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We identified the novel heterozygous de novo variant p.(Leu137Phe) in <jats:italic>PTDSS1<\/jats:italic> in a child with mild\u2010to\u2010moderate developmental delay. Skeletal survey revealed no evidence of LMHD in this patient. Functional assessment of the p.Leu137Phe variant was performed by overexpressing the mutant protein into HEK293 cells. Following C<jats:sup>14<\/jats:sup>\u2010serine labeling and TLC analysis of lipids, we observed that the p.(Leu137Phe) variant displayed no catalytic activity compared to the wild\u2010type enzyme. We conclude that p.(Leu137Phe) variant has decreased enzymatic activity and that is likely to be the etiology of the patient's symptoms given the gene's constraint in the population. This is the first report of the clinical phenotype seen in an individual with a heterozygous loss\u2010of\u2010function variant in <jats:italic>PTDSS1<\/jats:italic>. This phenotype is distinct from LMHD, which results from gain\u2010of\u2010function pathogenic variants in the same gene. Evaluation of the neurodevelopmental phenotype of additional individuals with loss\u2010of\u2010function variants in <jats:italic>PTDSS1<\/jats:italic> is indicated to determine the spectrum of associated phenotypes.<\/jats:p>","DOI":"10.1002\/ajmg.a.62695","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T05:18:19Z","timestamp":1646025499000},"page":"1739-1745","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["De novo loss\u2010of\u2010function variant in <scp><i>PTDSS1<\/i><\/scp> is associated with developmental delay"],"prefix":"10.1002","volume":"188","author":[{"given":"Sara","family":"Gracie","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Section of Genetics and Children's Hospital Colorado University of Colorado School of Medicine  Aurora Colorado 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