Objective: To identify the causative mutation in pedigrees with familial cortical myoclonic tremor with epilepsy (FCMTE) type 1.

Background: FCMTE is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (type 1-4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 5p15.31-p15.1, respectively) have been reported, the causative gene has not yet been identified.

Methods: Linkage and haplotype analysis were performed to narrow the candidate region. Whole-genome sequencing data were analyzed using a software tool called ExpansionHunter to detect potential repeat expansions. Long-range PCR and repeat-primed PCR were employed to further investigate the candidate repeat expansion.

Results: Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point LOD scores from 1.64 to 3.77 (LOD scores in 5 pedigrees were > 3.0) in chromosomal region 8q24 (FCMTE1) and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range PCR and repeat-primed PCR, we identified an intronic pentanucleotide (TTTCA)n insertion in SAMD12 gene as the cause, which was co-segregated with the disease among these 11 pedigrees and another 7 pedigrees. Repeat-primed PCR revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats.

Conclusions: We identified the pentanucleotide (TTTCA)n insertion in the intron of SAMD12 gene as the causative mutation of FCMTE1. Similar pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which indicates the similar pathogenic process in FCMTE1. The discovery of the causative mutation of FCMTE1 could shed light on the identification of causative genes for other subtypes. With the development of sequencing techniques and bioinformatic tools, we should pay more attention to the pathogenic repeat expansion in neurodegenerative diseases of unknown molecular etiology.

References: 1. Dolzhenko, E., van Vugt, J., Shaw, R.J., Bekritsky, M.A., van Blitterswijk, M., Narzisi, G., et al. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res 2017; 27: 1895-1903. 2. Seixas, A.I., Loureiro, J.R., Costa, C., Ordonez-Ugalde, A., Marcelino, H., Oliveira, C.L., et al. A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia. Am J Hum Genet 2017; 101: 87-103.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intronic-pentanucleotide-tttca-repeat-insertion-in-samd12-gene-causes-familial-cortical-myoclonic-tremor-with-epilepsy-type-1/