The Journal of clinical endocrinology and metabolism · 2019
Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum.
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da Silva Thatiana Evilen, Gomes Nathalia Lisboa, Lerário Antonio Marcondes, Keegan Catherine Elizabeth, Nishi Mirian Yumi, Carvalho Filomena Marino, Vilain Eric, Barseghyan Hayk, Martinez-Aguayo Alejandro, Forclaz María Verónica, Papazian Regina, Pedroso de Paula Leila Cristina, Costa Eduardo Corrêa, Carvalho Luciani Renata, Jorge Alexander Augusto Lima, Elias Felipe Martins, Mitchell Rod, Costa Elaine Maria Frade, Mendonca Berenice Bilharinho, Domenice Sorahia
Аннотация
CONTEXT: 46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS).
OBJECTIVE: To report a gene for 46,XY GD etiology, especially for ETRS.
DESIGN: Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing.
SETTING: Tertiary Referral Center for differences/disorders of sex development (DSD).
PATIENTS AND INTERVENTIONS: We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology.
RESULTS: We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells.
CONCLUSION: This strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.
OBJECTIVE: To report a gene for 46,XY GD etiology, especially for ETRS.
DESIGN: Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing.
SETTING: Tertiary Referral Center for differences/disorders of sex development (DSD).
PATIENTS AND INTERVENTIONS: We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology.
RESULTS: We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells.
CONCLUSION: This strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.