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Identification of mutation in ASPM gene in microcephaly families from Khyber Pakhtunkhwa
Arsalan Waqas Ahmad Shah1, Laraib Shah2, Fawad Inayat3
1Institute of Health Sciences Swabi, Khyber Medical University, Peshawar, 25000, Pakistan.
Background:
Microcephaly is a neurodevelopmental disorder characterized by a reduced head circumference, non-progressive intellectual disability (ID), and a smaller brain size relative to the age and sex-matched population. The condition is heterogeneous, with both environmental and genetic causes. Among the 27 genes implicated in its pathogenesis, the ASPM gene, primarily an autosomal recessive disorder, accounts for over 40% of reported cases, making it a key contributor to the genetic basis of microcephaly.
Method And Material:
In this study, two families (A and B) of Pashtun ethnicity from the Khyber Pakhtunkhwa (KPK) province of Pakistan were recruited. The phenotype in both families suggested the involvement of the ASPM gene, leading to its analysis via Sanger sequencing in affected members. For Family A, RNA was isolated from whole blood samples to assess the impact of the identified mutation on the ASPM transcript.
Results:
In Family A, Sanger sequencing revealed a nonsense mutation in the ASPM gene, c.9557 C > G (p.S3186*), along with an additional polymorphism (rs199422189) in affected members. This mutation, previously reported in MCPH cases from the KPK province, is known to cause nonsense-mediated decay (NMD) of the mRNA. The analysis indicated that ASPM transcripts could evade NMD in blood cells, though the presence of ASPM transcripts in the brain could not be confirmed. In Family B, a novel homozygous DNA variant, c.9316_9316delA, was identified in exon 22 of the ASPM gene, leading to a premature stop codon. However, this genetic variation did not co-segregate with the MCPH phenotype in carrier family members, indicating it might be non-pathogenic or not the primary cause of microcephaly in this family.
Conclusion:
The study identified a known pathogenic mutation in the ASPM gene in Family A, confirming its role in microcephaly. In contrast, the novel genetic variation found in Family B did not appear to be the primary cause of the condition. Further investigations, including real-time PCR, are necessary to explore differences in ASPM transcript expression and to confirm the presence of these transcripts in relevant tissues such as the brain.
Insights
Microcephaly, a neurodevelopmental disorder, was studied in two Pakistani families. A known ASPM gene mutation caused microcephaly in Family A, while a novel variant in Family B was not linked to the condition.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Molecular Biology
Background:
- Microcephaly is a neurodevelopmental disorder characterized by reduced head circumference and intellectual disability.
- It has diverse genetic and environmental causes, with ASPM gene mutations accounting for over 40% of cases.
- ASPM gene mutations are a significant genetic factor in microcephaly pathogenesis.
Purpose of the Study:
- To investigate the genetic basis of microcephaly in two Pashtun families from Pakistan.
- To identify mutations in the ASPM gene and assess their pathogenicity.
- To analyze the impact of identified mutations on ASPM gene expression.
Main Methods:
- Recruitment of two Pashtun families (A and B) with microcephaly phenotype.
- Sanger sequencing of the ASPM gene in affected individuals.
- RNA isolation and analysis of ASPM transcript in Family A.
Main Results:
- Family A: Identified a known nonsense mutation (c.9557 C>G, p.S3186*) in the ASPM gene, previously linked to microcephaly.
- This mutation causes mRNA decay, though transcripts may evade nonsense-mediated decay in blood cells.
- Family B: Identified a novel homozygous variant (c.9316_9316delA) in ASPM, but it did not co-segregate with the phenotype, suggesting it's not the primary cause.
Conclusions:
- A known ASPM mutation confirms its role in microcephaly in Family A.
- A novel ASPM variant in Family B was not found to be the primary cause of microcephaly.
- Further studies, including real-time PCR, are needed to investigate ASPM transcript expression in relevant tissues like the brain.
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