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.