DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis

Life, Journal Year: 2023, Volume and Issue: 13(5), P. 1093 - 1093

Published: April 27, 2023

The group of disorders known as 46,XY gonadal dysgenesis (GD) is characterized by anomalies in testis determination, including complete and partial GD (PGD) testicular regression syndrome (TRS). Several genes are to be involved sex development pathways, however approximately 50% all cases remain elusive. Recent studies have identified variants

Language: Английский

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A massive alteration of gene expression in undescended testicles of dogs and the association of KAT6A variants with cryptorchidism

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(7)

Published: Feb. 5, 2024

Cryptorchidism is the most common form of disorder sex development in male dogs, but its hereditary predisposition poorly elucidated. The gonadal transcriptome nine unilaterally cryptorchid dogs and seven control was analyzed using RNA-seq. Comparison between scrotal inguinal gonads unilateral revealed 8,028 differentially expressed genes (DEGs) (3,377 up-regulated 4,651 down-regulated). A similar number DEGs (7,619) found by comparing undescended testicles with descended dogs. methylation status selected also analyzed, three out studied showing altered patterns. Bioinformatic analysis cDNA sequences 20,366 SNP variants, six which showed significant differences allelic counts Validation studies larger cohorts ( n = 122) 173) that TT genotype (rs850666472, p.Ala1230Val) AA 3′UTR (16:23716202G>A) KATA6 , responsible for acetylation lysine 9 histone H3, are associated cryptorchidism P 0.0383). Both transcript level KAT6A H3K9 were lower testes, additionally, depended on genotypes exon 17 3′UTR. Our study massive alteration not caused germinal DNA variants DEG regulatory partly an aberrant Moreover, can be considered markers risk this disorder.

Language: Английский

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Bi-allelic variants inINSL3andRXFP2cause bilateral cryptorchidism and male infertility

Human Reproduction, Journal Year: 2023, Volume and Issue: 38(7), P. 1412 - 1423

Published: May 19, 2023

Abstract STUDY QUESTION What is the impact of variants in genes INSL3 (Insulin Like 3) and RXFP2 (Relaxin Family Peptide Receptor 2), respectively, on cryptorchidism male infertility? SUMMARY ANSWER Bi-allelic loss-of-function (LoF) result bilateral infertility, whereas heterozygous variant carriers are phenotypically unaffected. WHAT IS KNOWN ALREADY The small heterodimeric peptide its G protein-coupled receptor play a major role first step biphasic descent testes, have long been implicated inherited cryptorchidism. However, only one single homozygous missense has clearly linked to familial cryptorchidism, so effects bi-allelic both infertility remain unclear. DESIGN, SIZE, DURATION Exome data 2412 men from MERGE (Male Reproductive Genomics) study cohort including 1902 infertile with crypto-/azoospermia, whom 450 had history were screened for high-impact RXFP2. PARTICIPANTS/MATERIALS, SETTING, METHODS For patients rare, RXFP2, detailed clinical collected testicular phenotype was determined. Genotyping family members performed analyse co-segregation candidate condition. Immunohistochemical staining patient tissue measuring serum concentration functional INSL3. protein’s cell surface expression ability respond CRE reporter gene assay MAIN RESULTS AND THE ROLE OF CHANCE This presents correlates these Functional identified demonstrated by absence INSL3-specific patients’ Leydig cells as well undetectable blood levels. lead reduced mediated activation. LIMITATIONS, REASONS FOR CAUTION Further investigations needed explore potential direct spermatogenesis. With our data, we cannot determine whether observed consequence disruption possible function spermatogenesis or it occurs secondarily due WIDER IMPLICATIONS FINDINGS In contrast previous assumptions, this supports an autosomal recessive inheritance INSL3- RXFP2-related while LoF either can at most be regarded risk factor developing Our findings diagnostic value familial/bilateral additionally shed light importance fertility. FUNDING/COMPETING INTEREST(S) carried out within frame German Research Foundation (DFG) funded Clinical Unit ‘Male Germ Cells: Genes Function’ (DFG, CRU326). Florey supported NHMRC grant (2001027) Victorian Government Operational Infrastructure Support Program. A.S.B. DFG (‘Emmy Noether Programme’ project number 464240267). authors declare no conflict interest. TRIAL REGISTRATION NUMBER N/A.

Language: Английский

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Achieving an optimal pregnancy outcome through the combined utilization of micro-TESE and ICSI in cryptorchidism associated with a non-canonical splicing variant in RXFP2

Journal of Assisted Reproduction and Genetics, Journal Year: 2024, Volume and Issue: 41(5), P. 1307 - 1317

Published: March 2, 2024

Language: Английский

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DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives

Hormone Research in Paediatrics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 8

Published: Feb. 15, 2024

<b><i>Introduction:</i></b> The testicular regression syndrome (TRS) is a form of differences sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress. clinical phenotype TRS often overlaps with that partial gonadal dysgenesis (PGD). Previous studies have demonstrated causal association between TRS/PGD heterozygous missense variants <i>DHX37</i>. <b><i>Methods:</i></b> We enrolled 11 Japanese 46,XY individuals (from 10 families) who exhibited undetected or hypoplastic testes, Müllerian duct regression, low serum testosterone anti-Müllerian hormone levels. subjects underwent targeted sequencing 36 known causative genes for DSD, PCR-based Sanger <i>DHX37</i>, whole-exome sequencing. <b><i>Results:</i></b> Previously described pathogenic novel nonsense (<i>SRY</i>, <i>NR5A1</i>, <i>DMRT1</i>) were observed four out families. Additionally, we identified two rare <i>DHX37</i> families: previously reported variant (c.923G&gt;A, p.Arg308Gln) three likely (c.1882A&gt;C, p.Thr628Pro) one. external genitalia patients varied from female-type to male-type without micropenis. Eighty percent had monogenic disorders including being most commonly (40%). internal genital carriers others. <b><i>Conclusions:</i></b> one common genetic causes derivatives. Genetic test helpful detecting <i>DHX37</i>-related because phenotypic diversity this disorder.

Language: Английский

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Undiagnosed RASopathies in infertile men

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: April 9, 2024

RASopathies are syndromes caused by congenital defects in the Ras/mitogen-activated protein kinase (MAPK) pathway genes, with a population prevalence of 1 1,000. Patients typically identified childhood based on diverse characteristic features, including cryptorchidism (CR) &gt;50% affected men. As CR predisposes to spermatogenic failure (SPGF; total sperm count per ejaculate 0–39 million), we hypothesized that men seeking infertility management include cases undiagnosed RASopathies. Likely pathogenic or (LP/P) variants 22 RASopathy-linked genes were screened 521 idiopathic SPGF patients (including 155 cases) and 323 normozoospermic controls using exome sequencing. All 844 recruited ESTonian ANDrology (ESTAND) cohort underwent identical andrological phenotyping. RASopathy-specific variant interpretation guidelines used for pathogenicity assessment. LP/P PTPN11 (two), SOS1 (three), SOS2 (one), LZTR1 SPRED1 NF1 MAP2K1 (one). The findings six SPGF, three 366 only, one (of 323) subfertile man. subgroup “CR SPGF” had over 13-fold enrichment compared (3.9% vs. 0.3%; Fisher’s exact test, p = 5.5 × 10 −3 ). ESTAND subjects Ras/MAPK presented genitourinary anomalies, skeletal joint conditions, other health concerns. Rare forms malignancies (schwannomatosis pancreatic testicular cancer) reported four occasions. Genetics Male Infertility Initiative (GEMINI) (1,416 317 fertile men) was validate outcome. MRAS (one) 4/31 GEMINI CR) Undiagnosed detected 17 subjects, 15 (10 CR), two Affected RASopathy showed high expression somatic cells. In conclusion, represent new etiology syndromic male infertility. especially enriched among history cryptorchidism. Given relationship between infertile found have this molecular diagnosis should be evaluated known concerns, specific rare malignancies.

Language: Английский

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During Three Decades Prenatal Diagnoses of Differences in Sex Development Increased and Gonadectomy Rates Declined

Acta Paediatrica, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

ABSTRACT Aim The therapeutic approach to differences of sex development (DSD) has changed over recent decades. We aimed describe the evolution clinical diagnoses DSD in children attending a tertiary paediatric centre. Methods This retrospective observational study compared and management, before after introduction consensus guidelines for 2006. Results cohort included 87 patients with 46, XY (78.4%), 15 XX (13.5%) 9 chromosomal (8.1%). Gonadectomy rates were 27.9%, 6.6% 66.6% respective groups. mean age at presentation was younger among those than (0.5 ± 2.5 vs. 6.8 8.1 years, p = 0.007) higher proportion presented by one year (93.1% 60.0%, 0.001). During 1990–2006, 44 diagnosed, during 2007–2019, 67 children. Prenatal diagnosis increased from 4.5% 25.4% ( 0.004). Smaller proportions later earlier period underwent gonadectomy (19.4% 40.9%, 0.017) reassignment (1.5% 13.6%, < 0.02). Conclusion Over three‐decade period, rate prenatal declined. These findings reflect shift towards earlier, individualised multidisciplinary care, which facilitated advanced diagnostics.

Language: Английский

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Nonpalpable Testis Syndrome: History and Current State of the Issue. Literature Review.

Russian Journal of Pediatric Surgery, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 15, 2025

According to domestic and foreign literature, nonpalpable testes (NPT) are found in 20% of children with cryptorchidism. Approximately 50% them located the abdominal cavity, atrophied or vanished testes. The aim our review is systematize scientific literature data on testis syndrome children. Materials Methods. composed original articles databases such as eLibrary, PubMed, Scopus. Results Discussions. In often classified into three types: intra-abdominal, extra-abdominal, non-viable. Extra-abdominal gonads more normal volume compared intra-abdominal ones, which mostly hypoplastic. There many controversial issues regarding diagnostic methods treatment strategies for different types NPT Conclusions. problem diagnosing treating children, especially cases high localization gonad, remains highly relevant requires further research observations.

Language: Английский

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Identification of key genes related to unilateral cryptorchidism in sheep by comprehensive transcriptomics and proteomics analyses

BMC Genomics, Journal Year: 2025, Volume and Issue: 26(1)

Published: Feb. 19, 2025

Cryptorchidism is one of the most common reproductive abnormalities in rams, which seriously harms capacity rams and causes significant economic losses to sheep industry. However, there are few studies elucidating its hereditary predisposition sheep. In present study, transcriptome proteome cryptic (CT) contralateral (CLT) testis from four unilaterally cryptorchid normal (NT) healthy were analyzed using RNA-seq TMT-based proteomics, respectively. A total 10,357, 10,175, 132 differentially expressed genes (DEGs) identified between CT vs. CLT, NT, CLT NT. Venn diagram showed that 9744 DEGs (5499 up-regulated 4245 down-regulated) shared Functional enrichment analysis revealed 5499 mainly involved regulation programmed cell death metabolic process, while down-regulated closely related such as spermatogenesis, sexual reproduction, reproduction male gamete generation. Furthermore, 325 overlapped (114 211 DAPs same regulatory status by combining transcriptomics proteomics. Ten genes, including AKAP4, AKAP3, FSIP2, HSPA1L, HSPA4L, TUBB, TXNRD2, CDC42, PGK1 HSPA1A, candidate key unilateral cryptorchidism. Our results both gene protein expression massively altered. Bioinformatics unveiled several signaling pathways potentially These findings provide new insights into molecular mechanism underlying spermatogenesis failure caused

Language: Английский

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Comparative proteomic and transcriptomic analysis of testicular tissue of yaks with or without cryptorchidism

Theriogenology, Journal Year: 2025, Volume and Issue: 239, P. 117376 - 117376

Published: March 6, 2025

Language: Английский

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