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Lessons learned from additional research analyses of unsolved clinical exome cases
Mohammad K Eldomery1,2, Zeynep Coban-Akdemir1, Tamar Harel1
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Genome Medicine
|March 23, 2017
Summary
Collaborative research and advanced genomics pipelines improve molecular diagnosis for rare Mendelian disorders, accelerating novel gene discovery and understanding genetic disease mechanisms.
Area of Science:
- Genomics
- Medical Genetics
- Bioinformatics
Background:
- Single-gene Mendelian disorders are rare, necessitating data sharing between clinical and research communities.
- Optimizing molecular diagnosis and discovering new disease genes requires collaborative efforts.
Purpose of the Study:
- To accelerate novel disease gene discovery.
- To increase diagnostic yield of whole exome sequencing (WES).
- To gain insights into genetic mechanisms of rare diseases.
Main Methods:
- Implemented protocols for unsolved clinical exome cases in a research setting.
- Utilized whole exome sequencing (WES) from additional family members.
- Employed complementary bioinformatics approaches with relaxed variant filtering.
Main Results:
- A likely contributory variant was identified in 36% of cases, with potential variants in ~51%.
- Molecular diagnosis was achieved in 47.6% of trios and higher rates in other family structures.
- Identified novel disease genes including PURA, TANGO2, EMC1, GNB5, ATAD3A, MIPEP, DHX30, and EBF3.
Conclusions:
- An efficient genomics pipeline combining diagnostic and research efforts enhances molecular diagnostic yield.
- Reanalysis of unsolved cases with advanced bioinformatics and family data provides mechanistic insights.
- Collaborative clinical and research efforts are crucial for advancing Mendelian disorder diagnostics and research.
