Abstract
Intellectual disability (ID) is a genetically heterogeneous neurodevelopmental disorder characterised by significantly impaired intellectual and adaptive functioning. ID is commonly syndromic and associated with developmental, metabolic and/or neurological findings. Autosomal recessive ID (ARID) is a significant component of ID especially in the presence of parental consanguinity. Several ultra rare ARID associated variants in numerous genes specific almost to single families have been identified by unbiased next generation sequencing technologies. However, most of these new candidate ARID genes have not been replicated in new families due to the rarity of associated alleles in this highly heterogeneous condition. To determine the genetic component of ARID in a consanguineous family from Turkey, we have performed SNP-based linkage analysis in the family along with whole exome sequencing (WES) in an affected sibling. Eventually, we have identified a novel pathogenic variant in EEF1D, which has recently been recognised as a novel candidate gene for ARID in a single family. EEF1D encodes a ubiquitously expressed translational elongation factor functioning in the cytoplasm. Herein, we suggest that the loss of function variants exclusively targeting the long EEF1D isoform may explicate the ARID phenotype through the heat shock response pathway, rather than interfering with the canonical translational elongation.
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Acknowledgements
The authors are grateful to the patients and their relatives for their participation in this study. The authors would also like to acknowledge Prof Dr. Akin Iscan for his assistance. This work was supported by the grants of Scientific Research Projects Coordination Unit of Istanbul University, Project Number: 52853 and The Scientific and Technology Research Council of Turkey (TUBITAK) Project Number: 113S331. Biobanking support was given by Istanbul Development Agency (Project Number: TR10/15/YNK/0093). EY and YK have been fellows of TUBITAK Project Number: 113S331. The variants presented in Table 1 have been submitted to ClinVar database (Accession Numbers: SCV000864187, SCV000864186 and SCV000864188).
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Ugur Iseri, S.A., Yucesan, E., Tuncer, F.N. et al. Biallelic loss of EEF1D function links heat shock response pathway to autosomal recessive intellectual disability. J Hum Genet 64, 421–426 (2019). https://doi.org/10.1038/s10038-019-0570-z
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DOI: https://doi.org/10.1038/s10038-019-0570-z
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