Delineation of molecular findings by whole-exome sequencing for suspected cases of paediatric-onset mitochondrial diseas
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PRIMARY RESEARCH
Open Access
Delineation of molecular findings by wholeexome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population Mandy H.Y. Tsang1†, Anna K.Y. Kwong1†, Kate L.S. Chan1, Jasmine L.F. Fung1, Mullin H.C. Yu1, Christopher C.Y. Mak1, Kit-San Yeung1, Richard J.T. Rodenburg2, Jan A.M. Smeitink2, Rachel Chan3, Thomas Tsoi3, Joannie Hui4, Shelia S.N Wong4, Shuk-Mui Tai5, Victor C.M. Chan5, Che-Kwan Ma6, Sharon T.H. Fung7, Shun-Ping Wu8, W.K. Chak9, Brian H.Y. Chung1,4,10,11* and Cheuk-Wing Fung1,4*
Abstract Background: Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs. Methods: We recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤ 1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines. Results: Sixty-six patients with pre-biopsy MDC scores of 3–8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n = 3, two were siblings), ALDH5A1, ARX, FA2H, KCNT1, LDHD, NEFL, NKX2-2, TBCK, and WAC. Conclusions: We confirmed that the COQ4:c.370G>A, p.(Gly124Ser) variant, was a founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous. Keywords: Mitochondrial disease, Paediatrics, Whole-exome sequencing
* Correspondence: [email protected]; [email protected] † Mandy H. Y. Tsang and Anna K. Y. Kwong contributed equally to this work. 1 Department of Paediatrics & Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the ori
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