Zuhair N Al-Hassnan1,2,3, Abdulrahman Almesned4, Sahar Tulbah1,2, Ali Alakhfash4, Faten Alhadeq1,5, Nadiah Alruwaili1,6, Maarab Alkorashy1,6,5, Amal Alhashem7,3, Ahmad Alrashdan8, Eissa Faqeih9, Salwa M Alkhalifi10, Zainab Al Humaidi5,10, Sameera Sogaty11, Nawal Azhari12, Abdulrahman M Bakhaider4,13, Ali Al Asmari9, Ali Awaji14, Buthaina Albash15, Mohammed Alhabdan, Malak A Alghamdi16, Walaa Alshuaibi16, Raghad Z Al-Hassnan17, Abduljabbar Alshenqiti18, Aisha Alqahtani1,2, Zarghuna Shinwari1, Monther Rbabeh1,6, Saud Takroni1,2, Ahmed Alomrani19, Dimpna C Albert Brotons6, Abdullah M AlQwaee, Waleed Almanea20, Fadel A Alfadley6, Majid Alfayyadh6, Abdullah Alwadai21. 1. Cardiovascular Genetics Program (Z.N.A.-H., S. Tulbah, F.A., N. Alruwaili, M. Alkorashy, A. Alqahtani, Z.S., M.R., S. Takroni), King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh. 2. Department of Medical Genetics (Z.N.A.-H., S. Tulbah, A. Alqahtani, S. Takroni), King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh. 3. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia (Z.N.A.-H., A. Alhashem). 4. Prince Sultan Cardiac Centre, Qassim (A. Almesned, A. Alakhfash, A.M.A.). 5. Department of Genetics (Z.N.A.-H., F.A., M. Alkorashy), King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh. 6. Heart Center (N. Alruwaili, M. Alhabdan, M.R., D.C.A.B., F.A.A., M. Alfayyadh), King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh. 7. Division of Medical Genetics, Department of Pediatrics, Prince Sultan Medical Military City, Riyadh (A. Alhashem). 8. Department of Pediatrics, King Salman Specialist Hospital, Hail (A. Alrashdan). 9. Medical Genetics, King Fahad Medical City, Children's Specialist Hospital, Riyadh (E.F., A.A.a.). 10. Pediatrics Department, Maternity & Children's Hospital, Dammam (S.M.A., Z.A.h.). 11. King Fahad Hospital (S.S.). 12. King Abdulaziz Hospital (N. Azhari). 13. Jeddah East Hospital, Jeddah (A.M.B.). 14. King Fahad Central Hospital, Jazan, Saudi Arabia (A. Awaji). 15. Kuwait Medical Genetics Ctr, Shuwaikh, Kuwait (B.A.). 16. Medical Generics Division, Department of Pediatrics, College of Medicine, King Saudi University Hospital (M.A.A., W. Alshuaibi). 17. College of Computer & Information Sciences, King Saud University (R.Z.A.-H.). 18. Genetics & Metabolic Unit, Children's Hospital, King Saud Medical City (A. Alshenqiti). 19. King Abdulaziz Cardiac Center (A. Alomrani). 20. Pediatric Cardiology, Security Forces Hospital (W. Almanea). 21. Heart Failure & Transplant Program, Prince Sultan Cardiac Center (A. Alwadai).
Abstract
BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.
BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.
Authors: Hemanth Nannapaneni; Stephanie Ghaleb; Sandeep Arya; Viswanath Gajula; Mary B Taylor; Bibhuti B Das Journal: J Cardiovasc Dev Dis Date: 2022-02-22