Abstract
Lafora disease (LD) is a severe form of progressive myoclonus epilepsy inherited in an autosomal recessive fashion. It is associated with biallelic pathogenic variations in EPM2A or NHLRC1, which encode laforin and malin, respectively. The disease usually starts with adolescent onset seizures followed by progressive dementia, refractory status epilepticus and eventually death within 10 years of onset. LD is generally accepted as having a homogenous clinical course with no considerable differences between EPM2A or NHLRC1 associated forms. Nevertheless, late-onset and slow progressing forms of the disease have also been reported. Herein, we have performed clinical and genetic analyses of 14 LD patients from 12 different families and identified 8 distinct biallelic variations in these patients. Five of these variations were novel and/or associated with the LD phenotype for the first time. Interestingly, almost half of the cases were homozygous for the rare rs769301934 (NM_198586.3(NHLRC1): c.436 G > A; p.(Asp146Asn)) allele in NHLRC1. A less severe phenotype with an onset at a later age may be the reason for the biased inflation of this variant, which is already present in the human gene pool and can hence arise in the homozygous form in populations with increased parental consanguinity.
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Acknowledgements
The authors are grateful to the patients and their relatives for their participation in this study. This work was supported by the grants of Scientific Research Projects Coordination Unit of Istanbul University (grant reference numbers TDP-2017-25510 and 25323). EY & YK and OO & BS have been fellows of The Scientific and Technology Research Council of Turkey (TUBITAK) projects with number: 113S331 and 214S222, respectively. We also thank to Turkish Academy of Sciences for the 2019 Distinguished Young Scientist Award to SAUI.
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Haryanyan, G., Ozdemir, O., Tutkavul, K. et al. The rare rs769301934 variant in NHLRC1 is a common cause of Lafora disease in Turkey. J Hum Genet 66, 1145–1151 (2021). https://doi.org/10.1038/s10038-021-00944-8
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DOI: https://doi.org/10.1038/s10038-021-00944-8