46,XY Disorder of Sex Development Caused by 17<i>α</i>-Hydroxylase/17,20-Lyase Deficiency due to Homozygous Mutation of<i>CYP17A1</i>Gene: Consequences of Late Diagnosis

Papi, Giampaolo; Paragliola, Rosa Maria; Concolino, Paola; Donato, Carlo Di; Pontecorvi, Alfredo; Corsello, Salvatore Maria

doi:10.1155/2018/2086861

Cited by 7 publications

(5 citation statements)

References 20 publications

(21 reference statements)

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“…46,XY DSD patients with comorbidities of hypertension and hypokalemia may have mutations in the CYP17A1 gene, 29 and hence were excluded from our study. However, we found three patients with CYP17A1 gene mutations.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing

Liu

Gao

et al. 2021

Asian Journal of Andrology

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46,XY disorders of sex development (DSD) is characterized by incomplete masculinization genitalia, with gonadal dysplasia and with/without the presence of Müllerian structures. At least 30 genes related to 46,XY DSD have been found. However, the clinical phenotypes of patients with different gene mutations overlap, and accurate diagnosis relies on gene sequencing technology. Therefore, this study aims to determine the prevalence of pathogenic mutations in a Chinese cohort with 46,XY DSD by the targeted next-generation sequencing (NGS) technology. Eighty-seven 46,XY DSD patients were enrolled from the Peking Union Medical College Hospital (Beijing, China). A total of fifty-four rare variants were identified in 60 patients with 46,XY DSD. The incidence of these rare variants was approximately 69.0% (60/87). Twenty-five novel variants and 29 reported variants were identified. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, thirty-three variants were classified as pathogenic or likely pathogenic variants and 21 variants were assessed as variants of uncertain significance. The overall diagnostic rate was about 42.5% based on the pathogenic and likely pathogenic variants. Androgen receptor ( AR ), steroid 5-alpha-reductase 2 ( SRD5A2 ) and nuclear receptor subfamily 5 Group A member 1 ( NR5A1 ) gene variants were identified in 21, 13 and 13 patients, respectively. The incidence of these three gene variants was about 78.3% (47/60) in patients with rare variants. It is concluded that targeted NGS is an effective method to detect pathogenic mutations in 46,XY DSD patients and AR , SRD5A2 , and NR5A1 genes were the most common pathogenic genes in our cohort.

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Section: Discussionmentioning

confidence: 99%

Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing

Liu

Gao

et al. 2021

Asian Journal of Andrology

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“…Additionally, protein structure analysis has been done to examine the impact of specific mutants on a form of CAH known as salt-water wasting disease, which if left undiagnosed leads to low sodium levels and death (Haider et al, 2013). CYP17A1 is heavily involved in steroidogenesis, with deletion mutations leading to hormone production inhibition and sex development abnormalities (Keskin et al, 2015;Turkkahraman et al, 2015;Zhang et al, 2015;Papi et al, 2018;Xia et al, 2021). Recent genome studies of 17OHD patients revealed 46,XY karyotype in physically presenting females which cooccur with multiple mutations in the CYP17A1 gene (Zhang et al, 2015;Xia et al, 2021).…”

Section: Investigation Of Outlier Genes Associated With Genital Morphologymentioning

confidence: 99%

Evolution of genes involved in the unusual genitals of the bear macaque,Macaca arctoides

Stevison

Szpiech

Bailey

et al. 2020

Preprint

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13Genital divergence contributes to reproductive barriers between species. Emergence of a 14 novel accessory structure, the baculum, has independently evolved and been lost throughout 15 mammalian evolution, purportedly driven by sexual selection. In primates, the longest recorded 16 baculum belongs to Macaca arctoides, the bear macaque. This species has been proposed to be of 17 homoploid hybrid origin via ancient hybridization between representatives from the fascicularis 18 and sinica species groups. To investigate the evolutionary origins of the bear macaque and its 19 unique morphology, we used whole genome sequences to quantify gene flow and phylogenetic 20 relationships in 10 individuals from 5 species, including the bear macaque (n=3), and two species 21 each from the sinica (n=3) and fascicularis (n=4) species groups. The results of these analyses were 22 concordant, and identified 608 genes in the bear macaque that supported both clustering between 23 M. arctoides and the sinica group (topo2) and had shared derived alleles between species from the 24 two groups. Similarly, 361 genes supported both clustering between M. arctoides and the 25 fascicularis group (topo3) and had shared derived alleles between both groups. Further, sliding 26 window analysis of phylogenetic relationships revealed 53% of the genomic regions supported 27 placement of M. arctoides in the sinica species group (topo2), 16% supported placement in the 28 fascicularis species group (topo3), and 11% supported M. arctoides in a grouping distinct from the 29 sinica and fascicularis groups (topo1). Genomic regions with topo1 were intersected with 30 previously identified QTL for mouse baculum morphology, and 47 genes were found, including five 31 of sixteen major candidate loci that govern mouse baculum variation (KIF14, KIAA0586, RHOJ, 32 TGM2, and DACT1). Although baculum morphology in the bear macaque is diverged from its parent 33 taxa, it most closely resembles that of the fascicularis group. Outliers of shared ancestry from the 34 fascicularis species group located within these same QTL regions overlap with the gene BMP4, 35 which is an important component of the hedgehog signaling pathway that controls gonadogenesis. 36Two additional outlier genes (one shared with each species group) outside of the baculum QTL are 37 known to interact with BMP4, suggesting this pathway may be involved in baculum morphology in 38 primates. These results highlight how the mosaic ancestry of the bear macaque could explain its 39 unique baculum evolution and collectively contribute to reproductive isolation. 40 Introductory Paragraph 41In mammals, the baculum has extreme morphological variability, a dynamic evolutionary 42 history characterized by repeated gain and loss, and is often used in species identification. The bear 43 macaque has divergent genital morphology, including the longest baculum among all primates, and 44 is proposed to have evolved via ancient hybrid speciation. Here, population genetic and 45 phylogenomic approaches were used to e...

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“…Additionally, protein structure analysis has been done to examine the impact of specific mutants on a form of CAH known as the salt‐water wasting disease, which if left undiagnosed leads to low sodium levels and death (Haider et al, 2013 ). CYP17A1 is heavily involved in steroidogenesis, with deletion mutations leading to hormone production inhibition and sex development abnormalities (Keskin et al, 2015 ; Papi et al, 2018 ; Turkkahraman et al, 2015 ; Xia et al, 2021 ; Zhang et al, 2015 ). Recent genome studies of 17OHD patients revealed 46,XY karyotypes in physically presenting females which co‐occur with multiple mutations in the CYP17A1 gene (Xia et al, 2021 ; Zhang et al, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, a histogram of the results from 100 permutations where the mean difference was recalculated using the same number of randomly selected genes as the candidate genital genes is shown. deletion mutations leading to hormone production inhibition and sex development abnormalities (Keskin et al, 2015;Papi et al, 2018;Turkkahraman et al, 2015;Xia et al, 2021;Zhang et al, 2015). Recent genome studies of 17OHD patients revealed 46,XY karyotypes in physically presenting females which co-occur with multiple mutations in the CYP17A1 gene (Xia et al, 2021;Zhang et al, 2015).…”

Section: Investigation Of Outlier Genes Associated With Genital Morph...mentioning

confidence: 99%

Evolution of genes involved in the unusual genitals of the bear macaque, Macaca arctoides

Stevison

Bailey

Szpiech

et al. 2022

Ecology and Evolution

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Genital divergence is thought to contribute to reproductive barriers by establishing a “lock‐and‐key" mechanism for reproductive compatibility. One such example, Macaca arctoides , the bear macaque, has compensatory changes in both male and female genital morphology as compared to close relatives. M . arctoides also has a complex evolutionary history, having extensive introgression between the fascicularis and sinica macaque species groups. Here, phylogenetic relationships were analyzed via whole‐genome sequences from five species, including M . arctoides , and two species each from the putative parental species groups. This analysis revealed ~3x more genomic regions supported placement in the sinica species group as compared to the fascicularis species group. Additionally, introgression analysis of the M . arctoides genome revealed it is a mosaic of recent polymorphisms shared with both species groups. To examine the evolution of their unique genital morphology further, the prevalence of candidate genes involved in genital morphology was compared against genome‐wide outliers in various population genetic metrics of diversity, divergence, introgression, and selection, while accounting for background variation in recombination rate. This analysis identified 67 outlier genes, including several genes that influence baculum morphology in mice, which were of interest since the bear macaque has the longest primate baculum. The mean of four of the seven population genetic metrics was statistically different in the candidate genes as compared to the rest of the genome, suggesting that genes involved in genital morphology have increased divergence and decreased diversity beyond expectations. These results highlight specific genes that may have played a role in shaping the unique genital morphology in the bear macaque.

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46,XY Disorder of Sex Development Caused by 17α-Hydroxylase/17,20-Lyase Deficiency due to Homozygous Mutation ofCYP17A1Gene: Consequences of Late Diagnosis

Cited by 7 publications

References 20 publications

Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing

Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing

Evolution of genes involved in the unusual genitals of the bear macaque,Macaca arctoides

Evolution of genes involved in the unusual genitals of the bear macaque, Macaca arctoides

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