A translocation breakpoint disrupts the ASPM gene in a patient with primary microcephaly
Bruno Pichon1, Sophie Vankerckhove, Georges Bourrouillou
1Service de Génétique Médicale, Hôpital Erasme, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Bruxelles, Belgium.
Abstract:
Primary microcephaly (microcephalia vera) is a developmental abnormality resulting in a small brain, with mental retardation. It is usually transmitted as an autosomal recessive trait, and six loci have been reported to date. We analyzed a translocation breakpoint previously reported in a patient with apparently sporadic primary microcephaly, at 1q31, where locus MCPH5 maps. The patient was lost to follow-up, and we sampled a maternal aunt who carried the familial translocation. FISH analyses showed that the insert of BAC clone RP11-32D17 spanned the breakpoint. The breakpoint was further located within a fragment of this insert corresponding to intron 17 of the ASPM gene, resulting in a predicted transcript truncated of more than half of its coding sequence. It is very likely that the proband carried a second ASPM mutation in trans, but he was not available for sampling and hence we could not confirm this hypothesis. Our observation adds to the mutation spectrum of ASPM in primary microcephaly, and is to our knowledge the second example of a constitutional, reciprocal translocation responsible for a bona fide autosomal recessive phenotype.
Insights
Primary microcephaly, a developmental brain disorder, can be caused by ASPM gene mutations. A translocation breakpoint within the ASPM gene was identified, contributing to this autosomal recessive condition.
Area of Science:
- Genetics
- Developmental Biology
- Neurology
Background:
- Primary microcephaly (microcephalia vera) is a rare congenital disorder characterized by a significantly small brain and intellectual disability.
- It is typically inherited in an autosomal recessive pattern, with several genetic loci identified previously.
- Six loci for primary microcephaly have been reported, indicating genetic heterogeneity.
Observation:
- Analysis focused on a translocation breakpoint at 1q31, previously linked to sporadic primary microcephaly and the MCPH5 locus.
- FISH analysis identified the breakpoint within intron 17 of the ASPM gene.
- This breakpoint results in a predicted ASPM transcript truncated by over half its coding sequence.
Findings:
- The identified translocation disrupts the ASPM gene, a known contributor to primary microcephaly.
- This finding suggests a constitutional reciprocal translocation can cause an autosomal recessive phenotype.
- While the proband was unavailable for confirmation, it is hypothesized he carried a second ASPM mutation in trans.
Implications:
- This case expands the known mutation spectrum of the ASPM gene in primary microcephaly.
- It highlights the role of ASPM gene mutations in neurodevelopmental disorders.
- The study provides a rare example of a balanced translocation causing a bona fide autosomal recessive condition.
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