Two Unrelated Undervirilized 46,XY Males with Inherited NR5A1 Variants Identified by Whole-Exome Sequencing

Swartz, Jonathan M.; Ciarlo, Ryan; Guo, Michael H.; Abrha, Aser; Diamond, David A.; Chan, Yee-Ming; Hirschhorn, Joel N.

doi:10.1159/000448754

Cited by 8 publications

(11 citation statements)

References 30 publications

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“…Our study and others (Camats et al., ; Swartz et al. ) have suggested that neither the mutation in NR5A1 nor its reduction in SF1 activity is a good indicator of a patient's phenotype or clinical outcome. Inherited mutations in DSD tend to be rare as fertility is often affected; however, familial cases of NR5A1 including those shown here are shifting this paradigm (Brauner et al., ).…”

Section: Discussioncontrasting

confidence: 61%

“…Paternally inherited cases of NR5A1 insufficiency have been previously reported where the father has been asymptomatic (Philibert et al., ; Swartz et al. ; Yagi et al., ) or affected with retained spontaneous fertility (Baetens et al., ; Fabbri et al., ). Furthermore, there have been reports of siblings with the same mutation who present with vastly different effects on Leydig and Sertoli cell function (Coutant et al., ; Philibert et al.…”

Section: Discussionmentioning

confidence: 99%

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Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development

et al. 2017

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Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans‐activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute.

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Section: Discussioncontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development

et al. 2017

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“…There will likely be overlap with DSD genes, potentially with milder mutations in genes known to be associated with gonadal or genital development such as NR5A1 [22]. Indeed, the present authors recently performed whole-exome sequencing in 10 subjects with bifid scrotum and hypospadias, and identified NR5A1 mutations in two of these subjects [23]. There may also be distinct genes/loci identified, as suggested by a recent genome wide association study of hypospadias that identified 22 loci, many of which do not lie near genes known to be related to DSD [24].…”

Section: Discussionmentioning

confidence: 99%

Variation in the clinical and genetic evaluation of undervirilized boys with bifid scrotum and hypospadias

Swartz

Ciarlo

Denhoff

et al. 2017

Journal of Pediatric Urology

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Summary Background Bifid scrotum and hypospadias can be signs of undervirilization, yet boys presenting with these findings often do not undergo genetic evaluation. In some cases, identifying an underlying genetic diagnosis can help to optimize clinical care and improve guidance given to patients and families. Objectives The aim of this study was to characterize current practice for genetic evaluation of patients with bifid scrotum, and to identify approaches with a good diagnostic yield. Methods A retrospective study of the Boston Children’s Hospital electronic medical records (1993–2015) was conducted using the search term “bifid scrotum” and clinical data were extracted. Data were abstracted into a REDCap database for analysis. Statistical analysis was performed using SPSS, SAS, and Excel software. Results The search identified 110 subjects evaluated in the Urology and/or Endocrinology clinics for bifid scrotum. Genetic testing (including karyotype, microarray, or targeted testing) was performed on 64% of the subjects with bifid scrotum; of those tested, 23% (15% of the total cohort of 110 subjects) received a confirmed genetic diagnosis. Karyotype analysis, when performed, led to a diagnosis in 17% of patients. Of the ten instances when androgen receptor gene sequencing was performed, a pathogenic mutation was identified 20% of the time. Conclusion This study demonstrated that the majority of individuals with moderate undervirilization resulting in bifid scrotum do not receive a genetic diagnosis. Over a third of the analyzed subjects did not have any genetic testing, even though karyotype analysis and androgen receptor (AR) sequencing were both relatively high yield for identifying a genetic etiology. Increased utilization of traditional genetic approaches could significantly improve the ability to find a genetic diagnosis.

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“…Whole-exome sequencing of blood- and testis-derived genomic DNA was performed at the Broad Institute (Cambridge, Massachusetts, USA) on the proband and her parents, as previously described[8]. For hybrid selection, we used the custom Illumina Content Exome capture kit (Illumina, San Diego, California, USA).…”

Section: Methods and Subjectsmentioning

confidence: 99%

A 46,XX Ovotesticular Disorder of Sex Development Likely Caused by a Steroidogenic Factor-1 (NR5A1) Variant

et al. 2016

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Background: A variant in steroidogenic factor-1 (SF-1, encoded by the gene NR5A1), p.Arg92Trp, has recently been reported in multiple families with 46,XX ovotesticular or testicular disorders of sex development (DSD). This amino acid change impacts the DNA-binding domain and perturbs gonadal differentiation pathways. Methods: Whole-exome sequencing was performed on a 46,XX subject with ovotesticular DSD. Results: Exome results identified a heterozygous NR5A1 variant, p.Arg92Gln, in the 46,XX ovotesticular DSD proband. This arginine-to-glutamine change has been previously reported in the homozygous state in a 46,XY patient with gonadal and adrenal dysgenesis, though 46,XY and 46,XX heterozygous carriers of this variant have not been previously reported to have any clinical phenotype. Conclusions: The NR5A1 p.Arg92Gln variant, which has thus far only been seen in a family with 46,XY DSD, most likely contributes to the ovotesticular DSD in this case. In light of the recent reports of unrelated 46,XX subjects with testicular or ovotesticular DSD with the NR5A1 variant p.Arg92Trp, it appears that other mutations in the DNA binding domain have the potential to impact the factors determining testicular and ovarian differentiation. This case demonstrates the variability of phenotypes with the same genotype and broadens our understanding of the role of SF-1 in gonadal differentiation.

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Two Unrelated Undervirilized 46,XY Males with Inherited NR5A1 Variants Identified by Whole-Exome Sequencing

Cited by 8 publications

References 30 publications

Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development

Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development

Variation in the clinical and genetic evaluation of undervirilized boys with bifid scrotum and hypospadias

A 46,XX Ovotesticular Disorder of Sex Development Likely Caused by a Steroidogenic Factor-1 (NR5A1) Variant

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