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Background <p>Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder that primarily affects cognitive functions, including memory and accounts for 60–80% of dementia cases. While it predominantly impacts older adults, early-onset cases can occur in individuals as young as their 30–40&#xa0;s. This study investigates eight families exhibiting autosomal dominant inheritance of AD.</p> Methods <p>Whole exome sequencing (WES) was performed on probands from five families, while three additional families were screened by Sanger sequencing. Variant filtering involved gene relevance, functional impact, allele frequency, and pathogenicity predictions using multiple bioinformatics tools. Confirmatory Sanger sequencing was conducted on all available affected and unaffected family members. Molecular modeling and dynamic simulations were employed to evaluate the structural and functional effects of identified variants.</p> Results <p>Three novel heterozygous variants in the <i>ADAM10</i>—c.429T &gt; A (p.Tyr143Ter), c.1571G &gt; A (p.Cys524Tyr), and c.1511G &gt; A (p.Ser504Asn)—were identified. These variants segregated with disease in all available affected individuals and were absent in 339 ethnically matched controls and public databases. Bioinformatic analyses predicted these variants to be deleterious, and molecular simulations indicated notable structural impacts.</p> Conclusion <p>Our findings suggest a potential contribution of these novel <i>ADAM10</i> variants to familial Alzheimer’s disease in this population. However, given the limited sample size and lack of functional assays, further validation is needed. This study highlights the value of comprehensive genetic analysis and expands understanding of AD genetics in diverse populations.</p>

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Whole Exome Sequencing Reveals Novel Genetic Mutations in the ADAM10 Underlying Familial Alzheimer’s Disease

  • 期刊论文

  • 发表日期：

    2025年10月10日

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  • Aman Ullah,
  • Sadaf Iftikhar

摘要

Background

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder that primarily affects cognitive functions, including memory and accounts for 60–80% of dementia cases. While it predominantly impacts older adults, early-onset cases can occur in individuals as young as their 30–40 s. This study investigates eight families exhibiting autosomal dominant inheritance of AD.

Methods

Whole exome sequencing (WES) was performed on probands from five families, while three additional families were screened by Sanger sequencing. Variant filtering involved gene relevance, functional impact, allele frequency, and pathogenicity predictions using multiple bioinformatics tools. Confirmatory Sanger sequencing was conducted on all available affected and unaffected family members. Molecular modeling and dynamic simulations were employed to evaluate the structural and functional effects of identified variants.

Results

Three novel heterozygous variants in the ADAM10—c.429T > A (p.Tyr143Ter), c.1571G > A (p.Cys524Tyr), and c.1511G > A (p.Ser504Asn)—were identified. These variants segregated with disease in all available affected individuals and were absent in 339 ethnically matched controls and public databases. Bioinformatic analyses predicted these variants to be deleterious, and molecular simulations indicated notable structural impacts.

Conclusion

Our findings suggest a potential contribution of these novel ADAM10 variants to familial Alzheimer’s disease in this population. However, given the limited sample size and lack of functional assays, further validation is needed. This study highlights the value of comprehensive genetic analysis and expands understanding of AD genetics in diverse populations.