RT Journal Article SR Electronic T1 Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9 JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 83 OP 89 DO 10.1136/jmedgenet-2011-100577 VO 49 IS 2 A1 Tobias B Haack A1 Florence Madignier A1 Martina Herzer A1 Eleonora Lamantea A1 Katharina Danhauser A1 Federica Invernizzi A1 Johannes Koch A1 Martin Freitag A1 Rene Drost A1 Ingo Hillier A1 Birgit Haberberger A1 Johannes A Mayr A1 Uwe Ahting A1 Valeria Tiranti A1 Agnes Rötig A1 Arcangela Iuso A1 Rita Horvath A1 Marketa Tesarova A1 Ivo Baric A1 Graziella Uziel A1 Boris Rolinski A1 Wolfgang Sperl A1 Thomas Meitinger A1 Massimo Zeviani A1 Peter Freisinger A1 Holger Prokisch YR 2012 UL http://jmg.bmj.com/content/49/2/83.abstract AB Background Mitochondrial complex I deficiency is the most common cause of mitochondrial disease in childhood. Identification of the molecular basis is difficult given the clinical and genetic heterogeneity. Most patients lack a molecular definition in routine diagnostics.Methods A large-scale mutation screen of 75 candidate genes in 152 patients with complex I deficiency was performed by high-resolution melting curve analysis and Sanger sequencing. The causal role of a new disease allele was confirmed by functional complementation assays. The clinical phenotype of patients carrying mutations was documented using a standardised questionnaire.Results Causative mutations were detected in 16 genes, 15 of which had previously been associated with complex I deficiency: three mitochondrial DNA genes encoding complex I subunits, two mitochondrial tRNA genes and nuclear DNA genes encoding six complex I subunits and four assembly factors. For the first time, a causal mutation is described in NDUFB9, coding for a complex I subunit, resulting in reduction in NDUFB9 protein and both amount and activity of complex I. These features were rescued by expression of wild-type NDUFB9 in patient-derived fibroblasts.Conclusion Mutant NDUFB9 is a new cause of complex I deficiency. A molecular diagnosis related to complex I deficiency was established in 18% of patients. However, most patients are likely to carry mutations in genes so far not associated with complex I function. The authors conclude that the high degree of genetic heterogeneity in complex I disorders warrants the implementation of unbiased genome-wide strategies for the complete molecular dissection of mitochondrial complex I deficiency.