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Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development.
- Source :
-
American journal of medical genetics. Part A [Am J Med Genet A] 2021 Jun; Vol. 185 (6), pp. 1666-1677. Date of Electronic Publication: 2021 Mar 19. - Publication Year :
- 2021
-
Abstract
- Disorders/differences of sex development (DSD) comprise a group of congenital disorders that affect the genitourinary tract and usually involve the endocrine and reproductive system. The aim of this work was to identify genetic variants responsible for disorders of human urogenital development in a cohort of Egyptian patients. This three-year study included 225 patients with various DSD forms, referred to the genetic DSD and endocrinology clinic, National Research Centre, Egypt. The patients underwent thorough clinical examination, hormonal and imaging studies, detailed cytogenetic and fluorescence in situ hybridization analysis, and molecular sequencing of genes known to commonly cause DSD including AR, SRD5A2, 17BHSD3, NR5A1, SRY, and WT1. Whole exome sequencing (WES) was carried out for 18 selected patients. The study revealed a high rate of sex chromosomal DSD (33%) with a wide array of cytogenetic abnormalities. Sanger sequencing identified pathogenic variants in 33.7% of 46,XY patients, while the detection rate of WES reached 66.7%. Our patients showed a different mutational profile compared with that reported in other populations with a predominance of heritable DSD causes. WES identified rare and novel pathogenic variants in NR5A1, WT1, HHAT, CYP19A1, AMH, AMHR2, and FANCA and in the X-linked genes ARX and KDM6A. In addition, digenic inheritance was observed in two of our patients and was suggested to be a cause of the phenotypic variability observed in DSD.<br /> (© 2021 Wiley Periodicals LLC.)
- Subjects :
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase genetics
Acyltransferases genetics
Adolescent
Adult
Aromatase genetics
Child
Child, Preschool
Cohort Studies
Disorder of Sex Development, 46,XY physiopathology
Egypt epidemiology
Fanconi Anemia Complementation Group A Protein genetics
Female
Histone Demethylases genetics
Homeodomain Proteins genetics
Humans
In Situ Hybridization, Fluorescence
Infant
Male
Membrane Proteins genetics
Mutation genetics
Phenotype
Receptors, Androgen genetics
Receptors, Peptide genetics
Receptors, Transforming Growth Factor beta genetics
SOXB1 Transcription Factors genetics
Sexual Development physiology
Steroidogenic Factor 1 genetics
Transcription Factors genetics
WT1 Proteins genetics
Exome Sequencing
Young Adult
Disorder of Sex Development, 46,XY genetics
Genetic Predisposition to Disease
Genomics
Sexual Development genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4833
- Volume :
- 185
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of medical genetics. Part A
- Publication Type :
- Academic Journal
- Accession number :
- 33742552
- Full Text :
- https://doi.org/10.1002/ajmg.a.62129