title: Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene.
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.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Kernohan
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.|Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Pupavac
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Cramer
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Arran
authors.initials: A
authors.lastname: McBride
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Bernard
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada.
authors.forename: Isabella
authors.initials: I
authors.lastname: Straub
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tetreault
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Taila
authors.initials: T
authors.lastname: Hartley
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Lijia
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Erick
authors.initials: E
authors.lastname: Sell
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Shoubridge
authors.affiliation: Section of Genetics and Metabolism, Children's Hospital and the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Aziz
authors.initials: A
authors.lastname: Mhanni
authors.affiliation: Department of Pediatrics, Children's Mercy Hospitals, Kansas City, Missouri.
authors.forename: Tara
authors.initials: T
authors.lastname: Myers
authors.affiliation: Division of Medical Genetics and Metabolism, Children's Hospital of the King's Daughters, Norfolk, Virginia.
authors.forename: Virginia
authors.initials: V
authors.lastname: Proud
authors.affiliation: Division of Medical Genetics and Metabolism, Children's Hospital of the King's Daughters, Norfolk, Virginia.
authors.forename: Samanta
authors.initials: S
authors.lastname: Vergano
authors.affiliation: Division of Medical Genetics and Metabolism, Children's Hospital of the King's Daughters, Norfolk, Virginia.
authors.forename: Brooke
authors.initials: B
authors.lastname: Spangler
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
authors.forename: Emily
authors.initials: E
authors.lastname: Farrow
authors.affiliation: Department of Pediatrics, Children's Mercy Hospitals, Kansas City, Missouri.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kussman
authors.affiliation: Department of Pediatrics, Children's Mercy Hospitals, Kansas City, Missouri.
authors.forename: Nicole
authors.initials: N
authors.lastname: Safina
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
authors.forename: Carol
authors.initials: C
authors.lastname: Saunders
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.|Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.|University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
mesh_terms: D000293:Adolescent; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D000483:Alleles; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019066:Facies; D005260:Female; D005808:Genes, Recessive; D005820:Genetic Testing; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype
chemical_list: D019883:Alkyl and Aryl Transferases; C000595656:TRIT1 protein, human
keywords: TRIT1; brain anomalies; developmental disorders; epilepsy; intellectual disability; tRNA