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The late\u2010infantile type is the most severe phenotype presenting with hypotonia, weakness, gait abnormalities, which progresses to mental and physical decline leading to early death. MLD is considered to be pan\u2010ethnic and no founder variants have previously been described in the Ashkenazi Jewish population. We identified three unrelated individuals of Ashkenazi Jewish descent with homozygosity or compound heterozygosity for the c.178C&gt;T (p.Arg60Trp) variant in the <jats:italic>ARSA<\/jats:italic> gene, with a phenotype consistent with late\u2010infantile MLD. The carrier frequency was calculated among 93,293 individuals of Ashkenazi Jewish descent through the Dor Yeshorim screening program and found to have a carrier frequency on 1 in 1554 or 0.06%, which may be representative of a founder variant. Molecular protein modeling showed that the variant affects regional folding. Late\u2010infantile MLD should be considered when the c.178C&gt;T (p.Arg60Trp) variant in the <jats:italic>ARSA<\/jats:italic> gene is present in either the homozygous or the compound heterozygous states.<\/jats:p>","DOI":"10.1002\/ajmg.a.63919","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T08:18:41Z","timestamp":1730276321000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<i>ARSA<\/i> Variant Associated With Late Infantile Metachromatic Leukodystrophy and Carrier Rate in Individuals of Ashkenazi Jewish Ancestry"],"prefix":"10.1002","volume":"197","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3061-3652","authenticated-orcid":false,"given":"Kevin T. 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