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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
An unusual familial Xp22.12 microduplication including EIF1AX: A novel candidate dosage-sensitive gene for premature ovarian insufficiency
European Journal of Medical Genetics, Volume 65, No. 11, Article 104613, Year 2022
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Description
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. © 2022 Elsevier Masson SAS
Authors & Co-Authors
Sakka, Rim
Tunisia, Sfax
University of Sfax
Armenia, Yerevan
Center for Medical Genetics and Primary Health Care
Abdelhedi, Fatma
Tunisia, Sfax
University of Sfax
Tunisia, Sfax
Chu Hedi-chaker
Sellami, Hanen
Tunisia, Tunis
University of Carthage
Tunisia, Sfax
University of Sfax
Pichon, Bruno
Armenia, Yerevan
Center for Medical Genetics and Primary Health Care
Lajmi, Yosra
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Mnif, Mouna Feki
Tunisia, Sfax
Chu Hedi-chaker
Kebaïli, Sahbi
Tunisia, Sfax
Chu Hedi-chaker
Derbel, Rihab
Tunisia, Sfax
University of Sfax
Kammoun, Hassen
Tunisia, Sfax
Chu Hedi-chaker
Gdoura, Radhouane
Tunisia, Sfax
University of Sfax
Delbaere, Anne
Belgium, Brussels
Université Libre de Bruxelles
Désir, Julie
Armenia, Yerevan
Center for Medical Genetics and Primary Health Care
Abramowicz, Marc Joel
Armenia, Yerevan
Center for Medical Genetics and Primary Health Care
Vialard, François
France, Poissy
Centre Hospitalier Intercommunal Poissy-st-germain-en-laye
France, Versailles
Université de Versailles Saint-quentin-en-yvelines
Dupont, Jean Michel
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Ammar-Keskes, Leila
Tunisia, Sfax
University of Sfax
Statistics
Citations: 1
Authors: 16
Affiliations: 8
Identifiers
Doi:
10.1016/j.ejmg.2022.104613
ISSN:
17697212
Research Areas
Disability
Genetics And Genomics
Maternal And Child Health
Sexual And Reproductive Health
Participants Gender
Female