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Novel MED12 variant in a multiplex Fragile X syndrome family: dual molecular etiology of two X-linked intellectual disabilities with autism in the same family

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Abstract

Studies of X-linked pedigrees were the first to identify genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD). However, some pedigrees present a huge clinical variability between the affected members. This intrafamilial heterogeneity may be due to cooccurrence of two disorders. In the present study, we describe a multiplex X-linked pedigree in which three siblings have ID, ASD and dysmorphic features but with variable severity. Through Fragile X syndrome test, we identified the full FMR1 mutation in only two males. Whole exome sequencing allowed us to identify a novel hemizygous variant (p.Gln2080_Gln2083del) in MED12 gene in two males. So, the first patient has FXS, the second has both FMR1 and MED12 mutations while the third has only the MED12 variant. MED12 mutations are implicated in several forms of X-linked ID. Family segregation and genotype–phenotype–correlation were in favor of a cooccurrence of two forms of X-linked ID. Our work provides further evidence of the involvement of MED12 in XLID. Moreover, through these results, it is noteworthy to raise awareness that intrafamilial heterogeneity in FXS multiplex families could result from the cooccurrence of multiple clinical entities involving at least two separate genetic loci. This should be taken into consideration for genetic testing and counselling in patients/families with atypical disease symptoms.

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Acknowledgements

We are grateful to the family members for their collaboration. This work was supported by the Tunisian Ministry of Public Health and by the Ministry of Higher Education and Scientific Research (LR16IPT05).

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Authors and Affiliations

  1. Biomedical Genomics and Oncogenetics Laboratory LR16IPT05, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia

    Saida Lahbib, Hamza Dallali, Rym Kefi & Sonia Abdelhak

  2. Laboratoire de Génétique Humaine, Faculté de Médecine de Tunis, Université de Tunis El Manar, Tunis, Tunisia

    Mediha Trabelsi & Ridha Mrad

  3. Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital, Tunis, Tunisia

    Mediha Trabelsi & Ridha Mrad

  4. National Institute of Applied Sciences and Technology, University of Carthage, Tunis, Tunisia

    Hamza Dallali

  5. Laboratory of Histology and Cytogenetics (Research Unit of Genetic, Genotoxicity and Childhood Diseases UR12ES10), Faculty of Medicine, University of Monastir, Street Avicenne, 5019, Monastir, Tunisia

    Rania Sakka

  6. Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia

    Rym Bourourou & Naoufel Gaddour

  7. University of Monastir, 5000, Monastir, Tunisia

    Naoufel Gaddour

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  1. Saida Lahbib
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Correspondence to Saida Lahbib.

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Ethical standards

All procedures performed in this study were approved by the Institute Pasteur of Tunis ethics committee (Reference: 2016/17/I/LR11IPT05) and were in accordance with the Helsinki Declaration and its later amendments or comparable ethical standards.

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The participants to the study provided their written informed consent. Informed consent was obtained from the mother, the legal guardian of the minors involved in the study for their participation.

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Lahbib, S., Trabelsi, M., Dallali, H. et al. Novel MED12 variant in a multiplex Fragile X syndrome family: dual molecular etiology of two X-linked intellectual disabilities with autism in the same family. Mol Biol Rep 46, 4185–4193 (2019). https://doi.org/10.1007/s11033-019-04869-6

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