An unusual familial Xp22.12 microduplication including EIF1AX: A novel candidate dosage-sensitive gene for premature ovarian insufficiency

Rim Sakka; Fatma Abdelhedi; Hanen Sellami; Bruno Pichon; Yosra Lajmi; Mouna Mnif; Sahbi Kebaili; Rihab Derbel; Hassen Kamoun; Radhouane Gdoura; Anne Delbaere; Julie Desir; Marc Abramowicz; François Vialard; Jean-Michel Dupont; Leila Ammar-Keskes

doi:10.1016/j.ejmg.2022.104613

An unusual familial Xp22.12 microduplication including EIF1AX: A novel candidate dosage-sensitive gene for premature ovarian insufficiency

Eur J Med Genet. 2022 Nov;65(11):104613. doi: 10.1016/j.ejmg.2022.104613. Epub 2022 Sep 14.

Authors

Rim Sakka¹, Fatma Abdelhedi², Hanen Sellami³, Bruno Pichon⁴, Yosra Lajmi⁵, Mouna Mnif⁶, Sahbi Kebaili⁷, Rihab Derbel⁸, Hassen Kamoun⁹, Radhouane Gdoura¹⁰, Anne Delbaere¹¹, Julie Desir⁴, Marc Abramowicz⁴, François Vialard¹², Jean-Michel Dupont⁵, Leila Ammar-Keskes⁸

Affiliations

¹ 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.
² Human Molecular Genetics Laboratory, Faculty of Medicine of Sfax, University of Sfax, Tunisia; Medical Genetics Department, Hedi Chaker Hospital, Sfax, Tunisia. Electronic address: [email protected].
³ Water Researches and Technologies Center (CERTE), University of Carthage, Tourist Road Soliman, Nabeul, Tunisia; Toxicology, Environmental Microbiology and Health Research Laboratory (LR17ES06), Faculty of Sciences of Sfax, University of Sfax, Tunisia.
⁴ Center of Medical Genetics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
⁵ Cytogenetics Department, Cochin Hospital, Assistance Publique des Hôpitaux de Paris, Sorbonne Paris Cité, Paris Descartes University, Medical School, Paris, France.
⁶ Department of Endocrinology, Hedi Chaker Hospital, Sfax, Tunisia.
⁷ Department of Gynecology, HediChaker Hospital, Sfax, Tunisia.
⁸ Human Molecular Genetics Laboratory, Faculty of Medicine of Sfax, University of Sfax, Tunisia.
⁹ Medical Genetics Department, Hedi Chaker Hospital, Sfax, Tunisia.
¹⁰ Toxicology, Environmental Microbiology and Health Research Laboratory (LR17ES06), Faculty of Sciences of Sfax, University of Sfax, Tunisia.
¹¹ Fertility Clinic, Department of Gynecology and Obstetrics, Erasme Hospital, UniversitéLibre de Bruxelles, Brussels, Belgium.
¹² Genetics Department, CHI Poissy St Germain-en-Laye, F-78300, Poissy, France; RHuMA Team, UMR-BREED, INRAE-UVSQ-ENVA, UFR-SVS, F-78180, Montigny le Bretonneux, France.

PMID: 36113757
DOI: 10.1016/j.ejmg.2022.104613

Abstract

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.

Keywords: EIF1AX gene; Primary ovarian insufficiency; SPIDR gene; Whole exome sequencing; Xp22.12 microduplication.

MeSH terms

Chromosomes, Human, X
Exome Sequencing
Female
Heterozygote
Humans
Phenotype
Primary Ovarian Insufficiency* / genetics
RNA, Messenger

Substances

RNA, Messenger