Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series
Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5–15% of ca...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/8/7428 |
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| author | Rossella Cannarella Carmelo Gusmano Rosita A. Condorelli Andrea Bernini Jurgen Kaftalli Paolo Enrico Maltese Stefano Paolacci Astrit Dautaj Giuseppe Marceddu Matteo Bertelli Sandro La Vignera Aldo E. Calogero |
| author_facet | Rossella Cannarella Carmelo Gusmano Rosita A. Condorelli Andrea Bernini Jurgen Kaftalli Paolo Enrico Maltese Stefano Paolacci Astrit Dautaj Giuseppe Marceddu Matteo Bertelli Sandro La Vignera Aldo E. Calogero |
| author_sort | Rossella Cannarella |
| collection | DOAJ |
| description | Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5–15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype–phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the <i>CHD7</i> gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in <i>IL17RD</i> (c.960G>A, p.Met320Ile), <i>FGF17</i> (c.208G>A, p.Gly70Arg), and <i>DUSP6</i> (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the <i>PROK2</i> (c.163del, p.Ile55*), <i>CHD7</i> (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), <i>FLRT3</i> (c.1106C>T, p.Ala369Val), and <i>CCDC103</i> (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, <i>FGF17</i> (p.Gly70Arg), <i>DUSP6</i> (p.Leu145Arg), and <i>CHD7</i> p.(Thr917Met). Except for <i>DUSP6</i>, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the <i>CHD7</i> gene. The molecular modeling results suggest that the VUS of the <i>DUSP6</i> (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the <i>IL17RD</i> (c.960G>A, p.Met320Ile) and <i>FGF17</i> (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis. |
| first_indexed | 2024-03-11T04:55:41Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:55:41Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-07855f83a94a45ed9af0e277e5700bfc2023-11-17T19:40:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01248742810.3390/ijms24087428Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case SeriesRossella Cannarella0Carmelo Gusmano1Rosita A. Condorelli2Andrea Bernini3Jurgen Kaftalli4Paolo Enrico Maltese5Stefano Paolacci6Astrit Dautaj7Giuseppe Marceddu8Matteo Bertelli9Sandro La Vignera10Aldo E. Calogero11Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, ItalyDepartment of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, ItalyDepartment of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, ItalyDiagnostics Unit, MAGI EUREGIO, 39100 Bolzano, ItalyDiagnostics Unit, MAGI’S LAB, 38068 Rovereto, ItalyDiagnostics Unit, MAGI’S LAB, 38068 Rovereto, ItalyDiagnostics Unit, MAGI’S LAB, 38068 Rovereto, ItalyDiagnostics Unit, MAGI EUREGIO, 39100 Bolzano, ItalyDiagnostics Unit, MAGI EUREGIO, 39100 Bolzano, ItalyDepartment of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, ItalyDepartment of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, ItalyCongenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5–15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype–phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the <i>CHD7</i> gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in <i>IL17RD</i> (c.960G>A, p.Met320Ile), <i>FGF17</i> (c.208G>A, p.Gly70Arg), and <i>DUSP6</i> (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the <i>PROK2</i> (c.163del, p.Ile55*), <i>CHD7</i> (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), <i>FLRT3</i> (c.1106C>T, p.Ala369Val), and <i>CCDC103</i> (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, <i>FGF17</i> (p.Gly70Arg), <i>DUSP6</i> (p.Leu145Arg), and <i>CHD7</i> p.(Thr917Met). Except for <i>DUSP6</i>, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the <i>CHD7</i> gene. The molecular modeling results suggest that the VUS of the <i>DUSP6</i> (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the <i>IL17RD</i> (c.960G>A, p.Met320Ile) and <i>FGF17</i> (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.https://www.mdpi.com/1422-0067/24/8/7428hypogonadotropic hypogonadismKallmann syndromeamino acid conservationmolecular modeling |
| spellingShingle | Rossella Cannarella Carmelo Gusmano Rosita A. Condorelli Andrea Bernini Jurgen Kaftalli Paolo Enrico Maltese Stefano Paolacci Astrit Dautaj Giuseppe Marceddu Matteo Bertelli Sandro La Vignera Aldo E. Calogero Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series International Journal of Molecular Sciences hypogonadotropic hypogonadism Kallmann syndrome amino acid conservation molecular modeling |
| title | Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series |
| title_full | Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series |
| title_fullStr | Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series |
| title_full_unstemmed | Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series |
| title_short | Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series |
| title_sort | genetic analysis of patients with congenital hypogonadotropic hypogonadism a case series |
| topic | hypogonadotropic hypogonadism Kallmann syndrome amino acid conservation molecular modeling |
| url | https://www.mdpi.com/1422-0067/24/8/7428 |
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