{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T14:22:40Z","timestamp":1747146160184,"version":"3.40.5"},"reference-count":18,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,5]],"date-time":"2020-02-05T00:00:00Z","timestamp":1580860800000},"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":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>3\u2010Hydroxyisobutyryl\u2010CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome\u2010like phenotype, mitochondrial dysfunction, and increased C4\u2010OH. We report the most severe case to date in a full\u2010term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI\/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in <jats:italic>HIBCH<\/jats:italic> with a paternal pathogenic variant (c.852delA, p.L284FfsX10<jats:bold>)<\/jats:bold> and a maternal likely pathogenic variant (c.488G&gt;T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow\u2010up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.<\/jats:p>","DOI":"10.1002\/ajmg.a.61498","type":"journal-article","created":{"date-parts":[[2020,2,5]],"date-time":"2020-02-05T13:26:53Z","timestamp":1580909213000},"page":"780-784","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A phenotypically severe, biochemically \u201csilent\u201d case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-5328","authenticated-orcid":false,"given":"Alissa M.","family":"D'Gama","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomics, Department of Medicine Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital  Boston Massachusetts"},{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William J.","family":"Brucker","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Medicine Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Medicine Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital  Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia S.","family":"Gubbels","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Medicine Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital  Boston Massachusetts"},{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sacha","family":"Ferdinandusse","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahai","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences City University of Hong Kong  Kowloon Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia Ellen","family":"Grant","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Department of Medicine Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"},{"name":"Department of Radiology Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace","family":"VanNoy","sequence":"additional","affiliation":[{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casie A.","family":"Genetti","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Medicine Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital  Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Juusola","sequence":"additional","affiliation":[{"name":"Clinical Genomics GeneDx, Inc.  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