Trio Exome Sequencing in VACTERL Association.
Jasmina Ćomić1,2, Erik Tilch1, Korbinian M Riedhammer1,2,3
1Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
Kidney International Reports
|April 14, 2025
Summary
Genetic testing reveals few monogenic causes for VACTERL association, indicating that most cases stem from unknown genetic factors or mechanisms beyond exome sequencing detection. Further research is needed to uncover these underlying causes.
Area of Science:
- Genetics
- Developmental Biology
- Rare Diseases
Background:
- Limited data exists on monogenic causes of VACTERL (vertebral defects, anorectal malformations, cardiac defects, esophageal atresia/tracheoesophageal fistula, renal malformations, limb defects) association.
- Understanding genetic underpinnings is crucial for diagnosis and treatment of complex congenital anomalies.
Purpose of the Study:
- To identify disease-causing variants in known genes associated with VACTERL association.
- To determine the diagnostic yield of monogenic causes in VACTERL association.
- To discover novel candidate genes and rare variants through comprehensive genetic analysis.
Main Methods:
- Whole exome sequencing (WES) was performed on 96 individuals with VACTERL association and their parents.
- Case-control gene and pathway burden tests were conducted.
- Family-based association tests (FBAT) were utilized for variant and pathway analysis.
Main Results:
- Disease-causing variants in known genes were identified in only 5 out of 96 individuals, linked to Kabuki syndrome, Sotos syndrome, MELAS syndrome, and a TWIST1 deletion syndrome.
- No causative variants were found in 91 individuals.
- FBAT identified 14 significant variants, 2 significant genes (LOC645752, ZNF417), and 8 significant pathways.
Conclusions:
- The majority of VACTERL association cases do not appear to be caused by known discrete genetic syndromes detectable by current exome sequencing.
- The findings suggest the involvement of unidentified pathomechanisms or genetic variants not captured by WES.
- Further investigation is warranted to elucidate the genetic basis of VACTERL association in the remaining cases.
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