S R Johnson1,2,3,4, P J Leo4, A M McInerney-Leo4, L K Anderson4, M Marshall4, I McGown5, F Newell4, M A Brown4, L S Conwell1,3, M Harris1,2,3, E L Duncan3,4,6. 1. Department of Endocrinology, Lady Cilento Children's Hospital, South Brisbane, Australia. 2. University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Woolloongabba, Australia. 3. Faculty of Medicine, University of Queensland, Brisbane, Australia. 4. Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba, Australia. 5. Department of Pathology, Mater Health Services, South Brisbane, Australia. 6. Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Australia.
Abstract
BACKGROUND: To assess the utility of whole-exome sequencing (WES) for mutation detection in maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI). MODY and CHI are the two commonest monogenic disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. The large number of potential genes makes comprehensive screening using traditional methods expensive and time-consuming. METHODS: Ten subjects with MODY and five with CHI with known mutations underwent WES using two different exome capture kits (Nimblegen SeqCap EZ Human v3.0 Exome Enrichment Kit, Nextera Rapid Capture Exome Kit). Analysis was blinded to previously identified mutations, and included assessment for large deletions. The target capture of five exome capture technologies was also analyzed using sequencing data from >2800 unrelated samples. RESULTS: Four of five MODY mutations were identified using Nimblegen (including a large deletion in HNF1B). Although targeted, one mutation (in INS) had insufficient coverage for detection. Eleven of eleven mutations (six MODY, five CHI) were identified using Nextera Rapid (including the previously missed mutation). On reconciliation, all mutations concorded with previous data and no additional variants in MODY genes were detected. There were marked differences in the performance of the capture technologies. CONCLUSIONS: WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection.
BACKGROUND: To assess the utility of whole-exome sequencing (WES) for mutation detection in maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI). MODY and CHI are the two commonest monogenic disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. The large number of potential genes makes comprehensive screening using traditional methods expensive and time-consuming. METHODS: Ten subjects with MODY and five with CHI with known mutations underwent WES using two different exome capture kits (Nimblegen SeqCap EZ Human v3.0 Exome Enrichment Kit, Nextera Rapid Capture Exome Kit). Analysis was blinded to previously identified mutations, and included assessment for large deletions. The target capture of five exome capture technologies was also analyzed using sequencing data from >2800 unrelated samples. RESULTS: Four of five MODY mutations were identified using Nimblegen (including a large deletion in HNF1B). Although targeted, one mutation (in INS) had insufficient coverage for detection. Eleven of eleven mutations (six MODY, five CHI) were identified using Nextera Rapid (including the previously missed mutation). On reconciliation, all mutations concorded with previous data and no additional variants in MODY genes were detected. There were marked differences in the performance of the capture technologies. CONCLUSIONS: WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection.
Authors: Shu-Qin Lei; Jie-Ying Wang; Rong-Min Li; Jie Chang; Zhen Li; Li Ren; Yan-Mei Sang Journal: Am J Transl Res Date: 2020-10-15 Impact factor: 4.060
Authors: Mustafa Tosur; Claudia Soler-Alfonso; Katie M Chan; Michael M Khayat; Shalini N Jhangiani; Qingchang Meng; Ahmad Refaey; Donna Muzny; Richard A Gibbs; David R Murdock; Jennifer E Posey; Ashok Balasubramanyam; Maria J Redondo; Aniko Sabo Journal: Pediatr Diabetes Date: 2021-08-19 Impact factor: 4.866
Authors: Maria Gϋemes; Sofia Asim Rahman; Ritika R Kapoor; Sarah Flanagan; Jayne A L Houghton; Shivani Misra; Nick Oliver; Mehul Tulsidas Dattani; Pratik Shah Journal: Rev Endocr Metab Disord Date: 2020-12 Impact factor: 6.514
Authors: Sarah M Graff; Stephanie R Johnson; Paul J Leo; Prasanna K Dadi; Matthew T Dickerson; Arya Y Nakhe; Aideen M McInerney-Leo; Mhairi Marshall; Karolina E Zaborska; Charles M Schaub; Matthew A Brown; David A Jacobson; Emma L Duncan Journal: JCI Insight Date: 2021-07-08