{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T17:05:02Z","timestamp":1776013502729,"version":"3.50.1"},"reference-count":65,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T00:00:00Z","timestamp":1630195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012280","name":"Rare Disease Foundation","doi-asserted-by":"publisher","award":["3143"],"award-info":[{"award-number":["3143"]}],"id":[{"id":"10.13039\/100012280","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011775","name":"BC Children\u2019s Hospital Foundation","doi-asserted-by":"publisher","award":["3143"],"award-info":[{"award-number":["3143"]}],"id":[{"id":"10.13039\/100011775","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Foundation Fighting Blindness","award":["CD-CL-0617-0727-HSC"],"award-info":[{"award-number":["CD-CL-0617-0727-HSC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Identifying multiple ultra-rare genetic syndromes with overlapping phenotypes is a diagnostic conundrum in clinical genetics. This study investigated the pathogenicity of a homozygous missense variant in GNB5 (GNB5L; NM_016194.4: c.920T &gt; G (p. Leu307Arg); GNB5S; NM_006578.4: c.794T &gt; G (p. Leu265Arg)) identified through exome sequencing in a female child who also had 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (newborn screening positive) and hemoglobin E trait. The proband presented with early-onset intellectual disability, the severity of which was more in keeping with GNB5-related disorder than 3-MCC deficiency. She later developed bradycardia and cardiac arrest, and upon re-phenotyping showed cone photo-transduction recovery deficit, all known only to GNB5-related disorders. Patient-derived fibroblast assays showed preserved GNB5S expression, but bioluminescence resonance energy transfer assay showed abolished function of the variant reconstituted G\u03b25S containing RGS complexes for deactivation of D2 dopamine receptor activity, confirming variant pathogenicity. This study highlights the need for precise phenotyping and functional assays to facilitate variant classification and clinical diagnosis in patients with complex medical conditions.<\/jats:p>","DOI":"10.3390\/genes12091352","type":"journal-article","created":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T21:45:16Z","timestamp":1630273516000},"page":"1352","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Extended Phenotyping and Functional Validation Facilitate Diagnosis of a Complex Patient Harboring Genetic Variants in MCCC1 and GNB5 Causing Overlapping Phenotypes"],"prefix":"10.3390","volume":"12","author":[{"given":"Zhuo","family":"Shao","sequence":"first","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikuo","family":"Masuho","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA"},{"name":"Pediatrics and Rare Diseases Group, Sanford Research, 2301 East 60th Street North, Sioux Falls, SD 57104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anupreet","family":"Tumber","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason T.","family":"Maynes","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"},{"name":"Department of Anesthesiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Tavares","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asim","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"},{"name":"Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacy","family":"Hewson","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8491-1095","authenticated-orcid":false,"given":"Andreas","family":"Schulze","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"},{"name":"Department of Paediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Kannu","sequence":"additional","affiliation":[{"name":"Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirill A.","family":"Martemyanov","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6446-3846","authenticated-orcid":false,"given":"Ajoy","family":"Vincent","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"},{"name":"Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"},{"name":"Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1056\/NEJMoa1306555","article-title":"Clinical whole-exome sequencing for the diagnosis of mendelian disorders","volume":"369","author":"Yang","year":"2013","journal-title":"N. 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