Molecular genetic analysis of consanguineous families with primary microcephaly identified pathogenic variants in the ASPM gene
Muzammil Ahmad Khan1, Christian Windpassinger, Muhammad Zeeshan Ali
1Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar. ZNAWAZ@hamad.qa.
Abstract:
Autosomal recessive primary microcephaly is a rare genetic disorder that is characterized by reduced head circumference and a varying degree of intellectual disability. Genetic studies on consanguineous families with primary microcephaly have identified 15 (MCPH) causative genes that include MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6 MFSD2A ANKLE2 and CIT (Khan et al. 2014; Yamamoto et al. 2014; Alakbarzade et al. 2015;Morris-Rosendahl and Kaindl 2015; Basit et al. 2016). Physiologically, most of these MCPH proteins are involved in cell cycle and its regulation. In the present clinical genetic study, we have present two consanguineous Pakistani families segregating primary microcephaly and intellectual disability. These families were ascertained from the Saraiki ethnic part of Khyber-Pakhtunkhwa province in Pakistan. Whole exome sequencing in one family revealed a novel 1-bp deletion NM_018136.4: c.10013delA (p.Asp3338Valfs*2), while the other family showed a previously reported nonsense mutation NM_018136.4: c.9730C>T (rs199422195 (p.Arg3244*)) in ASPM gene. The novel frame-shift mutation (p.Asp3338Valfs*2) in ASPM presumably truncates the protein synthesis that results in loss of armadillo-type fold domain.
Insights
Primary microcephaly, a rare genetic disorder, was studied in two Pakistani families. Genetic analysis identified novel and known mutations in the ASPM gene, crucial for brain development.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder causing reduced head circumference and intellectual disability.
- Over 15 MCPH genes have been identified, with most encoded proteins regulating the cell cycle.
- ASPM is a key gene implicated in primary microcephaly.
Purpose of the Study:
- To investigate the genetic basis of primary microcephaly and intellectual disability in two consanguineous Pakistani families.
- To identify novel or known mutations in MCPH-associated genes.
Main Methods:
- Clinical genetic study of two consanguineous Pakistani families.
- Whole exome sequencing was performed on one family.
- Mutation analysis of the ASPM gene.
Main Results:
- A novel 1-bp deletion (c.10013delA) in the ASPM gene, leading to a frameshift mutation (p.Asp3338Valfs*2), was identified in one family.
- A previously reported nonsense mutation (c.9730C>T, p.Arg3244*) in the ASPM gene was found in the other family.
- The novel mutation is predicted to cause premature protein truncation and loss of the armadillo-type fold domain.
Conclusions:
- ASPM gene mutations are a significant cause of primary microcephaly and intellectual disability in the studied Pakistani population.
- The identified novel mutation expands the spectrum of ASPM mutations associated with MCPH.
- Further research into ASPM's role in cell cycle regulation and brain development is warranted.
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