DEAH-Box 解旋酶 37 缺陷与 46,XY 性腺发育不全谱的遗传证据。

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

机构信息

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.

Laboratório de Sequenciamento em Larga Escala, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

出版信息

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

DOI:10.1210/jc.2019-00984

PMID:31287541

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.

摘要

背景

46,XY 性腺发育不全（GD）是一组具有广泛表型谱的异质性疾病，包括胚胎睾丸退化综合征（ETRS）。

目的

报告一个与 46,XY GD 病因相关的基因，特别是与 ETRS 相关的基因。

设计

使用全外显子组测序对 46,XY GD 的家族性病例进行筛选，对散发性病例进行靶向基因panel 测序。

地点

三级转诊性别发育差异/障碍（DSD）中心。

患者和干预措施

我们选择了 87 例 46,XY DSD 患者（17 例来自 8 个无关家庭的家族性病例和 70 例散发性病例）；55 例 GD 患者（其中 5 个家庭的 10 例患者和 8 例散发性病例为 ETRS），32 例 46,XY DSD 病因不明。

结果

我们在 5 个家庭（n = 11 例患者）和 6 例散发性病例中发现了 4 个杂合错义罕见变异，这些变异被归类为致病性或可能致病性的 Asp-Glu-Ala-His-box（DHX）解旋酶 37（DHX37）基因。两个变体是复发性的：p.Arg308Gln（在两个家庭和三个散发性病例中）和 p.Arg674Trp（在两个家庭和两个散发性病例中）。这些变异与 ETRS 密切相关（7/14 索引病例；50%）。在该队列中，罕见的、预测为有害的 DHX37 变异的频率（14%）显著高于基因组聚集数据库中的频率（0.4%；P < 0.001）。在人类睾丸中的免疫组织化学分析显示，DHX37 主要在睾丸成熟的不同阶段的生殖细胞、Leydig 细胞中表达，很少在 Sertoli 细胞中表达。