Purpose

Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome consists of congenital absence of the uterus and vagina and is often associated with renal, skeletal, cardiac, and auditory defects. The genetic basis is largely unknown except for rare variants in several genes. Many candidate genes have been suggested by mouse models and human studies. The purpose of this study was to narrow down the number of candidate genes.

Methods

Whole exome sequencing was performed on 111 unrelated individuals with MRKH; variant analysis focused on 72 genes suggested by mouse models, human studies of physiological candidates, or located near translocation breakpoints in t(3;16). Candidate variants (CV) predicted to be deleterious were confirmed by Sanger sequencing.

Results

Sanger sequencing verified 54 heterozygous CV from genes identified through mouse (13 CV in 6 genes), human (22 CV in seven genes), and translocation breakpoint (19 CV in 11 genes) studies. Twelve patients had ≥ 2 CVs, including four patients with two variants in the same gene. One likely digenic combination of LAMC1 and MMP14 was identified.

Conclusion

We narrowed 72 candidate genes to 10 genes that appear more likely implicated. These candidate genes will require further investigation to elucidate their role in the development of MRKH.

中文翻译：

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子宫和阴道发育不全/发育不全的遗传学：缩小 Mayer-Rokitansky-Küster-Hauser 综合征的候选基因数量

目的

Mayer-Rokitansky-Küster-Hauser (MRKH) 综合征由先天性子宫和阴道缺失组成，通常与肾脏、骨骼、心脏和听觉缺陷有关。除了几个基因的罕见变异外，遗传基础在很大程度上是未知的。小鼠模型和人类研究已经提出了许多候选基因。这项研究的目的是缩小候选基因的数量。

方法

对 111 名 MRKH 无关个体进行了全外显子组测序；变异分析侧重于由小鼠模型、人类生理候选研究建议或位于 t(3;16) 中易位断点附近的 72 个基因。Sanger测序证实了预测为有害的候选变体（CV）。

结果

Sanger 测序验证了通过小鼠（6 个基因中的 13 个 CV）、人类（7 个基因中的 22 个 CV）和易位断点（11 个基因中的 19 个 CV）研究确定的 54 个杂合 CV。12 名患者的 CV ≥ 2，其中 4 名患者在同一基因中有两种变异。确定了LAMC1和MMP14的一种可能的双基因组合。

结论

我们将 72 个候选基因缩小到 10 个似乎更有可能涉及的基因。这些候选基因需要进一步研究以阐明它们在 MRKH 发展中的作用。