Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Genet Med. 2018 Jul;20(7):717-727. doi: 10.1038/gim.2017.163.

Dorien Baetens ¹, Tülay Güran ², Berenice B Mendonca ³, Nathalia L Gomes ³, Lode De Cauwer ⁴ ⁵, Frank Peelman ⁴ ⁵, Hannah Verdin ¹, Marnik Vuylsteke ⁶, Malaïka Van der Linden ⁷, ESR2 STUDY GROUP, Zeynep Atay, Abdullah Bereket, Ronald R de Krijger, Katleen de Preter, Sorahia Domenice, Serap Turan, Hans Stoop ⁸, Leendert H Looijenga ⁸, Karolien De Bosscher ⁴ ⁵, Martine Cools ⁹, Elfride De Baere ¹⁰

Affiliations

1 Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
2 Zeynep Kamil Maternity and Children's Diseases Training and Research Hospital, Division of Pediatric Endocrinology and Diabetes, Istanbul, Turkey.
3 Disciplina de Endocrinologia, Laboratorio de Hormonios e Genetica Molecular LIM/42, Unidade de Adrenal, Disc. de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
4 Receptor Research Laboratories, Nuclear Receptor Lab, Department of Medical Protein Research, VIB, Ghent, Belgium.
5 Department of Biochemistry, Ghent University, Ghent, Belgium.
6 GNOMIXX ltd, Statistics for Genomics, Melle, Belgium.
7 Department of Medical and Forensic Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium.
8 Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
9 Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University and Ghent University Hospital, Ghent, Belgium.
10 Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium. Elfride.DeBaere@ugent.be.

PMID: 29261182 DOI: 10.1038/gim.2017.163

Abstract

Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.

Methods: Homozygosity mapping and whole-exome Sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome Sequencing and targeted next-generation Sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.

Results: We identified a homozygous ESR2 variant, c.541_543del p.(Asn181del), located in the highly conserved DNA-binding domain of ER-β, in an individual with syndromic 46,XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-β, were found in unrelated, nonsyndromic 46,XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-β immunostaining was positive in the developing intestine and eyes.

Conclusion: Our study supports a role for ESR2 as a novel candidate gene for 46,XY DSD.

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