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The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
Davut Pehlivan1, Yavuz Bayram2, Nilay Gunes3
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
American Journal of Human Genetics
|June 25, 2019
Summary
Exome sequencing identified the molecular causes of arthrogryposis in over 65% of families studied. This genetic analysis revealed new candidate genes and highlighted the importance of reanalyzing unsolved cases.
Area of Science:
- Genetics
- Molecular Biology
- Medical Genetics
Background:
- Arthrogryposis is a complex clinical sign linked to over 400 Mendelian conditions.
- The genetic basis of arthrogryposis is often unclear due to significant genetic and phenotypic diversity.
Purpose of the Study:
- To identify the molecular etiology of arthrogryposis using exome sequencing.
- To investigate the role of copy number variants and mosaicism in arthrogryposis.
Main Methods:
- Exome sequencing (ES) was performed on 89 families with arthrogryposis.
- Array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were used for specific genetic analyses.
- Reanalysis of previously unsolved cases was conducted.
Main Results:
- A molecular diagnosis was achieved in 65.2% of families.
- RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 were identified as likely causative genes.
- Evidence for copy number variants (CNVs) and the impact of allelic variation (mono-allelic vs. bi-allelic) was found.
Conclusions:
- Family-based exome sequencing effectively delineates arthrogryposis etiology.
- The study identified novel candidate genes and supports the role of mutational burden in disease pathways.
- Reanalysis of unsolved cases, especially with extended family data, is crucial for diagnosis.
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