{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T05:07:53Z","timestamp":1764997673961,"version":"3.44.0"},"reference-count":16,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"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":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Since 2016, variants <jats:italic>in SLC12A2<\/jats:italic> have been implicated in human disease, with several different phenotypes being linked to the gene. The first report concerned a child with a complex syndrome marked by metabolic derangement but normal hearing and cognition and a de novo heterozygous loss of function variant. Subsequently, several patients with severe developmental delay, sensorineural hearing loss, and bi\u2010allelic loss of function variants were reported; this condition is known as Kilquist syndrome. The SLC12A2 knockout mouse model has a phenotype that is quite similar to Kilquist patients. In 2020, heterozygous variants in <jats:italic>SLC12A2<\/jats:italic> were identified as a cause of non\u2010syndromic deafness associated with vestibular areflexia (DFNA78; MIM 619081). In addition, de novo heterozygous <jats:italic>SLC12A2<\/jats:italic> variants have also been implicated in developmental delay with autistic features. <jats:italic>SLC12A2<\/jats:italic> encodes a Na+K+2Cl\u2212 cotransporter (NKCC) that is widely expressed in neurons, glial cells, the trachea, salivary glands, intestine, sweat glands, and the cochlea. In the inner ear, K+ transport is required for the mechano\u2010transduction of auditory stimuli. <jats:italic>SLC12A2<\/jats:italic> functions as a dimer and has several isoforms; only one isoform contains exon 21, and this isoform is almost exclusively expressed in the inner ear\/cochlea. This isoform is necessary for homeostasis of the endolymph. To date, the published pathogenic variants causing DFNA78 are missense mutations located within exon 21 or in the 3\u2032 splice site of exon 21. We report a patient with profound congenital hearing loss and vestibular areflexia with a de novo variant in <jats:italic>SLC12A2<\/jats:italic> located in the splice donor site: NM_001046.2: c.2977+4_2977+7del causing an in\u2010frame skip of exon 21, as shown by cDNA analysis. Our case adds to the evidence that loss of exon 21 of <jats:italic>SLC12A2<\/jats:italic> leads to a cochlear restricted phenotype. From a genetic counseling point of view, it reminds us that beyond syndromic forms such as Usher syndrome, several non\u2010syndromic forms of genetically determined sensorineural hearing loss, including those involving the <jats:italic>SLC12A2<\/jats:italic> gene, may also present with vestibular areflexia. This underscores the need for a broad sequencing approach when faced with this clinical scenario.<\/jats:p>","DOI":"10.1002\/ajmg.a.64150","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T06:15:09Z","timestamp":1749708909000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["De Novo <i>SLC12A2<\/i> Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia"],"prefix":"10.1002","volume":"197","author":[{"given":"Katja","family":"Ludin","sequence":"first","affiliation":[{"name":"Genetica, Genetic Consultations and Laboratory  Z\u00fcrich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna M.","family":"Kopps","sequence":"additional","affiliation":[{"name":"Genetica, Genetic Consultations and Laboratory  Z\u00fcrich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0001-7879","authenticated-orcid":false,"given":"Celine","family":"Richard","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head &amp; Neck Surgery University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Division of Pediatric Otolaryngology Le Bonheur Children's Hospital  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8693-4571","authenticated-orcid":false,"given":"Sheila","family":"Unger","sequence":"additional","affiliation":[{"name":"Genetica, Genetic Consultations and Laboratory  Z\u00fcrich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-021-00954-6"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-021-00904-2"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/9713"},{"issue":"6","key":"e_1_2_9_5_1","doi-asserted-by":"crossref","DOI":"10.1101\/mcs.a001289","article-title":"A Patient With Multisystem Dysfunction Carries a Truncation Mutation in Human SLC12A2, the Gene Encoding the Na\u2010K\u20102Cl Cotransporter, NKCC1","volume":"2","author":"Delpire E.","year":"2016","journal-title":"Cold Spring Harbor Molecular Case Studies"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5876(99)00206-2"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjoto.2020.102830"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23722"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12017-015-8378-2"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa176"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/21695717.2020.1726670"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq0952"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008643"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.01.006"},{"issue":"3","key":"e_1_2_9_15_1","first-page":"173","article-title":"Association Between Hearing Loss and Vestibular Disorders: A Review of the Interference of Hearing in the Balance","volume":"4","author":"Santos T. G.","year":"2015","journal-title":"International Journal of Otorhinolaryngology and Head & Neck Surgery"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000478"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.12442"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.64150","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:28:57Z","timestamp":1757500137000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.64150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,12]]},"references-count":16,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/ajmg.a.64150"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.64150","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"type":"print","value":"1552-4825"},{"type":"electronic","value":"1552-4833"}],"subject":[],"published":{"date-parts":[[2025,6,12]]},"assertion":[{"value":"2025-03-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e64150"}}