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Profound congenital sensorineural hearing impairment can be due to an abnormal cochleovestibular nerve (CVN) and cochleovestibular malformations, however, the etiology of these conditions remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a trio\u2010based exome sequencing approach to unravel the underlying molecular etiology of a child with a rare nonsyndromic CVN abnormality and cochlear hypoplasia. Clinical and imaging data were also reviewed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a de novo missense variant [p(Asn174Tyr)] in the DNA\u2010binding Homeodomain of <jats:italic>SIX1,<\/jats:italic> a gene which previously has been associated with autosomal dominant hearing loss (ADHL) and branchio\u2010oto\u2010renal or Branchio\u2010otic syndrome, a condition not seen in this patient.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>SIX1<\/jats:italic> has an important function in otic vesicle patterning during embryogenesis, and mice show several abnormalities to their inner ear including loss of inner ear innervation. Previous reports on patients with <jats:italic>SIX1<\/jats:italic> variants lack imaging data and nonsyndromic AD cases were reported to have no inner ear malformations. In conclusion, we show that a de novo variant in <jats:italic>SIX1<\/jats:italic> in a patient with sensorineural hearing loss leads to cochleovestibular malformations and abnormalities of the CVN, without any other abnormalities. Without proper interventions, severe to profound hearing loss is devastating to both education and social integration. Choosing the correct intervention can be challenging and a molecular diagnosis may adjust intervention and improve outcomes, especially for rare cases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.995","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T02:05:03Z","timestamp":1570586703000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A de novo <i>SIX1<\/i> variant in a patient with a rare nonsyndromic cochleovestibular nerve abnormality, cochlear hypoplasia, and bilateral sensorineural hearing loss"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8612-1695","authenticated-orcid":false,"given":"Elina","family":"Kari","sequence":"first","affiliation":[{"name":"Division of Otolaryngology, Head and Neck Surgery Department of Surgery University of California, San Diego La Jolla CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorida","family":"Llaci","sequence":"additional","affiliation":[{"name":"Neurogenomics Division and Center for Rare Childhood Disorders Translational Genomics Research Institute Phoenix AZ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L.","family":"Go","sequence":"additional","affiliation":[{"name":"Department of Radiology Keck School of Medicine University of Southern California Los Angeles CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Naymik","sequence":"additional","affiliation":[{"name":"Neurogenomics Division and Center for Rare Childhood Disorders Translational Genomics Research Institute Phoenix AZ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A.","family":"Knowles","sequence":"additional","affiliation":[{"name":"Department of Cell Biology \u2010 MSC 5 SUNY Downstate Medical Center Brooklyn NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne M.","family":"Leal","sequence":"additional","affiliation":[{"name":"Center for Statistical Genetics, Molecular and Human Genetics Department Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sampath","family":"Rangasamy","sequence":"additional","affiliation":[{"name":"Neurogenomics Division and Center for Rare Childhood Disorders Translational Genomics Research Institute Phoenix AZ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Huentelman","sequence":"additional","affiliation":[{"name":"Neurogenomics Division and Center for Rare Childhood Disorders Translational Genomics Research Institute Phoenix AZ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rick A.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology, Head and Neck Surgery Department of Surgery University of California, San Diego La Jolla CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7310-6082","authenticated-orcid":false,"given":"Isabelle","family":"Schrauwen","sequence":"additional","affiliation":[{"name":"Neurogenomics Division and Center for Rare Childhood Disorders Translational Genomics Research Institute Phoenix AZ USA"},{"name":"Center for Statistical Genetics, Molecular and Human Genetics Department Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,10,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/MAO.0000000000000997"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200402000-00025"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.22032"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1148\/radiology.202.3.9051033"},{"key":"e_1_2_7_6_1","unstructured":"CDC. 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