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Compound heterozygous\n                    <jats:italic>SLC5A6<\/jats:italic>\n                    variants have been reported in individuals with variable multisystemic disorder, including failure to thrive, developmental delay, seizures, cerebral palsy, brain atrophy, gastrointestinal problems, immunodeficiency, and\/or osteopenia. We expand the phenotypic spectrum associated with biallelic\n                    <jats:italic>SLC5A6<\/jats:italic>\n                    variants affecting function by reporting five individuals from three families with motor neuropathies. We identified the homozygous variant c.1285\u2009A\u2009&gt;\u2009G [p.(Ser429Gly)] in three affected siblings and a simplex patient and the maternally inherited c.280\u2009C\u2009&gt;\u2009T [p.(Arg94*)] variant and the paternally inherited c.485\u2009A\u2009&gt;\u2009G [p.(Tyr162Cys)] variant in the simplex patient of the third family. Both missense variants were predicted to affect function by in silico tools. 3D homology modeling of the human SMVT revealed 13 transmembrane helices (TMs) and Tyr162 and Ser429 to be located at the cytoplasmic facing region of TM4 and within TM11, respectively. The\n                    <jats:italic>SLC5A6<\/jats:italic>\n                    missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter suggesting reduced but not abolished function, such as lower catalytic activity. Targeted therapeutic intervention yielded clinical improvement in four of the five patients. Early molecular diagnosis by exome sequencing is essential for timely replacement therapy in affected individuals.\n                  <\/jats:p>","DOI":"10.1038\/s41431-021-01033-2","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T21:02:39Z","timestamp":1641848559000},"page":"439-449","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Novel biallelic variants expand the SLC5A6-related phenotypic spectrum"],"prefix":"10.1038","volume":"30","author":[{"given":"Tess","family":"Holling","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9575-0722","authenticated-orcid":false,"given":"Sheela","family":"Nampoothiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bedirhan","family":"Tarhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline E.","family":"Schneeberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kollencheri Puthenveettil","family":"Vinayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanya","family":"Yesodharan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun Grace","family":"Roy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Periyasamy","family":"Radhakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5993-7709","authenticated-orcid":false,"given":"Malik","family":"Alawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Rhodes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0139-8239","authenticated-orcid":false,"given":"Katta Mohan","family":"Girisha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4270-7325","authenticated-orcid":false,"given":"Peter B.","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-8963","authenticated-orcid":false,"given":"Kerstin","family":"Kutsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"1033_CR1","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1007\/s00424-020-02433-x","volume":"472","author":"G Gyimesi","year":"2020","unstructured":"Gyimesi G, Pujol-Gimenez J, Kanai Y, Hediger MA. 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Ltd. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The parents of three siblings (patients 1\u20131, 1\u20132, and 1\u20133 \u2013 family 1) and patient 3\u20131 (family 3) provided informed consent for their participation in the study, clinical data and specimen collection, genetic analysis, and publication of relevant findings. Informed consent was obtained for patient 2\u20131 and her parents (family 2) under a protocol approved by the Institutional Review Board of the University of Florida.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}