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

Abstract

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.

TTTCA repeat expansion causes familial cortical myoclonic tremor with epilepsy

“…Long‐read sequencing might be another choice instead of southern blot analysis. Additionally, as pointed out previously , it was found that TTTCA insertions may, or may not, be accompanied by abnormal TTTTA expansions. In our patients, TTTTA expansions were not detected in family 3 holding the mutation in RAPGEF2 .…”

“…The pentanucleotide repeats showed intergenerational instability and inversely correlated with age at onset of myoclonic tremor and epilepsy in our patient families, just as in spinocerebellar ataxia 31 (SCA31) . A founder effect between FCMTE1 pedigrees across China and Japan was indicated as a core haplotype containing the (TTTCA)n insertion was found to be shared among them . It should be noted that there is a chance that some repeat expansions could be missed by the current RP‐PCR strategy, e.g.…”

Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

“…In this type of dynamic mutation, the complex repeat without the insertion is not pathological (Seixas et al, 2017). In addition to SCA37, this type of mutation underlies SCA31 (MIM# 117210) and benign adult familial myoclonic epilepsy (BAFME1; MIM# 601068, 6 and 7) (Cen et al, 2018;Ishiura et al, 2018;Sato et al, 2009;Seixas et al, 2017).…”

“…The pentanucleotide repeat associated with SCA37 is located in the middle poly-A of an AluJb element (Seixas et al, 2017). Several other disease-causing repeats are in middle or 3 ′ -end poly-A regions of Alu elements, such as the repeat expansions responsible for FRDA, DM2, and SCA10, as well as the pentanucleotide repeat insertions associated with SCA31 and two types of BAFME (Cen et al, 2018;Chauhan, Dash, Grover, Rajamani, & Mukerji, 2002;Clark et al, 2004;Ishiura et al, 2018;Kurosaki et al, 2012;Kurosaki, Matsuura, Ohno, & Ueda, 2009;Montermini et al, 1997;Sato et al, 2009).…”

Intronic (TTTGA)n insertion in SAMD12 also causes familial cortical myoclonic tremor with epilepsy

“…This (TTTGA) n insertion was not detected using RP‐PCR or Sanger sequencing in 2 other FCMTE pedigrees without (TTTCA) n insertion. No (TTTGA) n insertion was detected in 238 Chinese controls using RP‐PCR or Sanger sequencing, although 24 controls with (TTTTA) n expansion were detected . Thus, similar to the previously reported (TTTCA) n insertion, the repeat expansion structure was speculated to be as follows: The (TTTGA) n insertion occurred between the (TTTTA) n expansion and its 3’ adjacent Alu element (Fig.…”