The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild
Marc Trimborn1, Reyk Richter, Nadine Sternberg
1Institut für Humangenetik, Charité - Universitätsmedizin Berlin, Germany.
Abstract:
Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2- and delayed decondensation in early G1-phase of the cell cycle. We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.
Insights
A novel genetic mutation in the MCPH1 gene results in a milder form of primary microcephaly (MCPH). This finding expands the known clinical spectrum of MCPH1-associated neurodevelopmental disorders.
Area of Science:
- Genetics
- Neurodevelopmental Biology
- Cell Biology
Background:
- Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder.
- MCPH is characterized by severe congenital microcephaly and intellectual disability.
- Truncating mutations in the MCPH1 gene cause a distinct cellular phenotype with premature chromosome condensation.
Purpose of the Study:
- To report the first patient with a specific MCPH1 gene substitution (Thr27Arg).
- To characterize the cellular and clinical phenotype associated with this novel MCPH1 mutation.
- To reassess the clinical definition of MCPH1-related disorders.
Main Methods:
- Genetic sequencing to identify the MCPH1 mutation (c.80C>G, Thr27Arg).
- Cellular analysis to quantify prophase-like cells.
- Clinical assessment of cognitive function and head circumference.
Main Results:
- The patient presented with a homozygous Thr27Arg substitution in the MCPH1 gene.
- Cellular analysis revealed a mild increase in prophase-like cells (3-4%).
- Clinical phenotype included mild intellectual disability, delayed motor skills, normal verbal IQ, and less severe microcephaly (-2.4 to -3 SD).
Conclusions:
- The MCPH1 Thr27Arg substitution results in a significantly milder phenotype than previously described truncating mutations.
- This case expands the clinical and cellular spectrum of MCPH1-associated disorders.
- The findings necessitate a broader definition of the clinical phenotype for MCPH1 mutations.
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