{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T18:44:10Z","timestamp":1774896250323,"version":"3.50.1"},"reference-count":21,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T00:00:00Z","timestamp":1615161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>THG1L\u2010<\/jats:italic>associated autosomal recessive ataxia belongs to a group of disorders that occur due to abnormal mitochondrial tRNA modification. The product of <jats:italic>THG1L<\/jats:italic> is the tRNA\u2010histidine guanylyltransferase 1\u2010like enzyme that catalyzes the 3\u2032\u20105\u201caddition of guanine to the 5\u201d\u2010end of tRNA\u2010histidine in the mitochondrion. To date, five individuals with homozygosity for p.(Val55Ala) in <jats:italic>THG1L<\/jats:italic> have been reported and presented with mild delays or normal development and cerebellar dysfunction. We present seven individuals with biallelic variants in <jats:italic>THG1L<\/jats:italic>. Three individuals were compound heterozygous for the p.(Cys51Trp) and p.(Val55Ala) variants and presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia. Four siblings were homozygous for the p.(Val55Ala) variant and presented with cerebellar ataxia with cerebellar vermis hypoplasia, dysarthria, mild developmental delays, and normal\/near\u2010normal cognition. All seven patients were of Ashkenazi Jewish descent. Carrier rates for the two variants were calculated in a cohort of 26,731 Ashkenazi Jewish individuals tested by the Dor Yeshorim screening program. The p.(Cys51Trp) variant is novel and was found in 40 of the Ashkenazi Jewish individuals tested, with a carrier rate of 1 in 668 (0.15%). The p.(Val55Ala) variant was found in 229 of the Ashkenazi Jewish individuals tested, with a carrier rate of 1 in 117 (0.85%). The individuals with compound heterozygosity of the p.(Val55Ala) and p.(Cys51Trp) variants expand the phenotypic spectrum of <jats:italic>THG1L<\/jats:italic>\u2010related disorders to include severe epileptic encephalopathy. The individuals with homozygosity of the p.(V55A) variant further establish the associated mild and slowly progressive or nonprogressive neurodevelopmental phenotype.<\/jats:p>","DOI":"10.1002\/ajmg.a.62147","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T09:45:40Z","timestamp":1615196740000},"page":"1589-1597","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Severe epileptic encephalopathy associated with compound heterozygosity of <scp>THG1L<\/scp> variants in the Ashkenazi Jewish population"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4906-7428","authenticated-orcid":false,"given":"Rachel","family":"Rabin","sequence":"first","affiliation":[{"name":"Clinical Genetic Services, Department of Pediatrics NYU Grossman School of Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoel","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Dor Yeshorim, Committee for Prevention Jewish Genetic Diseases  Brooklyn New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin M.","family":"Johansson","sequence":"additional","affiliation":[{"name":"Dor Yeshorim, Committee for Prevention Jewish Genetic Diseases  Brooklyn New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Ekstein","sequence":"additional","affiliation":[{"name":"Dor Yeshorim, Committee for Prevention Jewish Genetic Diseases  Brooklyn New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahron","family":"Ekstein","sequence":"additional","affiliation":[{"name":"Dor Yeshorim, Committee for Prevention Jewish Genetic Diseases  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5625-2598","authenticated-orcid":false,"given":"John","family":"Pappas","sequence":"additional","affiliation":[{"name":"Clinical Genetic Services, Department of Pediatrics NYU Grossman School of Medicine  New York New York USA"},{"name":"Clinical Genetics, NYU Langone Orthopedic Hospital  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200211046"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.026"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-016-0487-z"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2660(01)44087-9"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1113166109"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e31815f247c"},{"key":"e_1_2_9_8_1","volume":"88","author":"Heimer, G., Marek\u2010Yagel, D., Eyal, E., Barel, O., Oz Levi, D., Hoffmann, C., Ruzzo, E. 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