The molecular landscape of ASPM mutations in primary microcephaly
A K Nicholas1, E A Swanson, J J Cox
1Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
Background:
Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during fetal life resulting in a small but structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in ASPM being most commonly reported.
Methods And Results:
We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous ASPM mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, 11 (40%) had ASPM mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3 (7%) had an ASPM mutation. This report contains 27 novel mutations and almost doubles the number of MCPH associated ASPM mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation/phenotype correlation. ASPM mutations were found in all ethnic groups studied.
Conclusion:
This study confirms that mutations in ASPM are the most common cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype, and that ASPM testing in primary microcephaly is clinically useful.
Insights
Mutations in the ASPM gene are the most frequent cause of autosomal recessive primary microcephaly (MCPH), a condition affecting brain development. Identifying these ASPM mutations is clinically valuable for diagnosing MCPH.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced brain growth and intellectual disability.
- MCPH serves as a valuable model for studying human neurogenesis.
- Genetic heterogeneity exists in MCPH, with ASPM gene mutations being the most commonly identified cause.
Purpose of the Study:
- To investigate the spectrum and frequency of ASPM mutations in microcephalic individuals.
- To extend the understanding of the phenotype associated with MCPH.
- To assess the clinical utility of ASPM gene mutation testing in primary microcephaly.
Main Methods:
- Analysis of three cohorts: 99 consanguineous families with strict MCPH diagnosis, 27 non-consanguineous families with strict MCPH diagnosis, and 45 families with a broader phenotype including microcephaly and mental retardation.
- Genotyping to identify homozygous MCPH5 locus and ASPM mutations.
- Characterization of mutation types (nonsense, deletions, insertions, splicing, translocation) and assessment of recurrence and phenotype correlation.
Main Results:
- ASPM mutations were identified in 41% of consanguineous MCPH families and 40% of non-consanguineous MCPH families.
- Only 7% of families with a less restricted phenotype had ASPM mutations, suggesting specificity.
- 27 novel ASPM mutations were discovered, increasing the total known MCPH-associated mutations to 57. Mutations predominantly resulted in premature termination codons. No missense mutations or clear genotype-phenotype correlations were observed. ASPM mutations occurred across all ethnic groups.
Conclusions:
- Mutations in the ASPM gene are confirmed as the leading cause of primary microcephaly.
- ASPM mutations are specifically associated with the MCPH phenotype, not broader neurodevelopmental conditions.
- ASPM gene mutation analysis is a clinically useful diagnostic tool for primary microcephaly.
