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Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>X-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The <jats:italic>OTUD5<\/jats:italic> gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic <jats:italic>OTUD5<\/jats:italic> variants, was recently reported as a new XLID with additional congenital anomalies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A hemizygous <jats:italic>OTUD5<\/jats:italic> missense variant, c.878A&amp;gt;T, p.Asn293Ile [NM_017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C&amp;gt;T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple <jats:italic>in silico<\/jats:italic> prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic <jats:italic>OTUD5<\/jats:italic> variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Unlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense <jats:italic>OTUD5<\/jats:italic> variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2021.631428","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T04:36:16Z","timestamp":1614746176000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["OTUD5 Variants Associated With X-Linked Intellectual Disability and Congenital Malformation"],"prefix":"10.3389","volume":"9","author":[{"given":"Ken","family":"Saida","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tokiko","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daryl A.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Sengoku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Ogata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annarita","family":"Nicosia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andres","family":"Hernandez-Garcia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seema R.","family":"Lalani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahshid S.","family":"Azamian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haley","family":"Streff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongzheng","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Mizuguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoko","family":"Miyatake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miki","family":"Asahina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutomu","family":"Ogata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriko","family":"Miyake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomichi","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.4172\/2572-5203.1000108","article-title":"Genomewide array comparative genomic hybridization in 55 Japanese normokaryotypic patients with non-syndromic intellectual disability.","volume":"2","author":"Asahina","year":"2016","journal-title":"J. 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