How Far Should We Explore Hypospadias? Next-generation Sequencing Applied to a Large Cohort of Hypospadiac Patients

Ea, Vuthy; Bergougnoux, Anne; Philibert, Pascal; Servant-Fauconnet, Nadège; Faure, Alice; Bréaud, Jean; Gaspari, Laura; Sultan, Charles; Paris, Florentin; Kalfa, Nicolas

doi:10.1016/j.eururo.2020.12.036

Cited by 35 publications

(29 citation statements)

References 38 publications

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“…In addition, there is a recent report that identified Wnt5a polymorphisms in patients with hypospadias. 12 Our findings may provide insight into understanding the pathological mechanisms underlying the micropenis and hypospadias observed in RS patients.…”

Section: Discussionmentioning

confidence: 75%

“…Recently, several candidate genes have been identified, but the pathological mechanisms of hypospadias are yet to be elucidated. 9,12,13 Wnt5a is a well-studied member of the Wnt family of proteins. 14 Wnt5a conventional knockout mice (Wnt5a À/À ) led to perinatal lethality and truncation of outgrowing organs such as the limbs, the mandible, the tail, and the ExG.…”

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confidence: 99%

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Stage‐dependent function of Wnt5a during male external genitalia development

Alcantara

Suzuki

Acebedo

et al. 2021

Congenital Anomalies

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External genitalia development in mice involves multiple developmental processes under the regulation of various signaling pathways. Wnt5a, one of the major Wnt ligands, is a crucial developmental regulator of outgrowing organs such as the limb, the mandible, and the external genitalia. Defects in Wnt5a signaling have been linkedto Robinow syndrome, a genetic disorder in which male patients manifest a micropenis and defective urethral tube formation. Whereas Wnt5a is required for cell proliferation during embryonic external genitalia outgrowth, its role for urethral tube formation has yet to be understood. Here, we show that Wnt5a contributes to urethral tube formation as well as external genitalia outgrowth. Wnt5a is expressed in the embryonic external genitalia mesenchyme, and mesenchymal-specific conditional Wnt5a knockout mice resulted in hypospadias-like urethral defects. Early deletion of Wnt5a at E10.5 showed severe defects in both external genitalia outgrowth and urethral tube formation, along with reduced cell proliferation. The severe urethral tube defect persisted during later timing deletion of Wnt5a (E13.5). Further analyses revealed that loss of Wnt5a disrupted cell polarity and led to a reduction of the phosphorylated myosin light chain and the focal adhesion protein, vinculin. Altogether, these results suggest that Wnt5a coordinates cell proliferation and directed cell migration in a stage-dependent manner during male external genitalia development.Furthermore, Wnt5a may regulate cell polarity, focal adhesion formation, and cell contractility, leading to directed cell migration during male-type urethral formation in a manner that has not been reported in other organ fusion events.

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Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

Stage‐dependent function of Wnt5a during male external genitalia development

Alcantara

Suzuki

Acebedo

et al. 2021

Congenital Anomalies

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“…To date, only one variant in BRAF (c.16_40del) has been implicated in a sporadic case of midshaft hypospadias. But the gene-disease association was uncertain [ 12 ]. BRAF is an established causal gene for several autosomal dominant RASopathies, including Cardiofaciocutaneous syndrome (MIM 115150), Noonan syndrome (MIM 613706), and LEOPARD syndrome (MIM 613707).…”

Section: Resultsmentioning

confidence: 99%

Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients

Lin

Song

Wang

et al. 2022

Orphanet J Rare Dis

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Background Hypospadias is a congenital anomaly of the male urogenital system. Genetics factors play an important role in its pathogenesis. To search for potential causal genes/variants for hypospadias, we performed exome sequencing in a pedigree with three patients across two generations and a cohort of 49 sporadic patients with hypospadias. Results A novel BRAF variant (NM_004333.6: c.362C > A) was found to co-segregate with the hypospadias phenotype in the disease pedigree. In cells overexpressing the BRAF mutant, the phosphorylation level of p38 MAPK was significantly increased as compared with the cells overexpressing the wild-type BRAF or RASopathy-related BRAF mutant. This variant further led to a reduced transcription level of the SRY gene, which is essential for the normal development of the male reproductive system. In the cohort of sporadic patients, we identified two additional variants in p38 MAPK signaling-related genes (TRIM67 and DAB2IP) potentially associated with hypospadias. Conclusion Our study expands the phenotypic spectrum of variants affecting p38 MAPK signaling toward the involvement of hypospadias.

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“…In human hypospadias, the majority of genetic studies have either been variant analysis in GWAS studies or key genes in large affected hypospadias cohorts. Recently, Kalfa team attempted to address the “missing heritability” in hypospadias using targeted Next-generation sequencing (NGS) panel including 336 genes 14 . While they are valuable, these variants still give rise to “missing heritability” and do not prove pathogenicity 15 .…”

Section: Introductionmentioning

confidence: 99%

“…Unlike most previous hypospadias studies that focused primarily on common variant associations 11,12 or candidate genes 14 , we performed whole exome sequencing (WES) and RNA sequencing in a large hypospadias cohort. We identified a significant enrichment of damaging variants in outer dynein arm heavy chain ( ODNAH ) genes ( ODNAH5, ODNAH8, ODNAH9, ODNAH11, ODNAH17 ) in severe hypospadias cases.…”

Section: Introductionmentioning

confidence: 99%

Whole-exome Sequencing Study of Hypospadias

Chen

Lei

Finnell

et al. 2022

Preprint

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While hypospadias is one of the most common male congenital disorders, the missing heritability contributed by rare variants with larger effects is poorly understood. To systematically explore the variant patterns in the developing of hypospadias, we performed whole exome sequencing (WES) in 191 severe hypospadias cohort and three trios. Subsequent RNA sequencing of 12 severe hypospadiac foreskins and 6 non-hypospadiac foreskins were conducted. Among previous reported hypospadias risk associated genes, we found that NR5A1, SRD5A2 and AR genes are mutational hotspots in the etiology of severe hypospadias. Additionally, rare damaging variants in novel identified outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, and DNAH17) (p = 4.8×10-17) were significantly enriched in 191 sporadic severe hypospadias compared with 208 controls. The following transcriptomic analysis further demonstrated that the mutations in the DNAH8 and DNAH17 genes might affect the network regulation of testosterone (T)-dihydrotestosterone-androgen receptor (T-DHT-AR) signaling. We also identified a novel rare damaging variant of DNAH8 in a severe hypospadias case which was transmitted from the mother. Overall, a panel of ODNAH genes with rare damaging variants were identified in 22.5% of severe hypospadias patients. This study provides unequivocal evidence for association of ODNAH genes and hypospadias. This knowledge may guide the genetic counseling for hypospadias.

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How Far Should We Explore Hypospadias? Next-generation Sequencing Applied to a Large Cohort of Hypospadiac Patients

Cited by 35 publications

References 38 publications

Stage‐dependent function of Wnt5a during male external genitalia development

Stage‐dependent function of Wnt5a during male external genitalia development

Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients

Whole-exome Sequencing Study of Hypospadias

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