Analysis of the GCG repeat length in NIPA1 gene in C9orf72-mediated ALS in a large Italian ALS cohort

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons. The hexanucleotide repeatexpansioninC9orf72gene(C9orf72-HRE)isthemostfrequentgeneticcauseofALS.SincemanyALSpedigreesshowed incomplete penetrance, several genes have been analyzed as possible modifiers. Length of the GCG repeat tract in NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) gene has been recently investigated as a possible modifier factor for C9orf72HRE patientswith contrasting findings.To disclosethe possiblerole ofNIPA1GCG repeatlengthasmodifierofthedisease risk inC9orf72-HREcarriers,weanalyzedalargecohortof532ItalianALScasesenrichedinC9orf72-HREcarriers(172cases)and 483Italiancontrols.Thissamplesizeispowered(92%power,p=0.05)toreplicatethemodifiereffectobservedinliterature.We didnotobservehigherfrequencyofNIPA1longalleles(>8GCG)inC9orf72-HREcarriers(3.5%)comparedwithC9orf72-HRE negativepatients(4.1%)andhealthycontrols(5%).Forthelattercomparison,wemeta-analyzedourdatawithcurrentlyavailable literature data, and no statistically significant effect was observed (p=0.118). In conclusion, we did not confirm a role ofNIPA1 repeat length as a modifier of the C9orf72 ALS disease risk.