Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum

J Clin Endocrinol Metab. 2019 Dec 1;104(12):5923-5934. doi: 10.1210/jc.2019-00984.

Thatiana Evilen da Silva ¹, Nathalia Lisboa Gomes ¹, Antonio Marcondes Lerário ² ³, Catherine Elizabeth Keegan ⁴ ⁵, Mirian Yumi Nishi ¹, Filomena Marino Carvalho ⁶, Eric Vilain ⁷, Hayk Barseghyan ⁷, Alejandro Martinez-Aguayo ⁸, María Verónica Forclaz ⁹, Regina Papazian ⁹, Leila Cristina Pedroso de Paula ¹⁰, Eduardo Corrêa Costa ¹⁰, Luciani Renata Carvalho ¹, Alexander Augusto Lima Jorge ¹, Felipe Martins Elias ¹, Rod Mitchell ¹¹, Elaine Maria Frade Costa ¹, Berenice Bilharinho Mendonca ¹ ², Sorahia Domenice ¹

Affiliations

1 Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM/42) da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
2 Laboratório de Sequenciamento em Larga Escala, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
3 Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
4 Department of Pediatric Genetics, University of Michigan Medical School, Ann Arbor, Michigan.
5 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan.
6 Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
7 Center for Genetic Medicine Research, The Children's Research Institute, Children's National Medical Center, Children's National Health System, Washington, DC.
8 Division de Pediatria, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile.
9 Servicio de Pediatría, Hospital Nacional Prof. Dr. A. Posadas, Buenos Aires, Argentina.
10 Programa de Atendimento às Desordens do Desenvolvimento Sexual, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
11 Medical Research Council Centre for Reproductive Health, Queens Medical Research Institute, Edinburgh, United Kingdom.

PMID: 31287541 DOI: 10.1210/jc.2019-00984

Abstract

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.

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