Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1

Familial cortical myoclonic tremor with epilepsy is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (types 1-4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 3q26.32-3q28) have been reported, the causative gene has not yet been identified. Here, we report the genetic study in a cohort of 20 Chinese pedigrees with familial cortical myoclonic tremor with epilepsy. Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point logarithm of the odds (LOD) scores from 1.64 to 3.77 (LOD scores in five pedigrees were >3.0) in chromosomal region 8q24 and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range polymerase chain reaction and repeat-primed polymerase chain reaction, we identified an intronic pentanucleotide (TTTCA)n insertion in the SAMD12 gene as the cause, which co-segregated with the disease among the 11 pedigrees mapped on 8q24 and additional seven unmapped pedigrees. Only two pedigrees did not contain the (TTTCA)n insertion. Repeat-primed polymerase chain reaction revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats. The same pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which suggests the similar pathogenic process in familial cortical myoclonic tremor with epilepsy type 1.