Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development

Autor: Mona K. Mekkawy, Ken McElreavey, Anu Bashamboo, Mona El Gammal, Mona L. Essawi, Alaa K. Kamel, Mona O. El-Ruby, Khalda Amr, Heba A. Hassan, Hala Soliman, Mohamed S. Abdel-Hamid, Inas Mazen, Ahmed Torky, Aya Elaidy
Přispěvatelé: National Research Centre - NRC (EGYPT), Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The authors acknowledge the Science and Technology Development Fund (STDF), Egypt, and the French Institute of Research for Development (IRD), France., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2021
Předmět:
Male
disorders of sex development
syndromic DSD
XY DSD
Steroidogenic Factor 1
whole exome sequencing
sex chromosomal abnormalities
Cohort Studies
0302 clinical medicine
Disorders of sex development
Child
[SDV.BDD]Life Sciences [q-bio]/Development Biology
Genetics (clinical)
Exome sequencing
In Situ Hybridization
Fluorescence
Genetics
Sanger sequencing
Histone Demethylases
0303 health sciences
medicine.diagnostic_test
Fanconi Anemia Complementation Group A Protein
Sexual Development
Genomics
3. Good health
Testis determining factor
Phenotype
Receptors
Androgen
Child
Preschool
Cohort
symbols
Egypt
Female
Adult
Adolescent
Receptors
Peptide
030209 endocrinology & metabolism
03 medical and health sciences
symbols.namesake
Young Adult
Aromatase
HHAT
3-Oxo-5-alpha-Steroid 4-Dehydrogenase
Exome Sequencing
medicine
Humans
Genetic Predisposition to Disease
WT1 Proteins
030304 developmental biology
Homeodomain Proteins
Disorder of Sex Development
46
XY
Genitourinary system
business.industry
SOXB1 Transcription Factors
Infant
Membrane Proteins
medicine.disease
Mutation
business
Receptors
Transforming Growth Factor beta
Acyltransferases
Fluorescence in situ hybridization
Transcription Factors
Zdroj: American Journal of Medical Genetics Part A
American Journal of Medical Genetics Part A, Wiley, 2021, 185 (6), pp.1666-1677. ⟨10.1002/ajmg.a.62129⟩
American Journal of Medical Genetics Part A, 2021, 185 (6), pp.1666-1677. ⟨10.1002/ajmg.a.62129⟩
ISSN: 1552-4833
1552-4825
DOI: 10.1002/ajmg.a.62129⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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