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Its typical clinical manifestation is delayed puberty and azoospermia. Homozygous and compound heterozygous mutations in the GNRHR<\/jats:styled-content><\/jats:italic> gene (4q13.2) are the most frequent genetic causes of ncHH<\/jats:styled-content>.<\/jats:p><\/jats:sec>Objectives<\/jats:title>(i) Characterization at the molecular level (genetic origin and functional effect) of a unique homozygous mutation (p.Gly99Glu) in a ncHH<\/jats:styled-content> man; (ii) to provide a comprehensive catalog of GNRHR<\/jats:styled-content><\/jats:italic> mutations with genotype\u2013phenotype correlation and comparison of in\u00a0vitro studies vs. in silico prediction tools.<\/jats:p><\/jats:sec>Material and Methods<\/jats:title>A ncHH<\/jats:styled-content> man and his parents, in whom we performed the following: (i) Sanger sequencing, qPCR<\/jats:styled-content> of the GNRHR<\/jats:styled-content><\/jats:italic> gene; (ii) chromosome 4 SNP<\/jats:styled-content> array; and (iii) competition binding assay and inositol phosphate signaling assay. PubMed and Human Genome Mutation Database (HGMD<\/jats:styled-content>) search for GNRHR<\/jats:styled-content><\/jats:italic> mutations. Bioinformatic analysis of 55 reported variants.<\/jats:p><\/jats:sec>Results<\/jats:title>qPCR<\/jats:styled-content> showed two GNRHR<\/jats:styled-content><\/jats:italic> copies in the index case. SNP<\/jats:styled-content> array revealed the inheritance of two homologous chromosomes 4 from the mother (maternal heterodisomy; hUPD<\/jats:styled-content>) with two loss of heterozygosity regions, one of them containing the mutated gene (maternal isodisomy; iUPD<\/jats:styled-content>). Functional studies for the p.Gly99Glu mutation demonstrated a right\u2010shifted GnRH<\/jats:styled-content>\u2010stimulated signaling response. Bioinformatic tools show that commonly used in silico tools are poor predictors of the function of ncHH<\/jats:styled-content>\u2010associated GNRHR<\/jats:styled-content><\/jats:italic> variants.<\/jats:p><\/jats:sec>Discussion<\/jats:title>Functional analysis of the p.Gly99Glu mutation is consistent with severely decreased GnRH<\/jats:styled-content> binding affinity (a severe partial loss\u2010of\u2010function mutation). Complete LOF<\/jats:styled-content> variants are associated with severe and severe\/moderate phenotype, whereas partial LOF<\/jats:styled-content> variants show wide range of clinical manifestations.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>This is the first ncHH<\/jats:styled-content> patient carrying a novel causative missense mutation of GNRHR<\/jats:styled-content><\/jats:italic> with proven \u2018severe pLOF<\/jats:styled-content>\u2019 due to maternal hUPD<\/jats:styled-content>\/iUPD<\/jats:styled-content> of chromosome 4. Our literature review shows that functional studies\u00a0remain essential both for diagnostic and potential therapeutic purposes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.12563","type":"journal-article","created":{"date-parts":[[2018,12,21]],"date-time":"2018-12-21T16:09:29Z","timestamp":1545408569000},"page":"88-101","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature"],"prefix":"10.1111","volume":"7","author":[{"given":"F.","family":"Cioppi","sequence":"first","affiliation":[{"name":"Department of Biomedical, Experimental and Clinical Sciences \u201cMario Serio\u201d University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Riera\u2010Escamilla","sequence":"additional","affiliation":[{"name":"Andrology Department Fundaci\u00f3 Puigvert Universitat Aut\u00f2noma de Barcelona Instituto de Investigaciones Biom\u00e9dicas Sant Pau (IIB\u2010Sant Pau) Barcelona Catalonia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Manilall","sequence":"additional","affiliation":[{"name":"School of Physiology University of the Witwatersrand Faculty of Health Sciences Johannesburg South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Guarducci","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Experimental and Clinical Sciences \u201cMario Serio\u201d University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Todisco","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Experimental and Clinical Sciences \u201cMario Serio\u201d University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Corona","sequence":"additional","affiliation":[{"name":"Endocrinology Unit Maggiore\u2010Bellaria Hospital Bologna Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Colombo","sequence":"additional","affiliation":[{"name":"Department of Urology and Gynecology Bologna University Hospital \u2010 Policlinico S.Orsola Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Bonomi","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health University of Milan Milan Italy"},{"name":"Division of Endocrinology and Metabolism IRCCS Istituto Auxologico Italiano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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