TY - JOUR
T1 - Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development
AU - Baetens, Dorien
AU - Güran, Tülay
AU - Mendonca, Berenice B.
AU - Gomes, Nathalia L.
AU - De Cauwer, Lode
AU - Peelman, Frank
AU - Verdin, Hannah
AU - Vuylsteke, Marnik
AU - Van Der Linden, Malaïka
AU - Atay, Zeynep
AU - Bereket, Abdullah
AU - De Krijger, Ronald R.
AU - De Preter, Katleen
AU - Domenice, Sorahia
AU - Turan, Serap
AU - Stoop, Hans
AU - Looijenga, Leendert H.
AU - De Bosscher, Karolien
AU - Cools, Martine
AU - De Baere, Elfride
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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.
AB - 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.
KW - 46,XY DSD
KW - disorders of sex development
KW - ESR2 variants
KW - novel candidate gene
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85044621857&partnerID=8YFLogxK
U2 - 10.1038/gim.2017.163
DO - 10.1038/gim.2017.163
M3 - Article
AN - SCOPUS:85044621857
SN - 1098-3600
VL - 20
SP - 717
EP - 727
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -