Founder effect of the TTTCA repeat insertions in SAMD12 causing BAFME1

Abstract

Benign adult familial myoclonic epilepsy type 1 (BAFME1) in several Japanese and Chinese families has recently been found to be caused by pentanucleotide repeat expansions in SAMD12. We identified a Thai family with six members affected with BAFME. Microsatellite studies suggested a linkage to the BAFME1 region on chromosome 8q24. Subsequently, longread whole-genome sequencing showed the (TTTTA) 446 (TTTCA) 149 in intron 4 of SAMD12 in an affected member. Repeatprimed PCR and long-range PCR revealed that the pentanucleotide repeat expansions segregated with the disease status. Our Thai family is the first non-Japanese and non-Chinese family with BAFME1. SNP array showed that the aberrant repeats had the same haplotype as those previously determined in Japanese and Chinese patients suggesting a common ancestry. The variant is estimated to arise ~12,000 years ago.

Molecular Mechanisms in Pentanucleotide Repeat Diseases

“…Chinese families with FAME1, presenting the configuration of adjacent ATTTT repeats, have also exhibited a shared core haplotype with Japanese pedigrees [ 143 ]. The ATTTC repeat insertion in SAMD12 has been identified in 50 Japanese and 23 Chinese families and, more recently, two pedigrees of Sri Lankan and Indian origin, and one Thai family have been reported [ 143 , 145 , 146 , 147 , 148 , 149 ]. All the affected Asian subjects share a core ancestral haplotype and mutation dating based on the length of this haplotype has estimated that it has arisen 12,000–17,000 years ago [ 148 , 149 ].…”

“…The ATTTC repeat insertion in SAMD12 has been identified in 50 Japanese and 23 Chinese families and, more recently, two pedigrees of Sri Lankan and Indian origin, and one Thai family have been reported [ 143 , 145 , 146 , 147 , 148 , 149 ]. All the affected Asian subjects share a core ancestral haplotype and mutation dating based on the length of this haplotype has estimated that it has arisen 12,000–17,000 years ago [ 148 , 149 ]. The old age of this mutation could account for a larger spread than the currently reported, being important to carry out genetic screens for more than one repeat motif.…”

A novel FAME1 repeat configuration in a European family identified using a combined genomics approach

“…Common ancestral founder effects seem to play a role as individual loci expansions have been only associated with specific populations. 3,8,9 For example, SAMD12 expansions have hitherto only been reported in patients of Japanese, Chinese, Thai, Sri Lanka, and Indian descents. 3,8,9 Genetic testing for FAME is challenging as chromosomal microarray, gene panel sequencing and exome sequencing are likely to miss an intronic repeat expansion.…”

Solution Nuclear Magnetic Resonance Structures of ATTTT and ATTTC Pentanucleotide Repeats Associated with SCA37 and FAMEs

“…SCA37 is genetically caused by an insertion of expanded ATTTC repeats within polymorphic ATTTT repeats in the 5′ untranslated region of the Reelin adapter protein disabled-1 ( DAB1 ) gene, , whereas FAME1, 2, 3, 4, 6, and 7 show a linkage with expansions of endogenous ATTTT repeats and inserted ATTTC repeats in the sterile alpha motif domain containing 12 ( SAMD12 ) gene, ,− StAR-related lipid transfer domain containing 7 ( STARD7 ) gene, membrane-associated ring-CH-type finger 6 ( MARCH6 ) gene, YEATS domain containing 2 ( YEATS2 ) gene, trinucleotide repeat containing adaptor 6A ( TNRC6A ) gene, and rap guanine nucleotide exchange factor 2 ( RAPGEF2 ) gene, , respectively. The pathogenic alleles of SCA37 and FAME1 are unstable through transmission. , Remarkably, the length of ATTTC repeats in SCA37, FAME1 and FAME3 show an inverse correlation with the age of onset. ,, SCA37 and FAMEs remain incurable, and an understanding of the molecular mechanism of their genetic instability may facilitate the development of therapeutic strategies.…”