Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization arrays, and whole-exome sequencing analyses identified homozygous pathogenic variants in MCM9, a gene implicated in homologous recombination and repair of double-stranded DNA breaks. In one family, the MCM9 c.1732+2T>C variant alters a splice donor site, resulting in abnormal alternative splicing and truncated forms of MCM9 that are unable to be recruited to sites of DNA damage. In the second family, MCM9 c.394C>T (p.Arg132(∗)) results in a predicted loss of functional MCM9. Repair of chromosome breaks was impaired in lymphocytes from affected, but not unaffected, females in both families, consistent with MCM9 function in homologous recombination. Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. Preferential sensitivity of germline meiosis to MCM9 functional deficiency and compromised DNA repair in the somatic component most likely account for the ovarian failure and short stature.

中文翻译：

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MCM9突变与卵巢衰竭，身材矮小和染色体不稳定有关。

卵巢早衰（POF）在遗传上是异质的，并且表现为性腺功能亢进性腺功能减退症，既可以是综合征的一部分，也可以是孤立症状。我们研究了两个不相关的近亲家庭，其女儿表现出原发性闭经，身材矮小和46，XX核型。SNP阵列，比较基因组杂交阵列和全外显子组测序分析的组合确定了MCM9中的纯合致病性变异体，该基因与双链DNA断裂的同源重组和修复有关。在一个家族中，MCM9 c.1732 + 2T> C变体改变了剪接供体位点，导致异常的可变剪接和截短形式的MCM9无法募集到DNA损伤位点。在第二个家族中，MCM9 c.394C> T（p.Arg132（∗））导致功能性MCM9的预期损失。两个家族的受影响但并非不受影响的雌性的淋巴细胞中的染色体断裂修复均受损，这与同源重组中的MCM9功能一致。MCM9中的常染色体隐性变异体会导致与促性腺激素性性腺功能减退和身材矮小相关的基因组不稳定综合征。种系减数分裂对MCM9功能缺陷和受损的DNA修复体细胞成分的优先敏感性最可能是卵巢功能衰竭和身材矮小的原因。