Vassos Neocleous1,2, Pavlos Fanis3,4, Feride Cinarli3,4, Vasilis Kokotsis5, Anastasios Oulas4,6, Meropi Toumba3,7, George M Spyrou4,6, Leonidas A Phylactou3,4, Nicos Skordis8,9,10. 1. Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. vassosn@cing.ac.cy. 2. Cyprus School of Molecular Medicine, Nicosia, Cyprus. vassosn@cing.ac.cy. 3. Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. 4. Cyprus School of Molecular Medicine, Nicosia, Cyprus. 5. Pediatrics and Neonates, Luton and Dunstable Hospital, London, UK. 6. Bioinformatics Group, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. 7. Pediatric Endocrine Clinic, IASIS Hospital, Paphos, Cyprus. 8. Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. nicosskordis@paedi.org.cy. 9. Division of Pediatric Endocrinology, Paedi Center for Specialized Pediatrics, Nicosia, Cyprus. nicosskordis@paedi.org.cy. 10. School of Medicine, University of Nicosia, Nicosia, Cyprus. nicosskordis@paedi.org.cy.
Abstract
PURPOSE: Disorders of sex development (DSD) have been linked to gene defects that lead to gonadal dysgenesis. Herein, we aimed to identify the genetic cause of gonadal dysgenesis in a patient with primary amenorrhoea tracing it to a phenotypic female carrying a 46,XY karyotype of a consanguineous family. METHODS AND RESULTS: Whole exome sequencing (WES) was performed and revealed in homozygosity the rare and only once reported p.Arg164Pro missense mutation in exon 2 of the desert hedgehog (DHH) gene. Sanger sequencing was used to validate this candidate variant both in the patient, the parents, and two siblings. Both brother and sister of the index patient were found negative for the p.Arg164Pro mutation, while the consanguineous parents were found to carry the mutation in the heterozygous state. Neither the parents nor the unaffected siblings showed any reproductive malformations. CONCLUSIONS: Defects in the DHH gene have been reported as a very rare cause of DSD, and this report increases the number of 46,XY gonadal dysgenesis cases. Additionally, the present study highlights the importance of genetic validation of patients with DSD, since this is likely to alleviate the considerable psychological distress experienced by both the patient and the parents.
PURPOSE: Disorders of sex development (DSD) have been linked to gene defects that lead to gonadal dysgenesis. Herein, we aimed to identify the genetic cause of gonadal dysgenesis in a patient with primary amenorrhoea tracing it to a phenotypic female carrying a 46,XY karyotype of a consanguineous family. METHODS AND RESULTS: Whole exome sequencing (WES) was performed and revealed in homozygosity the rare and only once reported p.Arg164Pro missense mutation in exon 2 of the desert hedgehog (DHH) gene. Sanger sequencing was used to validate this candidate variant both in the patient, the parents, and two siblings. Both brother and sister of the index patient were found negative for the p.Arg164Pro mutation, while the consanguineous parents were found to carry the mutation in the heterozygous state. Neither the parents nor the unaffected siblings showed any reproductive malformations. CONCLUSIONS: Defects in the DHH gene have been reported as a very rare cause of DSD, and this report increases the number of 46,XY gonadal dysgenesis cases. Additionally, the present study highlights the importance of genetic validation of patients with DSD, since this is likely to alleviate the considerable psychological distress experienced by both the patient and the parents.
Authors: Hosneara Akter; Mohammad Shahnoor Hossain; Nushrat Jahan Dity; Md Atikur Rahaman; K M Furkan Uddin; Nasna Nassir; Ghausia Begum; Reem Abdel Hameid; Muhammad Sougatul Islam; Tahrima Arman Tusty; Mohammad Basiruzzaman; Shaoli Sarkar; Mazharul Islam; Sharmin Jahan; Elaine T Lim; Marc Woodbury-Smith; Dimitri James Stavropoulos; Darren D O'Rielly; Bakhrom K Berdeiv; A H M Nurun Nabi; Mohammed Nazmul Ahsan; Stephen W Scherer; Mohammed Uddin Journal: NPJ Genom Med Date: 2021-02-16 Impact factor: 8.617