Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1

Piscina, Idoia Martinez de la; Mahmoud, Rana; Sauter, Kay‐Sara; Esteva, Isabel; Alonso, Milagros; Costa, Inês; Rial-Rodriguez, Jose Manuel; Rodríguez-Estévez, Amaia; Vela, Amaia; Castaño, Luís; Flück, Christa E.

doi:10.3390/ijms21228554

Cited by 15 publications

(16 citation statements)

References 54 publications

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“…One possible explanation for this phenotypic variability is digenic or oligogenic inheritance. In 46,XY DSD patients with variants in NR5A1 , additional variants that potentially modify phenotypes have been identified in at least 37 genes [ 35 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Digenic inheritances are the simplest among the digenic/oligogenic inheritances and have occasionally been identified in a manner similar to the Mendelian inheritance [ 67 ].…”

Section: Nr5a1 (Nuclear Receptor Subfamily 5 Group a Member 1)mentioning

confidence: 99%

“…Digenic inheritances are the simplest among the digenic/oligogenic inheritances and have occasionally been identified in a manner similar to the Mendelian inheritance [ 67 ]. Among the 37 genes mentioned above, genes that potentially contribute to digenic inheritances in combination with NR5A1 include AMH , AR , FLRT3 , INHA , MAP3K1 , SOX3 , STAR , SRY , and ZFPM2 [ 35 , 61 , 62 , 63 , 64 , 65 , 66 ]. In many cases of digenic inheritance, proteins encoded by the two genes have protein-protein interactions [ 68 ].…”

Section: Nr5a1 (Nuclear Receptor Subfamily 5 Group a Member 1)mentioning

confidence: 99%

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Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

Hattori

Fukami

2023

Biomolecules

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Gonadal development is the first step in human reproduction. Aberrant gonadal development during the fetal period is a major cause of disorders/differences of sex development (DSD). To date, pathogenic variants of three nuclear receptor genes (NR5A1, NR0B1, and NR2F2) have been reported to cause DSD via atypical testicular development. In this review article, we describe the clinical significance of the NR5A1 variants as the cause of DSD and introduce novel findings from recent studies. NR5A1 variants are associated with 46,XY DSD and 46,XX testicular/ovotesticular DSD. Notably, both 46,XX DSD and 46,XY DSD caused by the NR5A1 variants show remarkable phenotypic variability, to which digenic/oligogenic inheritances potentially contribute. Additionally, we discuss the roles of NR0B1 and NR2F2 in the etiology of DSD. NR0B1 acts as an anti-testicular gene. Duplications containing NR0B1 result in 46,XY DSD, whereas deletions encompassing NR0B1 can underlie 46,XX testicular/ovotesticular DSD. NR2F2 has recently been reported as a causative gene for 46,XX testicular/ovotesticular DSD and possibly for 46,XY DSD, although the role of NR2F2 in gonadal development is unclear. The knowledge about these three nuclear receptors provides novel insights into the molecular networks involved in the gonadal development in human fetuses.

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Section: Nr5a1 (Nuclear Receptor Subfamily 5 Group a Member 1)mentioning

confidence: 99%

Section: Nr5a1 (Nuclear Receptor Subfamily 5 Group a Member 1)mentioning

confidence: 99%

Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

Hattori

Fukami

2023

Biomolecules

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“…For the targeted DSD-gene panel analysis, preparation of the libraries and sequencing have been described elsewhere (24). For variant filtration after panel analysis, same steps b to f were followed (Figure 1B).…”

Section: Genetic Analysismentioning

confidence: 99%

“…The DSD causing effect of the NR5A1/SF-1 p.Gly146Ala variant is therefore in doubt. However, given that oligogenic inheritance has been suggested for explaining the broad phenotype observed in individuals and families with NR5A1/SF-1 gene variants (23)(24)(25)(26)(27)(28)(29), the p.Gly146Ala variant might play a role as coregulator or disease modifier of sexual development.…”

Section: Introductionmentioning

confidence: 99%

TheNR5A1/SF-1variant p.Gly146Ala cannot explain the phenotype of individuals with a difference of sex development

Piscina

Kouri

Aurrekoetxea

et al. 2023

Preprint

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Steroidogenic factor 1 (SF-1, NR5A1) plays an important role in human sex development. Variants of NR5A1/SF-1 may cause mild to severe differences of sex development (DSD) or may be found in healthy carriers. So far, the broad DSD phenotypic variability associated NR5A1/SF-1 variants remains a conundrum. The NR5A1/SF-1 variant c.437G>C/p.Gly146Ala is common in individuals with a DSD and has been suggested to act as a susceptibility factor for adrenal disease or cryptorchidism. However, as the allele frequency in the general population is high, and as functional testing of the p.Gly146Ala variant in vitro revealed inconclusive results, the disease-causing effect of this variant has been questioned. However, a role as a disease modifier in concert with other gene variants is still possible given that oligogenic inheritance has been described in patients with NR5A1/SF-1 gene variants. Therefore, we performed next generation sequencing in DSD individuals harboring the NR5A1/SF-1 p.Gly146Ala variant to search for other DSD-causing variants. Aim was to clarify the function of this variant for the phenotype of the carriers. We studied 14 pediatric DSD individuals who carried the p.Gly146Ala variant. Panel and whole-exome sequencing was performed, and data were analyzed with a specific data filtering algorithm for detecting variants in NR5A1- and DSD-related genes. The phenotype of the studied individuals ranged from scrotal hypospadias and ambiguous genitalia in 46,XY DSD to typical male external genitalia and ovotestes in 46,XX DSD patients. Patients were of African, Spanish, and Asian origin. Of the 14 studied subjects, five were homozygous and nine heterozygous for the NR5A1/SF-1 p.Gly146Ala variant. In ten subjects we identified either a clearly pathogenic DSD gene variant (e.g. in AR, LHCGR) or one to four potentially deleterious variants that likely explain the observed phenotype alone (e.g. in FGFR3, CHD7, ADAMTS16). Our study shows that most individuals carrying the NR5A1/SF-1 p.Gly146Ala variant, harbor at least one other deleterious gene variant which can explain the DSD phenotype. This finding confirms that the p.Gly146Ala variant of NR5A1/SF-1 may not contribute to the pathogenesis of DSD and qualifies as a benign polymorphism. Thus, individuals, in whom the NR5A1/SF-1 p.Gly146Ala gene variant has been identified as the underlying genetic cause for their DSD in the past, should be re-evaluated with a next-generation sequencing method to reveal the real genetic diagnosis.

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“…Based on chromosome karyotype, DSD are usually classified into 46,XX DSD, 46,XY DSD and sex chromosome DSD (1). Heterozygous pathogenic NR5A1 variants account for 10-20% of 46,XY DSD cases (2). NR5A1 gene encodes for Steroidogenic factor 1 (SF1), which functions as a transcription factor for sex determination as well as regression of Mullerian structures (3).…”

Section: Introductionmentioning

confidence: 99%

Novel likely pathogenic variant in NR5A1 gene in a Tanzanian child with 46,XY differences of sex development, inherited from the mosaic father

Damji¹,

Alimohamed

Grinten

et al. 2023

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary Pathogenic variants in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1), which encodes steroidogenic factor 1 (SF1), result in 46,XY and 46,XX differences of sex development (DSD). In 46,XY individuals with a pathogenic variant in the NR5A1 gene a variable phenotype ranging from mild to severe is seen, including adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus and infertility. We report the clinical, endocrinological and genetic characteristics of a patient with 46,XY DSD with a novel likely pathogenic missense variant in the NR5A1 gene. A retrospective evaluation of the medical history, physical examination, limited endocrinological laboratory analysis and genetic analysis with DSD gene panel testing was performed. A 1.5-month-old individual was referred with ambiguous genitalia. The karyotype was 46,XY. The endocrinological analyses were within normal male reference including a normal response of cortisol within an adrenocorticotropic hormone test. A novel heterozygous missense variant c.206G>C p.(Arg69Pro) in the NR5A1 gene was detected. This variant was present in mosaic form (~20%) in his unaffected father. Because another missense variant at the same position and other missense variants involving the same highly conserved codon have been reported, we consider this NR5A1 variant in this 46,XY DSD patient as likely pathogenic in accordance with the ACMG/AMP 2015 guidelines causing ambiguous genitalia but no adrenal insufficiency. This variant was inherited from the apparently unaffected mosaic father, which might have implications for the recurrence risk in this family. Learning points The importance of performing trio (patient and parents) sequencing is crucial in pointing out the origin of inheritance. In a 46,XY differences of sex development patient, a normal adrenal function does not rule out an NR5A1 mutation. With the support of a dedicated overseas institute partnership, we could solve this complex clinical case by molecular diagnosis in a resource-limited setting.

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Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1

Cited by 15 publications

References 54 publications

Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

TheNR5A1/SF-1variant p.Gly146Ala cannot explain the phenotype of individuals with a difference of sex development

Novel likely pathogenic variant in NR5A1 gene in a Tanzanian child with 46,XY differences of sex development, inherited from the mosaic father

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