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We report here the first CPHD patient with a de novo pathogenic loss\u2010of\u2010function variant in <jats:italic>BMP4<\/jats:italic>. A 6\u2010year\u2010old boy, with macrocephaly, myopia\/astigmatism, mild psychomotor retardation, anterior pituitary hypoplasia and ectopic posterior pituitary, clinically diagnosed with growth hormone deficiency, and central hypothyroidism, was referred for genetic analysis of CPHD. Targeted NGS analysis with a custom panel (<jats:italic>n<\/jats:italic> =\u2009310 genes) identified a novel heterozygous <jats:italic>de novo<\/jats:italic> nonsense variant, NM_001202.5:c.794G\u2009&gt;\u2009A, p.(Trp265*) in <jats:italic>BMP4<\/jats:italic>, which introduces a premature stop codon in the BMP4 pro\u2010domain, impairing the transcription of the TGF\u2010\u03b2 mature peptide domain. Additional relevant variants in other genes implicated in pituitary development signaling pathways such as <jats:italic>SMAD4<\/jats:italic> and <jats:italic>E2F4<\/jats:italic> (BMP\/TGF\u2010pathway), <jats:italic>ALMS1<\/jats:italic> (NOTCH\u2010pathway), and <jats:italic>TSHZ1<\/jats:italic> (Prokineticin\u2010pathway), were also identified. Our results support the implication of the BMP\/TGF\u2010\u03b2 signaling pathway in the etiology of CPHD and suggest that oligogenic contribution of additional inherited variants may modify the phenotypic expressivity of <jats:italic>BMP4<\/jats:italic> pathogenic variants.<\/jats:p>","DOI":"10.1002\/ajmg.a.61201","type":"journal-article","created":{"date-parts":[[2019,5,23]],"date-time":"2019-05-23T18:57:51Z","timestamp":1558637871000},"page":"1591-1597","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Loss of function <i>BMP4<\/i> mutation supports the implication of the BMP\/TGF\u2010\u03b2 pathway in the etiology of combined pituitary hormone deficiency"],"prefix":"10.1002","volume":"179","author":[{"given":"Francisco J.","family":"Rodr\u00edguez\u2010Contreras","sequence":"first","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"},{"name":"Department of Pediatrics Centro de Salud Galapagar  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Marb\u00e1n\u2010Calz\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Hospital La Mancha Centro  Ciudad Real Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Vallesp\u00edn","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER; U753) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1ngela","family":"del Pozo","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER; U753) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Sol\u00eds\u2010L\u00f3pez","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nerea","family":"Lobato\u2010Vidal","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Fern\u00e1ndez\u2010Elvira","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"del Valle Rex\u2010Romero","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen E.","family":"Heath","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER; U753) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Gonz\u00e1lez\u2010Casado","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology Hospital Universitario La Paz  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4649-2971","authenticated-orcid":false,"given":"\u00c1ngel","family":"Campos\u2010Barros","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ Universidad Auton\u00f3ma de Madrid  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER; U753) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2007.09.023"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6823-13-56"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00801-2"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurad.2015.10.005"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1101\/gad.940001","article-title":"The activity and signaling range of mature BMP\u20104 is regulated by sequential cleavage at two sites within the prodomain of the precursor","volume":"15","author":"Cui Y.","year":"2001","journal-title":"Genes & Development."},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e04-08-0673"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2016-1101"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13272"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00496"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D079301"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0008"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201649"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.130344"},{"key":"e_1_2_7_16_1","unstructured":"PapadakisG. 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