Exome Sequencing and the Management of Neurometabolic Disorders.

BACKGROUND Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.).

Andrea Superti-Furga | Rupasri Mandal | Wyeth W Wasserman | David Wishart | Ron A Wevers | Suzanne Lewis | Jan M Friedman | Casper Shyr | Maja Tarailo-Graovac | Jiqiang Ling | Patrice Eydoux | Tammie Dewan | D. Wishart | M. Baumgartner | C. Ross | W. Wasserman | P. Ruben | D. Zafeiriou | M. Tarailo-Graovac | L. Kluijtmans | R. Wevers | C. V. van Karnebeek | M. Demos | A. Lehman | Jessica J. Y. Lee | C. Shyr | R. Mandal | J. Rozmus | G. Horvath | M. Connolly | Jessica J. Y. Lee | R. Salvarinova | S. Santra | P. Eydoux | H. Vallance | Linhua Zhang | Amit P. Bhavsar | G. Sinclair | S. Stockler-Ipsiroglu | A. Mattman | X. Ye | B. Drögemöller | Mena Abdelsayed | M. Alfadhel | L. Armstrong | P. Burda | J. Cameron | T. Dewan | Janis Dionne | A. Evans | J. Friedman | I. Garber | S. Lewis | Jiqiang Ling | M. McKinnon | A. Michoulas | D. Metzger | O. Ogunbayo | Bojana Rakić | B. Sayson | K. R. Schultz | K. Selby | Paul Shekel | S. Sirrs | C. Skrypnyk | A. Superti-Furga | S. Turvey | M. V. Van Allen | Jiang Wu | John Wu | Majid Alfadhel | Colin J Ross | Gabriella A Horvath | Ramona Salvarinova | Xin C Ye | Lin-Hua Zhang | Amit P Bhavsar | Jessica J Y Lee | Britt I Drögemöller | Mena Abdelsayed | Linlea Armstrong | Matthias R Baumgartner | Patricie Burda | Mary B Connolly | Jessie Cameron | Michelle Demos | Janis Dionne | A Mark Evans | Ian Garber | Andre Mattman | Margaret McKinnon | Aspasia Michoulas | Daniel Metzger | Oluseye A Ogunbayo | Bojana Rakic | Jacob Rozmus | Peter Ruben | Bryan Sayson | Saikat Santra | Kirk R Schultz | Kathryn Selby | Paul Shekel | Sandra Sirrs | Cristina Skrypnyk | Stuart E Turvey | Margot I Van Allen | Jiang Wu | John Wu | Dimitrios Zafeiriou | Leo Kluijtmans | Anna M Lehman | Hilary Vallance | Sylvia Stockler-Ipsiroglu | Graham Sinclair | Clara D van Karnebeek | J. Dionne | John K Wu | C. Karnebeek | M. V. Allen | Lin Hua Zhang

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