Sakka Rim, Abdelhedi Fatma, Sellami Hanen, Pichon Bruno, Lajmi Yosra, Mnif Mouna, Kebaili Sahbi, Derbel Rihab, Kamoun Hassen, Gdoura Radhouane, Delbaere Anne, Desir Julie, Abramowicz Marc, Vialard François, Dupont Jean-Michel, Ammar-Keskes Leila
Human Molecular Genetics Laboratory, Faculty of Medicine of Sfax, University of Sfax, Tunisia; Center of Medical Genetics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Human Molecular Genetics Laboratory, Faculty of Medicine of Sfax, University of Sfax, Tunisia; Medical Genetics Department, Hedi Chaker Hospital, Sfax, Tunisia.
Eur J Med Genet. 2022 Nov;65(11):104613. doi: 10.1016/j.ejmg.2022.104613. Epub 2022 Sep 14.
We report on the results of array-CGH and Whole exome sequencing (WES) studies carried out in a Tunisian family with 46,XX premature ovarian insufficiency (POI). This study has led to the identification of a familial Xp22.12 tandem duplication with a size of 559.4 kb, encompassing only three OMIM genes (RPS6KA3, SH3KBP1and EIF1AX), and a new heterozygous variant in SPIDR gene: NM_001080394.3:c.1845_1853delTATAATTGA (p.Ile616_Asp618del) segregating with POI. Increased mRNA expression levels were detected for SH3KBP1 and EIF1AX, while a normal transcript level for RPS6KA3 was detected in the three affected family members, explaining the absence of intellectual disability (ID). To the best of our knowledge, this is the first duplication involving the Xp22.12 region, reported in a family without ID, but rather with secondary amenorrhea (SA) and female infertility. As EIF1AX is a regulatory gene escaping X-inactivation, which has an extreme dosage sensitivity and highly expressed in the ovary, we suggest that this gene might be a candidate gene for ovarian function. Homozygous nonsense pathogenic variants of SPIDR gene have been reported in familial cases in POI. It has been suggested that chromosomal instability associated with SPIDR molecular defects supports the role of SPIDR protein in double-stranded DNA damage repair in vivo in humans and its causal role in POI. In this family, the variant (p.Ile616_Asp618del), present in a heterozygous state, is located in the domain that interacts with BLM and might disrupt the BLM binding ability of SPIDR protein. These findings strengthen the hypothesis that the additional effect of this variant could lead to POI in this family. Although the work represents the first evidence that EIF1AX duplication might be responsible for POI through its over-expression, further functional studies are needed to clarify and prove EIF1AX involvement in POI phenotype.
我们报告了对一个患有46,XX型早发性卵巢功能不全（POI）的突尼斯家族进行的阵列比较基因组杂交（array-CGH）和全外显子测序（WES）研究结果。该研究发现了一个大小为559.4 kb的家族性Xp22.12串联重复序列，仅包含三个《人类孟德尔遗传》（OMIM）基因（RPS6KA3、SH3KBP1和EIF1AX），以及SPIDR基因中的一个新的杂合变异：NM_001080394.3:c.1845_1853delTATAATTGA（p.Ile616_Asp618del），该变异与POI共分离。在三名受影响的家族成员中检测到SH3KBP1和EIF1AX的mRNA表达水平升高，而RPS6KA3的转录水平正常，这解释了智力残疾（ID）的缺失。据我们所知，这是首次在一个没有ID但有继发性闭经（SA）和女性不孕的家族中报道涉及Xp22.12区域的重复。由于EIF1AX是一个逃避X染色体失活的调控基因，具有极高的剂量敏感性且在卵巢中高表达，我们认为该基因可能是卵巢功能的候选基因。在POI的家族病例中已报道了SPIDR基因的纯合无义致病性变异。有人提出，与SPIDR分子缺陷相关的染色体不稳定性支持了SPIDR蛋白在人类体内双链DNA损伤修复中的作用及其在POI中的因果作用。在这个家族中，杂合状态存在的变异（p.Ile616_Asp618del）位于与BLM相互作用的结构域中，可能会破坏SPIDR蛋白与BLM的结合能力。这些发现强化了这样一种假设，即该变异的额外效应可能导致这个家族出现POI。尽管这项工作是EIF1AX重复可能通过其过表达导致POI的首个证据，但仍需要进一步的功能研究来阐明并证明EIF1AX与POI表型的关联。
