NR5A1 Gene Mutations: Clinical, Endocrine and Genetic Features in Two Girls with 46,XY Disorder of Sex Development

Abstract

Background: Steroidogenic factor 1, encoded by the NR5A1 gene, is a key regulator of endocrine function within the hypothalamic-pituitary-steroidogenic axis. Both homozygous, compound heterozygous and heterozygous mutations in the NR5A1 gene may determine 46,XY disorders of sex development (DSD). Patients and Methods:NR5A1 gene sequencing was performed in a cohort of 6 patients with 46,XY DSD without specific diagnosis. Results: Heterozygous NR5A1 gene mutations were found in 2 girls, aged 0.5 years and 14 years. The older girl harbored the c.250C>T transition in exon 4 (p.Arg84Cys), previously reported in a Japanese girl. The younger girl presented a de novo novel exon 6 heterozygous frameshift mutation (c.1074dupG) in codon 359 associated with the p.Gly146Ala polymorphism the latter inherited from her father. This baby showed severe impairment of androgen secretion from the first months of life. Overt adrenal insufficiency did not occur, but the older girl showed subnormal cortisol peak after ACTH stimulation. Conclusions:NR5A1 gene mutations are a relatively frequent cause of 46,XY DSD in humans. Clear indications for management of these individuals remain elusive, mainly when diagnosis is made in infancy. Long-term monitoring of adrenal function should be recommended.

NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes

“…Annotation and filtering of variants were performed with Variant Interpreter platform; the NGS coverage was analyzed in detail using Integrative Genome Viewer version 2.3. Variants and regions with a depth coverage below 50× were confirmed by Sanger sequencing using previously described procedures [Bertelloni et al, 2014] and were checked for previously reported causative mutations in published works and variant databases: Human Gene Mutation Database (HGMD) and Leiden Open Variation Database (LOVD). Variants were classified following the American College of Medical Genetics (ACMG) and genomics recommendations [Richards et al, 2015] using population frequency databases (dbSNP, ExAC, GnomAD exomes, and GnomAD genomes) and in silico tools including PolyPhen, SIFT, Align GVGD, DANN, FATHMM, Mutation Assessor, and Muta-tionTaster.…”

New NR5A1 mutations and phenotypic variations of gonadal dysgenesis

“…The majority of NR5A1 mutations were described in 46,XY DSD patients. The phenotypical spectrum encompasses hypospadias [10–12], ambiguous genitalia like a hypoplastic phallus [13–15], or a complete external female appearance [16–19], but also only male infertility [20–22]. Furthermore, NR5A1 mutations were found in 46,XX patients with premature ovarian failure and primary ovarian insufficiency [17, 23, 24].…”

“…Recently, three independent groups identified also a recurrent NR5A1 p.R92W mutation in several patients with 46,XX testicular/ ovotesticular DSD, highlighting the role of NR5A1 in the development of both testes and ovaries [25–27]. Except for five reported cases with adrenal insufficiency [28–32] and some patients with mild elevated ATCH [16, 33] most NR5A1 mutations were described in 46,XY DSD patients with normal adrenal function at the date of examination.…”

Comment on “Complete Androgen Insensitivity Syndrome: Optimizing Diagnosis and Management”

“…In our experience, more than 25% of the females referred to our departments with clinical/endocrine diagnosis of CAIS did not have this diagnosis confirmed by genetic analysis [20]. …”