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Matchmaking facilitates the diagnosis of an autosomal‐recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene |
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| Authors: | Kristin D. Kernohan David A. Dyment Mihaela Pupavac Zvi Cramer Arran McBride Genevieve Bernard Isabella Straub Martine Tetreault Taila Hartley Lijia Huang Erick Sell Jacek Majewski David S. Rosenblatt Eric Shoubridge Aziz Mhanni Tara Myers Samanta Vergano Brooke Spangler Emily Farrow Jennifer Kussman Nicole Safina CareRare Consortium Carol Saunders Kym M. Boycott Isabelle Thiffault |
| Affiliation: | 1. Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada;2. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada;3. Department of Human Genetics, McGill University, Montréal, Québec, Canada;4. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada;5. Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada;6. Section of Genetics and Metabolism, Children's Hospital and the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada;7. Department of Pediatrics, Children's Mercy Hospitals, Kansas City, Missouri;8. Division of Medical Genetics and Metabolism, Children's Hospital of the King's Daughters, Norfolk, Virginia;9. Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri;10. University of Missouri–Kansas City School of Medicine, Kansas City, Missouri |
| Abstract: | Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease–gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created “matching” platforms. We describe four individuals from three unrelated families “matched” by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease‐causing gene and interprets the variants as “pathogenic.” TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder. |
| Keywords: | TRIT1 developmental disorders epilepsy brain anomalies intellectual disability tRNA |