title: Novel cases of Tunisian patients with mutations in the gene encoding 17β-hydroxysteroid dehydrogenase type 3 and a founder effect.
abstract: 17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed almost exclusively in the testis and converts Δ4-androstene-3,17-dione to testosterone. Mutations in the HSD17B3 gene causing 17β-HSD3 deficiency are responsible for a rare recessive form of 46, XY Disorders of Sex Development (46, XY DSD). We report novel cases of Tunisian patients with 17β-HSD3 deficiency due to previously reported mutations, i.e. p.C206X and p.G133R, as well as a case with the novel compound heterozygous mutations p.C206X and p.Q176P. Moreover, the previously reported polymorphism p.G289S was identified in a heterozygous state in combination with a novel non-coding variant c.54G>T, also in a heterozygous state, in a male patient presenting with micropenis and low testosterone levels. The identification of four different mutations in a cohort of eight patients confirms the generally observed genetic heterogeneity of 17β-HSD3 deficiency. Nevertheless, analysis of DNA from 272 randomly selected healthy controls from the same geographic area (region of Sfax) revealed a high carrier frequency for the p.C206X mutation of approximately 1 in 40. Genotype reconstruction of the affected pedigree members revealed that all p.C206X mutation carriers harbored the same haplotype, indicating inheritance of the mutation from a common ancestor. Thus, the identification of a founder effect and the elevated carrier frequency of the p.C206X mutation emphasize the importance to consider this mutation in the diagnosis and genetic counseling of affected 17β-HSD3 deficiency pedigrees in Tunisia.
authors.affiliation: Human Molecular Genetic Laboratory, Faculty of Medicine of Sfax, 3030, University of Sfax, Tunisia. Electronic address: bochra.benrhouma@gmail.com.
authors.forename: Bochra
authors.initials: B
authors.lastname: Ben Rhouma
authors.affiliation: Human Molecular Genetic Laboratory, Faculty of Medicine of Sfax, 3030, University of Sfax, Tunisia.
authors.forename: Fakhri
authors.initials: F
authors.lastname: Kallabi
authors.affiliation: Department of Immunology, Hedi Chaker Hospital, 3029 Sfax, Tunisia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Mahfoudh
authors.affiliation: Human Molecular Genetic Laboratory, Faculty of Medicine of Sfax, 3030, University of Sfax, Tunisia.
authors.forename: Afif
authors.initials: A
authors.lastname: Ben Mahmoud
authors.affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmacenter, University of Basel, Basel, Switzerland.
authors.forename: Roger T
authors.initials: RT
authors.lastname: Engeli
authors.affiliation: Department of Medical Genetics, Hedi Chaker Hospital, 3029 Sfax, Tunisia.
authors.forename: Hassen
authors.initials: H
authors.lastname: Kamoun
authors.affiliation: Human Molecular Genetic Laboratory, Faculty of Medicine of Sfax, 3030, University of Sfax, Tunisia.
authors.forename: Leila
authors.initials: L
authors.lastname: Keskes
authors.affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmacenter, University of Basel, Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.affiliation: Human Molecular Genetic Laboratory, Faculty of Medicine of Sfax, 3030, University of Sfax, Tunisia; Department of Medical Genetics, Hedi Chaker Hospital, 3029 Sfax, Tunisia.
authors.forename: Neila
authors.initials: N
authors.lastname: Belguith
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005817:Genetic Counseling; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D014416:Tunisia
chemical_list: D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3
keywords: 17beta-hydroxysteroid dehydrogenase; 46, XY disorders of sex development; Founder effect; HSD17B3; Male sexual development; Mutation