NOTCH2NLC GGC repeats are not expanded in Italian amyotrophic lateral sclerosis patients

Abstract

Repeat expansions in genes other than C9orf72 and ATXN2 have been recently associated with Amyotrophic Lateral Sclerosis (ALS). Indeed, an abnormal number of GGC repeats in NOTCH2NLC has been recently reported in 0.7% of sporadic ALS patients from mainland China. This finding was not confirmed in an ALS cohort of subjects from Taiwan. As the involvement of expanded NOTCH2NLC alleles in ALS is debated, we addressed this point by evaluating NOTCH2NLC repeat expansions in an Italian cohort of ALS patients. A screening analysis of NOTCH2NLC GGC repeats was performed by repeat-primed polymerase chain reaction (RP-PCR) in a cohort of 385 probable/definite ALS Italian patients. Mean age at onset was 60.5 years (SD 13.7), and 60.9% were males. Sporadic cases were 357 (92.7%), and most patients had a spinal onset (71.8%). None of our patients showed the typical sawtooth tail pattern on RP-PCR, thus excluding abnormal repeat expansion in NOTCH2NLC. Overall, we suggest that NOTCH2NLC expanded alleles might be absent or at least extremely rare in ALS Italian patients. Further investigations in larger cohorts with different ethnic backgrounds are required to support the involvement of NOTCH2NLC in ALS.

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

“…While the details and frequencies of these intermediate repeats remain undisclosed, their absence in healthy controls hints at a potential association with neurodegenerative diseases, including ALS and dementia [24,42,43]. More recently, Manini and collaborators investigated an Italian cohort of ALS patients reporting the absence of pathological expansion [22]. In line with this, our study confirms this finding in our samples.…”

“…Otherwise, other studies have already analyzed the probable correlation between REs in the NOTCH2NLC (Notch2 N-Terminal-Like C, OMIM * 618025) gene and ALS [21,22]. In particular, trinucleotide expansions of this gene have been classified as pathogenetic for NIID (neuronal intranuclear inclusion disease), which shows clinical overlaps with ALS [1, 23,24].…”