brothers ([PMID:28878824]), and homozygous deletion of exons 1–8 recurred in a separate patient ([PMID:35456440]). Prenatal diagnosis in two fetuses carrying homozygous c.348del (p.Phe116LeufsTer30) further broadens the variant spectrum ([PMID:36553323]).

Inheritance is autosomal recessive, supported by consanguineous families and segregation of biallelic variants with disease (4 affected siblings) across six unrelated pedigrees. No clear founder alleles have been described, and both missense and loss-of-function (LoF) alleles contribute to the phenotype. The spectrum includes missense in BRCT1 (p.Thr27Arg), splice (c.322-2A>T), frameshift (c.348del), and multi‐exon deletions, consistent with haploinsufficiency.

Functional studies reveal that MCPH1‐deficient patient cells exhibit premature chromosome condensation (PCC), delayed decondensation, and defective G2–M checkpoint arrest. RNAi and patient‐derived lines show impaired Cdc25A degradation and failure to maintain inhibitory CDK1 phosphorylation ([PMID:16783362]). Mcph1⁻/⁻ mice display PCC in embryo fibroblasts, genomic instability, and impaired RAD51/BRCA2 recruitment, confirming its role in DNA repair and chromosome dynamics ([PMID:20107607]). Rescue experiments targeting the N‐terminal BRCT domain further validate domain‐specific functions.

A study of siblings with homozygous MCPH1 p.Arg741Ter and TRAPPC9 missense variants found an unaffected MCPH1-only homozygote, suggesting a bifunctional model where centrosomal BRCT1 activity drives MCPH, whereas DDR functions in BRCT3 may be dispensable for brain size. This nuance refines the pathogenic mechanism and points to allele‐specific effects.

In conclusion, definitive evidence from nine probands in six families, robust segregation data, and concordant cellular and animal models establish MCPH1 as a definitive gene for autosomal recessive primary microcephaly. Genetic testing for MCPH1 variants supports diagnostic decision-making and informs counseling. Key Take-home: MCPH1 variant screening is clinically actionable for early diagnosis of primary microcephaly.

References

• Human Mutation • 2005 • The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. PMID:16211557
• Gene • 2015 • A case report: Autosomal recessive microcephaly caused by a novel mutation in MCPH1 gene. PMID:26192461
• Molecular Cytogenetics • 2017 • CMA analysis identifies homozygous deletion of MCPH1 in 2 brothers with primary Microcephaly-1. PMID:28878824
• Genes • 2022 • MCPH1: A Novel Case Report and a Review of the Literature. PMID:35456440
• Children (Basel, Switzerland) • 2022 • Prenatal Identification of a Novel Mutation in the MCPH1 Gene Associated with Autosomal Recessive Primary Microcephaly (MCPH) Using Next Generation Sequencing (NGS). PMID:36553323
• Nature Cell Biology • 2006 • Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. PMID:16783362
• PLoS Genetics • 2010 • BRIT1/MCPH1 is essential for mitotic and meiotic recombination DNA repair and maintaining genomic stability in mice. PMID:20107607

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