7644 Novel Candidate Genes for SRY-Negative 46,XX Differences of Sex Development with Testicular Differentiation
Notice bibliographique
Résumé
Abstract Disclosure: M.M. Ferrari: None. M.Y. Nishi: None. A.A. Jorge: None. A.F. Benedetti,: None. R.L. Batista: None. E.S. Silva: None. A. Martinez: None. V. Mericq: None. F.M. Carvalho: None. B.B. Mendonca: None. S. Domenice: None. Introduction: Gonadal development in mammals is a dynamic and complex process, which requires the interaction of multiple factors in a meticulous feedback control and self-regulation system. Defects in genes involved in this process may cause differences of sex development (DSD). In rare cases, the gonads of 46,XX individuals differentiate completely into testes (46,XX testicular DSD, 46,XX TDSD), or with the coexistence of testicular and ovarian tissues in the same individual (46,XX ovotesticular DSD, 46,XX OTDSD). Strategies of large-scale parallel sequencing have enabled the simultaneous analysis of known genes, as well as the identification of novel candidate genes contributing to molecular diagnosis of these conditions. Objective: To establish the molecular diagnosis of a cohort of SRY-negative 46,XX T/OTDSD patients using the whole exome sequencing (WES) technique. Patients and Methods: Twenty-three families (24 patients) were evaluated, 22 patients with sporadic disease, and one family with two affected siblings. Histological diagnosis of OTDSD was confirmed in all patients, except in two with the presumptive (non-histological) diagnosis of TDSD. WES was performed using the Illumina platform. The variants were classified according to ACMG criteria. Results: Six different candidate genes associated with the 46,XX DSD phenotype were identified in the 23 families (26%) studied; all in patients with OTDSD diagnosis. Two variants were classified as likely pathogenic in FLNB and SOX10 genes, and four as VUS in IMMP2L, SOX8, PRKACG, and CLASP1 genes. The unavailability of analysis of case-parent trio samples hampered the classification of some of the novel candidate allelic variants. All these candidate genes were selected as potential causes of OTDSD, based on evidence of direct or indirect interactions of these proteins with SOX9. In the two siblings with 46,XX OTDSD, the allelic variant c.397delT (p.Ser133Leufs*7) in IMMP2L was identified in a heterozygous state and was absent in the unaffected family members (mother and third XY sibling). A potential role of Immp2l had been previously associated with the etiology of XX female-to-male sex reversal in sheep lineage. Conclusion: Although establishing the genetic etiology of gonadal development abnormalities in individuals with 46,XX TDSD/OTDSD remains a challenge, the results of this study generated new information and perspectives on the mechanisms involved in gonadal development. Presentation: 6/3/2024
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».