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, Virginia Proud, Samanta Vergano, Brooke Spangler, Emily Farrow, Jennifer Kussman, Nicole Safina, Care4Rare Consortium, Carol Saunders, Kym M. Boycott, Isabelle Thiffault

Deleterious variants in the same gene present in 2 or more families with overlapping clinical features provides convincing evidence of a disease-gene association; this can be a challenge in the study of ultra-rare 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 been previously reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease-causing gene and interpret 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. This article is protected by copyright. All rights reserved.