Abstract

BACKGROUND

BReast CAncer (BRCA) genes are extensively studied in the context of fertility and reproductive aging. BRCA proteins are part of the DNA repair Fanconi anemia (FA)/BRCA pathway, in which more than 20 proteins are implicated. According to which gene is mutated and which interactions are lost owing to the mutation, carriers and patients with monoallelic or biallelic FA/BRCA mutations exhibit very different phenotypes, from overt FA to cancer predisposition or no pathological implications. The effect of the so far neglected non-BRCA FA mutations on fertility also deserves consideration.

OBJECTIVE AND RATIONALE

As improved treatments allow a longer life expectancy in patients with biallelic FA mutations and overt FA, infertility is emerging as a predominant feature. We thus reviewed the mechanisms for such a manifestation, as well as whether they also occur in monoallelic carriers of FA non-BRCA mutations.

SEARCH METHODS

Electronic databases PUBMED, EMBASE and CENTRAL were searched using the following term: ‘fanconi’ OR ‘FANC’ OR ‘AND’ ‘fertility’ OR ‘pregnancy’ OR ‘ovarian reserve’ OR ‘spermatogenesis’ OR ‘hypogonadism’. All pertinent reports in the English-language literature were retrieved until May 2021 and the reference lists were systematically searched in order to identify any potential additional studies.

OUTCOMES

Biallelic FA mutations causing overt FA disease are associated with premature ovarian insufficiency (POI) occurring in the fourth decade in women and with primary non-obstructive azoospermia (NOA) in men. Hypogonadism in FA patients seems mainly associated with a defect in primordial germ cell proliferation in fetal life. In recent small, exploratory whole-exome sequencing studies, biallelic clinically occult mutations in the FA complementation group A (Fanca) and M (Fancm) genes were found in otherwise healthy patients with isolated NOA or POI, and also monoallelic carrier status for a loss-of-function mutation in Fanca has been implicated as a possible cause for POI. In those patients with known monoallelic FA mutations undergoing pre-implantation genetic testing, poor assisted reproduction outcomes are reported. However, the mechanisms underlying the repeated failures and the high miscarriage rates observed are not fully known.

WIDER IMPLICATIONS

The so far ‘neglected’ members of the FA/BRCA family will likely emerge as a relevant focus of investigation in the genetics of reproduction. Several (rather than a single) non-BRCA genes might be implicated. State-of-the-art methods, such as whole-genome/exome sequencing, and further exploratory studies are required to understand the prevalence and mechanisms for occult FA mutations in infertility and recurrent miscarriage.

中文翻译：

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被忽视的家庭成员：范可尼贫血/BRCA通路和生殖中的非BRCA突变

摘要

背景

乳腺癌 ( BRCA ) 基因在生育力和生殖衰老的背景下得到了广泛的研究。BRCA 蛋白是 DNA 修复范可尼贫血 (FA)/BRCA 通路的一部分，其中涉及 20 多种蛋白质。根据哪个基因发生突变以及哪些相互作用因突变而丢失，具有单等位基因或双等位基因 FA/BRCA 突变的携带者和患者表现出非常不同的表型，从明显的 FA 到癌症易感性或没有病理意义。迄今为止被忽视的非 BRCA FA 突变对生育能力的影响也值得考虑。

目标和理由

由于改进的治疗可以延长双等位基因 FA 突变和明显 FA 患者的预期寿命，不孕症正在成为一个主要特征。因此，我们回顾了这种表现的机制，以及它们是否也发生在 FA 非 BRCA 突变的单等位基因携带者中。

搜索方法

使用以下术语搜索电子数据库 PUBMED、EMBASE 和 CENTRAL：“fanconi”或“FANC”或“AND”“生育力”或“妊娠”或“卵巢储备”或“精子发生”或“性腺机能减退”。在 2021 年 5 月之前检索了英语文献中的所有相关报告，并系统地搜索了参考列表，以确定任何潜在的额外研究。

结果

导致明显 FA 疾病的双等位基因 FA 突变与 40 岁的女性卵巢早衰 (POI) 和男性的原发性非梗阻性无精子症 (NOA) 相关。FA 患者的性腺机能减退似乎主要与胎儿期原始生殖细胞增殖缺陷有关。在最近的小型探索性全外显子组测序研究中，FA 互补组 A ( Fanca ) 和 M ( Fancm ) 基因中的双等位基因临床隐匿性突变在其他方面健康的患者中发现了孤立的 NOA 或 POI，以及单等位基因携带者状态的丢失Fanca中的功能突变已被认为是 POI 的可能原因。在那些接受植入前基因检测的已知单等位 FA 突变的患者中，报告了较差的辅助生殖结果。然而，反复失败和观察到的高流产率背后的机制尚不完全清楚。

更广泛的影响

到目前为止，FA/BRCA 家族中“被忽视”的成员可能会成为生殖遗传学研究的相关焦点。可能涉及几个（而不是单个）非 BRCA 基因。需要最先进的方法，例如全基因组/外显子组测序，以及进一步的探索性研究，以了解隐匿性 FA 突变在不孕症和复发性流产中的普遍性和机制。