Zuhair N Al-Hassnan1, Majid Al-Fayyadh2, Bander Al-Ghamdi3, Azam Shafquat3, Yaseen Mallawi3, Faten Al-Hadeq4, Sahar Tulbah4, Zarghuna M A Shinwari4, Abdulrahman Almesned5, Ali Alakhfash5, Fadel Al Fadly3, Ahmed S Hersi6, Abdullah Alhayani7, Amal Al-Hashem8, Dia Arafah9, Nduna Dzimiri10, Brian Meyer10, Monther Rababh4, Waleed Al-Manea3. 1. Cardiovascular Genetics Program, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Medical Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. Electronic address: zhassnan@kfshrc.edu.sa. 2. Cardiovascular Genetics Program, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Heart Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. 3. Heart Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. 4. Cardiovascular Genetics Program, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. 5. Prince Sultan Cardiac Center, Qassim, Saudi Arabia. 6. Cardiac Sciences Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 7. Maternity and Children Hospital, Abha, Saudi Arabia. 8. Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 9. Maternity and Children Hospital, Makkah, Saudi Arabia. 10. Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
Abstract
BACKGROUND: Congenital long QT syndrome (LQTS) is an inherited, potentially fatal arrhythmogenic disorder. At least 16 genes have been implicated in LQTS; the yield of genetic analysis of 3 genes (KCNQ1, KCNH2, and SCN5A) is about 70%, with KCNQ1 mutations accounting for ∼50% of positive cases. LQTS is mostly inherited in an autosomal dominant pattern. Systemic analysis of LQTS has not been previously conducted in a population with a high degree of consanguinity. OBJECTIVES: To describe the clinical and molecular profiles of LQTS in the highly consanguineous Saudi population. METHODS: Fifty-six Saudi families with LQTS were consecutively recruited and evaluated. Sequencing of KCNQ1, KCNH2, and SCN5A genes was conducted on all probands, followed by screening of family relatives. RESULTS: Genetic analysis was positive in 32 (57.2%) families, with mutations in KCNQ1 identified in 28 families (50%). Surprisingly, 17 (53.1%) probands were segregating homozygous mutations. Family screening identified 123 individuals with mutations; 89 (72.4%) were heterozygous, 23 (18.7%) were homozygous, and 11 (8.9%) were compound heterozygous. Compared to heterozygous, the phenotype was more severe in homozygous individuals, with cardiac symptoms in 78.3% (vs 12.4%), family history of sudden death in 64.7% (vs 44.4%), and prolonged QT interval in 100% (vs 43.8%). Congenital deafness was found in 11 (47.8%) homozygous probands. CONCLUSION: Our study provides insight into the clinical and molecular profiles of LQTS in a consanguineous population. It underscores the importance of preemptive management in homozygous patients with LQTS and the value of clinical and molecular screening of at-risk relatives.
BACKGROUND:Congenital long QT syndrome (LQTS) is an inherited, potentially fatal arrhythmogenic disorder. At least 16 genes have been implicated in LQTS; the yield of genetic analysis of 3 genes (KCNQ1, KCNH2, and SCN5A) is about 70%, with KCNQ1 mutations accounting for ∼50% of positive cases. LQTS is mostly inherited in an autosomal dominant pattern. Systemic analysis of LQTS has not been previously conducted in a population with a high degree of consanguinity. OBJECTIVES: To describe the clinical and molecular profiles of LQTS in the highly consanguineous Saudi population. METHODS: Fifty-six Saudi families with LQTS were consecutively recruited and evaluated. Sequencing of KCNQ1, KCNH2, and SCN5A genes was conducted on all probands, followed by screening of family relatives. RESULTS: Genetic analysis was positive in 32 (57.2%) families, with mutations in KCNQ1 identified in 28 families (50%). Surprisingly, 17 (53.1%) probands were segregating homozygous mutations. Family screening identified 123 individuals with mutations; 89 (72.4%) were heterozygous, 23 (18.7%) were homozygous, and 11 (8.9%) were compound heterozygous. Compared to heterozygous, the phenotype was more severe in homozygous individuals, with cardiac symptoms in 78.3% (vs 12.4%), family history of sudden death in 64.7% (vs 44.4%), and prolonged QT interval in 100% (vs 43.8%). Congenital deafness was found in 11 (47.8%) homozygous probands. CONCLUSION: Our study provides insight into the clinical and molecular profiles of LQTS in a consanguineous population. It underscores the importance of preemptive management in homozygous patients with LQTS and the value of clinical and molecular screening of at-risk relatives.
Authors: Maliheh Najari Beidokhti; Alexander C Bertalovitz; Weizhen Ji; Jorge McCormack; Lauren Jeffries; Emily Sempou; Mustafa K Khokha; Thomas V McDonald; Saquib A Lakhani Journal: Mol Genet Genomics Date: 2021-04-19 Impact factor: 3.291
Authors: Andrew P Landstrom; Ernesto Fernandez; Jill A Rosenfeld; Yaping Yang; Andrew L Dailey-Schwartz; Christina Y Miyake; Hugh D Allen; Daniel J Penny; Jeffrey J Kim Journal: Heart Rhythm Date: 2018-03-02 Impact factor: 6.343
Authors: Michelle M Monasky; Emanuele Micaglio; Giuseppe Ciconte; Sara Benedetti; Chiara Di Resta; Gabriele Vicedomini; Valeria Borrelli; Andrea Ghiroldi; Marco Piccoli; Luigi Anastasia; Vincenzo Santinelli; Maurizio Ferrari; Carlo Pappone Journal: Front Physiol Date: 2019-05-28 Impact factor: 4.566