Sexuality and fertility desire in a large cohort of individuals with 46, XY differences in sex development

Objective: To analyze aspects of sexual life and fertility desire among 46, XY DSD people, including those who changed their gender. Methods: It is a cross-sectional study including 127 adults (> 16 years of age) with 46, XY DSD (83 females; 44 males) from a Single Brazilian Tertiary-Care Medical Center. Results: Sexual fantasies and masturbation were more frequent in 46, XY DSD males, whereas orgasm and sexual life satisfaction were similar in both genders. More 46, XY DSD men than women had a long-term romantic relationship. 46, XY DSD women with prenatal androgen exposure reported more fear of being romantically rejected. External genitalia appearance at birth did not impact the sexuality of 46, XY DSD women after surgical genital treatment had been completed. Overall, the sexual life was similar between 46, XY men assigned as males and those who changed to the male gender. Regarding sexual orientation, most self-reported as heterosexual (91% and 92% of women and men, respectively). The desire for fertility had a similar prevalence in both genders, but more women than men considered infertility a barrier to a long-term romantic relationship. Twelve individuals (7 males) had children; 10 out of 12 have adopted children. Conclusion: Fertility desire was shared among 46, XY DSD people, regardless of gender. Prenatal androgen exposure reduced the desire for motherhood in 46, XY women. 46, XY DSD people who changed from female to male gender presented similar sexual parameters as those assigned as males. Among females, virilized genitalia at birth did not affect sexuality once the surgical treatment is completed

Novel perspectives of the genetic etiology of the 46, XY disorders of sex development

Os distúrbios do desenvolvimento sexual (DDS) 46,XY constituem um grupo de doenças com etiologia heterogênea, o que dificulta a análise molecular pela tradicional estratégia de estudo do gene candidato. O diagnóstico molecular é identificado em menos de 50% desses pacientes avaliados pelo sequenciamento por Sanger, especialmente aqueles com disgenesia gonadal (DG). As técnicas de sequenciamento paralelo em larga escala (SPLE), desenvolvidas nos últimos anos, permitem a análise simultânea de múltiplos genes, bem como a identificação de novos genes, como foi o caso do gene DEAH-box helicase 37 (DHX37). Este gene foi previamente identificado em nossa casuística como novo gene candidato à síndrome de regressão testicular embrionária (SRTE), considerada um espectro da DG. Neste contexto, os objetivos deste projeto foram: 1) determinar a etiologia molecular de uma coorte de pacientes com DDS 46,XY, identificando variantes em genes já associados à etiologia dos DDS e também em genes candidatos aos DDS; 2) identificar novos genes candidatos à etiologia dos DDS, utilizando SPLE por painel de genes-alvo e por sequenciamento exômico global, respectivamente. Para confecção do painel, foram incluídas as regiões exônicas de 63 genes já associados ou candidatos aos DDS na literatura, incluindo o DHX37. O sequenciamento foi realizado na plataforma Illumina. Os dados brutos foram analisados utilizando um pipeline para a identificação de variantes de ponto, indels e alteração de número de cópias. As variantes foram classificadas de acordo com os critérios do American College of Medical Genetics. A casuística estudada incluiu 100 casos esporádicos e 14 casos famílias de 7 famílias distintas, sendo 45 casos índices com DG (12 deles com SRTE), 54 casos classificados com DDS de etiologia indeterminada e 8 casos índices com DDS por provável defeito de síntese de andrógenos. Os casos esporádicos foram estudados por SPLE por painel, e os familiais foram estudados em sua maioria por sequenciamento exômico. O diagnóstico molecular foi elucidado em 20.5% dos pacientes, sendo identificadas variantes patogênicas ou possivelmente patogênicas em 6 dos 45 casos índices (13%) com DG, 10 dos 54 índices (18.5%) com DDS de etiologia indeterminada e em 6 dos 8 casos índices (75%) com DDS com suspeita diagnóstica, incluindo variantes no NR5A1, DHX37, WT1, AMH, MAP3K1, SRD5A2 E HSD17B3. Variantes de significado incerto foram identificadas em 12% da casuística, destacando-se as variantes no GATA4, MAP3K1, ESR2, CBX2.2. Em 5% dos pacientes foram identificadas duas variantes, sugerindo herança digênica. As variantes no DXH37 (n=4) foram as mais frequentes sendo identificadas em quatro casos esporádicos e em três casos familiais de duas famílias distintas com fenótipos variados, de SRTE a DG parcial, a maioria deles sem derivados Mullerianos. As variantes estão localizadas em dois domínios conservados da proteína (helicase C-terminal e de ligação ao ATP) e sua frequência foi significativamente superior em pacientes com fenótipo de SRTE (44%) e DG (8%) em relação aos controles (p < 0.001). Os achados desse trabalho reforçam a relevância do SPLE na determinação etiológica dos DDS 46,XY e indicam que variantes no DHX37 são causa frequente de DDS disgenético, em todo o seu espectro, especialmente de SRTE, sendo este gene importante não só na formação como na manutenção testicularSince the genetic etiology of the 46,XY disorders of sex development (DSD) is highly heterogeneous, obtaining a definitive molecular diagnosis by single gene test is challenging. A molecular diagnosis is identified in less than 50% of these patients who are studied by Sanger sequencing, especially those with gonadal dysgenesis (GD). In the last years, massively parallel sequencing (MPS) technologies have been proposed as an efficient sequencing approach by analyzing multiple genes at the same time, as well as allowing the identification of novel genes, as the DEAH-box helicase 37 (DHX37). This gene was previously identified in our cohort as a candidate gene for the embryonic testicular regression syndrome (ETRS), which is considered part of the spectrum of gonadal dysgenesis (GD). In this context, the objectives of this project were: 1) to investigate the molecular etiology of a cohort of patients with 46,XY DSD, identifying variants in genes previously known to be associated with DSD and also in DSD candidate genes; 2) identify novel candidate genes for the DSD etiology, using MPS by panel sequencing and by whole exome sequencing (WES), respectively. We designed an amplicon-based capture panel of 63 genes for targeted sequencing including genes already associated and candidate genes for the DSD etiology, including the DHX37. Sequencing was performed in the Illumina platform. The data was analyzed by an in-house pipeline in order to identify the missense and indels variants and for copy number variations. The variants were classified according to the American College of Medical Genetics. We studied 100 sporadic cases and 14 familial cases from 7 different families, including 45 index-cases with GD (12 of them had ETRS), 54 cases classified as DSD of unknown etiology and 8 cases with androgen synthesis defect. The sporadic cases were studied by target MPS and most of the familial cases were studied by WES. A genetic diagnosis was established in 20.5% of the patients. Pathogenic or likely pathogenic variants were identified in 6 of 45 index-cases (18%) with GD, 10 of 55 index-cases (18.5%) with DSD of unknown etiology and 6 of 8 patients (75%) suspected of having a testosterone synthesis defect, including variants in NR5A1, DHX37, WT1, AMH, MAP3K1, SRD5A2 E HSD17B3 genes. Variants of uncertain significance were identified in 12% of the cohort, highlighting variants in GATA4, MAP3K1, ESR2, CBX2.2. Two variants were identified in 5% of the patients, suggesting a digenic inheritance. The DHX37 variants (n=4) were the most frequent and were identified in four sporadic cases and in three familial cases from two unrelated families with variable phenotypes, including ETRS and partial GD, most of them without Mullerian derivatives. The variants were identified in two conserved domains of the protein (helicase C-terminal and ATP binding domain) and their frequency was enriched among patients with ETRS (44%) and GD (9%) from the cohort in comparison to the frequency of deleterious variants among controls (p < 0.001). The present findings reinforce the relevance of MPS in the 46,XY DSD investigation and indicate that DHX37 variants are a frequent cause of all GD spectrum of, especially for ETRS, being this gene important not only for the development but also for the maintenance of the testicular tissu

NEOTROPICAL CARNIVORES: a data set on carnivore distribution in the Neotropics

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data