Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency
Amalia Sertedaki,
Elizabeth Barbara Tatsi,
Ioannis Anargyros Vasilakis,
Irene Fylaktou,
Eirini Nikaina,
Nicoletta Iacovidou,
Tania Siahanidou,
Christina Kanaka-Gantenbein
Affiliations
Amalia Sertedaki
Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, “Aghia Sophia” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
Elizabeth Barbara Tatsi
Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, “Aghia Sophia” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
Ioannis Anargyros Vasilakis
Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, “Aghia Sophia” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
Irene Fylaktou
Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, “Aghia Sophia” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
Eirini Nikaina
Neonatology Unit, First Department of Pediatrics, Medical School, “Aghia Sophia” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
Nicoletta Iacovidou
Department of Neonatology, Medical School, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece
Tania Siahanidou
Neonatology Unit, First Department of Pediatrics, Medical School, “Aghia Sophia” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
Christina Kanaka-Gantenbein
Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, “Aghia Sophia” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
Combined pituitary hormone deficiency (CPHD) is characterized by deficiency of growth hormone and at least one other pituitary hormone. Pathogenic variants in more than 30 genes expressed during the development of the head, hypothalamus, and/or pituitary have been identified so far to cause genetic forms of CPHD. However, the etiology of around 85% of the cases remains unknown. The aim of this study was to unveil the genetic etiology of CPHD due to congenital hypopituitarism employing whole exome sequencing (WES) in two newborn patients, initially tested and found to be negative for PROP1, LHX3, LHX4 and HESX1 pathogenic variants by Sanger sequencing and for copy number variations by MLPA. In this study, the application of WES in these CPHD newborns revealed the presence of three different heterozygous gene variants in each patient. Specifically in patient 1, the variants BMP4; p.Ala42Pro, GNRH1; p.Arg73Ter and SRA1; p.Gln32Glu, and in patient 2, the SOX9; p.Val95Ile, HS6ST1; p.Arg306Gln, and IL17RD; p.Pro566Ser were identified as candidate gene variants. These findings further support the hypothesis that CPHD constitutes an oligogenic rather than a monogenic disease and that there is a genetic overlap between CPHD and congenital hypogonadotropic hypogonadism.
