Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.

Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy

“…Furthermore, copy number variations (CNVs) in ALS have recently been the research focus of [11]. Excluding REs in C9orf72, 17.6% of individuals who were clinically diagnosed with ALS or frontotemporal dementia (FTD) had at least one short expansion tandem repeat (STR) allele [12] reported as pathogenic or intermediate for other NDs such as ATXN1 (spinal cerebellar ataxia type, SCA1), ATXN2 (SCA2), ATXN8 (Ataxin 8, OMIM *613289, SCA8), TBP (TATA box-binding protein OMIM *600075, SCA17), HTT (Huntingtin, OMIM * 613004, Huntington's disease), DMPK (Dystrophia Myotonica Protein Kinase OMIM * 160900, Myotonic Dystrophy 1, DM1), CNBP (Cchc-Type Zinc Finger Nucleic Acid-Binding Protein OMIM * 116955, DM2), and FMR1 (Fragile X Messenger Ribonucleoprotein 1 OMIM * 309550, fragile X disorders) [12][13][14].…”