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Mécanismes physiopathologiques impliqués dans la différenciation du tractus génital masculin

Abstract : Background. Hypospadias is the most common malformation affecting the male genitalia. Although the causes remain often unknown, endocrine, vascular and environmental factors have been implicated. However, the genetic basis is probably underestimated. Objectives. To study the genetic factors implicated in sexual differentiation. Methods. A cohort of 284 children born with hypospadias has been established since 2011. DNA was extracted from blood lymphocytes and fibroblasts obtained after a foreskin biopsy. Sanger sequencing of AR, MAMLD1 and NR5A1, SNP-array analysis, and Whole Exome Sequencing (WES) were performed. A second cohort of 1,311 pregnant women was established to evaluate an association between maternal fhCGb and hypospadias. Results. No mutation in AR and MAMLD1 was found. Non-described variations of AR, MAMLD1 and NR5A1 were identified without any splicing activity. Some polymorphisms in AR gene had a MAF significantly higher (p<0.01). A heterozygous intragenic duplication of NR5A1 was found. Pangenomic analysis included 35 anomalies (15.7%) that could be a potential cause of isolated, distal, non-hereditary hypospadias encompassing 25 candidate genes. 22 variants was classified as pathogenic on WES. Finally, a significant difference of fhCGb for severe types was identified even after adjustment for placenta dysfunction (p<0.03). Conclusion. Our hypothesis about “somatic” mutations in 3 candidate genes was not ascertained. However, pangenomic analysis found 15.7% anomalies which could be likely linked to hypospadias. The use of WES could be an attractive method for exploring further these results as we identified 22 variants in 30 cases of familial hypospadias.
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Submitted on : Friday, February 26, 2021 - 11:26:30 AM
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Matthieu Peycelon. Mécanismes physiopathologiques impliqués dans la différenciation du tractus génital masculin. Génétique humaine. Sorbonne Université, 2019. Français. ⟨NNT : 2019SORUS461⟩. ⟨tel-03153249⟩

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