Jessie M Cameron1, Nevena MacKay2, Annette Feigenbaum3, Mark Tarnopolsky4, Susan Blaser5, Brian H Robinson6, Andreas Schulze7. 1. Genetics & Genome Biology Program, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON M5G 0A4, Canada. Electronic address: jessie.cameron@sickkids.ca. 2. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. 3. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: Annette.feigenbaum@sickkids.ca. 4. Department of Pediatrics, McMaster University Medical Center, Hamilton, ON L8N 3Z5, Canada. Electronic address: tarnopol@mcmaster.ca. 5. Department of Radiology, The Hospital for Sick Children and University of Toronto, ON M5G 1X8, Canada. Electronic address: Susan.blaser@sickkids.ca. 6. Genetics & Genome Biology Program, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: Brian.robinson@sickkids.ca. 7. Genetics & Genome Biology Program, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: Andreas.schulze@sickkids.ca.
Abstract
BACKGROUND: Two siblings with hypertrophic cardiomyopathy and brain atrophy were diagnosed with Complex I deficiency based on low enzyme activity in muscle and high lactate/pyruvate ratio in fibroblasts. METHODS: Whole exome sequencing results of fibroblast gDNA from one sibling was narrowed down to 190 SNPs or In/Dels in 185 candidate genes by selecting non-synonymous coding sequence base pair changes that were not present in the SNP database. RESULTS: Two compound heterozygous mutations were identified in both siblings in NDUFV2, encoding the 24 kDa subunit of Complex I. The intronic mutation (c.IVS2 + 1delGTAA) is disease causing and has been reported before. The other mutation is novel (c.669_670insG, p.Ser224Valfs*3) and predicted to cause a pathogenic frameshift in the protein. Subsequent investigation of 10 probands with complex I deficiency from different families revealed homozygosity for the intronic c.IVS2 + 1delGTAA mutation in a second, consanguineous family. In this family three of five siblings were affected. Interestingly, they presented with Leigh syndrome but no cardiac involvement. The same genotype had been reported previously in a two families but presenting with hypertrophic cardiomyopathy, trunk hypotonia and encephalopathy. CONCLUSION: We have identified NDUFV2 mutations in two families with Complex I deficiency, including a novel mutation. The diagnosis of Leigh syndrome expands the clinical phenotypes associated with the c.IVS2 + 1delGTAA mutation in this gene.
BACKGROUND: Two siblings with hypertrophic cardiomyopathy and brain atrophy were diagnosed with Complex I deficiency based on low enzyme activity in muscle and high lactate/pyruvate ratio in fibroblasts. METHODS: Whole exome sequencing results of fibroblast gDNA from one sibling was narrowed down to 190 SNPs or In/Dels in 185 candidate genes by selecting non-synonymous coding sequence base pair changes that were not present in the SNP database. RESULTS: Two compound heterozygous mutations were identified in both siblings in NDUFV2, encoding the 24 kDa subunit of Complex I. The intronic mutation (c.IVS2 + 1delGTAA) is disease causing and has been reported before. The other mutation is novel (c.669_670insG, p.Ser224Valfs*3) and predicted to cause a pathogenic frameshift in the protein. Subsequent investigation of 10 probands with complex I deficiency from different families revealed homozygosity for the intronic c.IVS2 + 1delGTAA mutation in a second, consanguineous family. In this family three of five siblings were affected. Interestingly, they presented with Leigh syndrome but no cardiac involvement. The same genotype had been reported previously in a two families but presenting with hypertrophic cardiomyopathy, trunk hypotonia and encephalopathy. CONCLUSION: We have identified NDUFV2 mutations in two families with Complex I deficiency, including a novel mutation. The diagnosis of Leigh syndrome expands the clinical phenotypes associated with the c.IVS2 + 1delGTAA mutation in this gene.
Authors: Cristina Mazzaccara; Bruno Mirra; Ferdinando Barretta; Martina Caiazza; Barbara Lombardo; Olga Scudiero; Nadia Tinto; Giuseppe Limongelli; Giulia Frisso Journal: Int J Mol Sci Date: 2021-05-27 Impact factor: 6.208
Authors: Tom E J Theunissen; Minh Nguyen; Rick Kamps; Alexandra T Hendrickx; Suzanne C E H Sallevelt; Ralph W H Gottschalk; Chantal M Calis; Alphons P M Stassen; Bart de Koning; Elvira N M Mulder-Den Hartog; Kees Schoonderwoerd; Sabine A Fuchs; Yvonne Hilhorst-Hofstee; Marianne de Visser; Jo Vanoevelen; Radek Szklarczyk; Mike Gerards; Irenaeus F M de Coo; Debby M E I Hellebrekers; Hubert J M Smeets Journal: Front Genet Date: 2018-10-12 Impact factor: 4.599