title: Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46,XY under-virilised boys.
abstract: Congenital hypogonadotrophic hypogonadism (CHH) and Kallmann syndrome (KS) are caused by disruption to the hypothalamic-pituitary-gonadal (H-P-G) axis. In particular, reduced production, secretion or action of gonadotrophin-releasing hormone (GnRH) is often responsible. Various genes, many of which play a role in the development and function of the GnRH neurons, have been implicated in these disorders. Clinically, CHH and KS are heterogeneous; however, in 46,XY patients, they can be characterised by under-virilisation phenotypes such as cryptorchidism and micropenis or delayed puberty. In rare cases, hypospadias may also be present.
  
  
  
  Here, we describe genetic mutational analysis of CHH genes in Indonesian 46,XY disorder of sex development patients with under-virilisation. We present 11 male patients with varying degrees of under-virilisation who have rare variants in known CHH genes. Interestingly, many of these patients had hypospadias.
  
  
  
  We postulate that variants in CHH genes, in particular PROKR2, PROK2, WDR11 and FGFR1 with CHD7, may contribute to under-virilisation phenotypes including hypospadias in Indonesia.
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Ayers
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.|The Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Aurore
authors.initials: A
authors.lastname: Bouty
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.
authors.forename: Gorjana
authors.initials: G
authors.lastname: Robevska
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.
authors.forename: Jocelyn A
authors.initials: JA
authors.lastname: van den Bergen
authors.affiliation: Division of Human Genetics, Centre for Biomedical Research, Faculty of Medicine, Diponegoro University (FMDU), JL. Prof. H. Soedarto, SH, Tembalang, Semarang, 50275, Central Java, Indonesia.
authors.forename: Achmad Zulfa
authors.initials: AZ
authors.lastname: Juniarto
authors.affiliation: Division of Human Genetics, Centre for Biomedical Research, Faculty of Medicine, Diponegoro University (FMDU), JL. Prof. H. Soedarto, SH, Tembalang, Semarang, 50275, Central Java, Indonesia.
authors.forename: Nurin Aisyiyah
authors.initials: NA
authors.lastname: Listyasari
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sinclair
authors.affiliation: Division of Human Genetics, Centre for Biomedical Research, Faculty of Medicine, Diponegoro University (FMDU), JL. Prof. H. Soedarto, SH, Tembalang, Semarang, 50275, Central Java, Indonesia. sultanafaradz@gmail.com.
authors.forename: Sultana M H
authors.initials: SM
authors.lastname: Faradz
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005768:Gastrointestinal Hormones / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D007214:Indonesia; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D004265:DNA Helicases; D004268:DNA-Binding Proteins; D005768:Gastrointestinal Hormones; D008565:Membrane Proteins; D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; C435527:WDR11 protein, human; D000092468:Bromodomain Containing Proteins; C496348:FGFR1 protein, human; C491434:CHD7 protein, human
keywords: Congenital hypogonadotrophic hypogonadism; Disorder of sex development; Hypospadias; Targeted gene sequencing; Under-virilisation