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Mutations in the <jats:italic>CHD7<\/jats:italic> gene cause CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and Ear abnormalities), but have also been found in patients with isolated CHH. The aim of this study was to identify <jats:italic>CHD7<\/jats:italic> mutations in patients with CHH. Fifty Portuguese patients with CHH were screened for mutations in the <jats:italic>CHD7<\/jats:italic> gene by DNA sequencing. Eight (16%) patients had <jats:italic>CHD7<\/jats:italic> rare sequence variants that consisted of six missense (p.Gly388Glu, p.His903Pro, p.Thr1082Ile, p.Val1452Leu, p.Asp1854Gly, and p.Arg2065His) and two synonymous (p.Ser559Ser, and p.Ala2785Ala) mutations. Five of these mutations have never been reported before. Three <jats:italic>CHD7<\/jats:italic> mutations occurred in patients that had mutations in additional CHH-genes. This study uncovered novel genetic variants that expand the known spectrum of mutations associated with CHH. The frequency of <jats:italic>CHD7<\/jats:italic> mutations in this cohort was higher than that of other major CHH-genes and confirms the importance of including <jats:italic>CHD7<\/jats:italic> in the genetic testing of CHH, even in the absence of additional CHARGE features.<\/jats:p>","DOI":"10.1038\/s41598-018-38178-y","type":"journal-article","created":{"date-parts":[[2019,2,7]],"date-time":"2019-02-07T11:05:41Z","timestamp":1549537541000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism"],"prefix":"10.1038","volume":"9","author":[{"given":"Catarina In\u00eas","family":"Gon\u00e7alves","sequence":"first","affiliation":[]},{"given":"Filipa Marina","family":"Patriarca","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 Maria","family":"Arag\u00fc\u00e9s","sequence":"additional","affiliation":[]},{"given":"Davide","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"Fernando","family":"Fonseca","sequence":"additional","affiliation":[]},{"given":"Sofia","family":"Martins","sequence":"additional","affiliation":[]},{"given":"Olinda","family":"Marques","sequence":"additional","affiliation":[]},{"given":"Bernardo Dias","family":"Pereira","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9","family":"Martinez-de-Oliveira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9326-8900","authenticated-orcid":false,"given":"Manuel Carlos","family":"Lemos","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2019,2,7]]},"reference":[{"key":"38178_CR1","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nrendo.2015.112","volume":"11","author":"U Boehm","year":"2015","unstructured":"Boehm, U. et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism\u2013pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 11, 547\u2013564, https:\/\/doi.org\/10.1038\/nrendo.2015.112 (2015).","journal-title":"Nat Rev Endocrinol"},{"key":"38178_CR2","doi-asserted-by":"publisher","first-page":"456","DOI":"10.3803\/EnM.2015.30.4.456","volume":"30","author":"SH Kim","year":"2015","unstructured":"Kim, S. H. Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future. Endocrinology and metabolism 30, 456\u2013466, https:\/\/doi.org\/10.3803\/EnM.2015.30.4.456 (2015).","journal-title":"Endocrinology and metabolism"},{"key":"38178_CR3","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/S0022-3476(81)80454-4","volume":"99","author":"RA Pagon","year":"1981","unstructured":"Pagon, R. A., Graham, J. M. Jr., Zonana, J. & Yong, S. L. 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