Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Human Molecular Genetics

Background:

• Primary microcephaly is an autosomal recessive neurodevelopmental disorder characterized by intellectual disability without other neurological deficits.
• It is genetically heterogeneous, with six known loci (MCPH1-MCPH6), but only MCPH1 and MCPH5 genes were previously identified.
• Genetic factors contributing to primary microcephaly require further elucidation.

Purpose of the Study:

• To investigate the genetic basis of primary microcephaly in nine Indian families.
• To identify potential genetic linkages to known MCPH loci.
• To discover novel mutations in genes associated with primary microcephaly.

Main Methods:

• Microsatellite marker genotyping was used to establish linkage to known MCPH loci in nine consanguineous families.
• DNA sequencing was performed on candidate genes in families showing suggestive linkage.
• Analysis included identification of mutations and normal population variants in the ASPM gene.

Main Results:

• Linkage was suggested for three families to the MCPH5 locus and one family to the MCPH2 locus.
• DNA sequencing identified one known (Arg117X) and two novel (Trp1326X, Gln3060X) homozygous mutations in the ASPM gene in the MCPH5-linked families.
• Three novel variants (c.7605G > A, c.4449G > A, c.5961 A > G) were detected in the ASPM gene in the normal population.

Conclusions:

• The ASPM gene is implicated in primary microcephaly, with identified mutations contributing to the disorder in the studied families.
• This research expands the spectrum of mutations associated with MCPH5 and highlights the genetic heterogeneity of primary microcephaly.
• Further investigation into the identified variants and loci is warranted to fully understand the genetic architecture of primary microcephaly.