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 ^[1] ; Gomes, Nathalia Lisboa ^[1] ; Lerario, Antonio Marcondes ^{[2, 3]} ; Keegan, Catherine Elizabeth ^{[4, 5]} ; Nishi, Mirian Yumi ^[1] ; Carvalho, Filomena Marino ^[6] ; Vilain, Eric ^[7] ; Barseghyan, Hayk ^[7] ; Martinez-Aguayo, Alejandro ^[8] ; Forclaz, Maria Veronica ^[9] ; Papazian, Regina ^[9] ; Pedroso de Paula, Leila Cristina ^[10] ; Costa, Eduardo Correa ^[10] ; Carvalho, Luciani Renata ^[1] ; Lima Jorge, Alexander Augusto ^[1] ; Elias, Felipe Martins ^[1] ; Mitchell, Rod ^[11] ; Frade Costa, Elaine Maria ^[1] ; Mendonca, Berenice Bilharinho ^{[3, 1]} ; Domenice, Sorahia ^[1]

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^[1] Univ Sao Paulo, Unidade Endocrinol Desenvolvimento, Lab Hormonios & Genet Mol LIM 42, BR-05403900 Sao Paulo - Brazil

^[2] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA

^[3] Univ Sao Paulo, Fac Med, Lab Sequenciamento Larga Escala, BR-01246903 Sao Paulo - Brazil

^[4] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI - USA

^[5] Univ Michigan, Sch Med, Dept Pediat Genet, Ann Arbor, MI 48109 - USA

^[6] Univ Sao Paulo, Fac Med, Dept Patol, BR-01246903 Sao Paulo - Brazil

^[7] Childrens Natl Hlth Syst, Ctr Genet Med Res, Childrens Res Inst, Childrens Natl Med Ctr, Washington, DC 20036 - USA

^[8] Pontificia Univ Catolica Chile, Escuela Med, Div Pediat, Santiago 7220436 - Chile

^[9] Hosp Nacl Prof Dr A Posadas, Serv Pediat, RA-1684 Buenos Aires, DF - Argentina

^[10] Univ Fed Rio Grande do Sul, Programa Atendimento Desordens Desenvolvimento Se, Hosp Clin Porto Alegre, BR-90035903 Porto Alegre, RS - Brazil

^[11] MRC, Ctr Reprod Hlth, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian - Scotland

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 104, n. 12, p. 5923-5934, DEC 2019.
• Citações Web of Science: 2

Resumo

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. (AU)

• Processo FAPESP: 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 10/51102-0 - Pesquisa de mutações nos genes BMP15 e GDF9 em mulheres portadoras de insuficiência ovariana prematura: desenvolvimento de metodologia para estudo funcional das mutações em células humanas de granulosa imorta
• Beneficiário: Mariza Augusta Gerdulo dos Santos
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 07/51215-6 - Pesquisa de mutacoes no gene stra8 em pacientes portadores de disturbios do desenvolvimento gonadal 46, xx.
• Beneficiário: Mariza Augusta Gerdulo dos Santos
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/50137-5 - Caracterização molecular de doenças monogênicas do desenvolvimento por sequenciamento em larga escala
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 05/04726-0 - Caracterização molecular das doenças endócrinas congênitas que afetam o crescimento e o desenvolvimento
• Beneficiário: Ana Claudia Latronico Xavier
• Modalidade de apoio: Auxílio à Pesquisa - Temático