Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients

We report rare/novel missense variants from 154 Indian ALS patients, identified through targeted sequencing of 25 ALS-associated genes. As pathogenic variants could explain only a small percentage of ALS pathophysiology in our cohort, we investigated the frequency of tolerated and benign novel/rare variants, which could be potentially ALS susceptible. These variants were identified in 5.36% (8/149) of sporadic ALS (sALS) cases; with one novel variant each inERBB4,SETX,DCTN1, andMATR3; four rare variants, one each inPON2 andANG and two different rare variants inSETX. Identified variants were either absent or present at extremely rare frequencies (MAF  <  0.01) in large population databases and were absent in 50 healthy controls sequenced through Sanger method. Furthermore, an oligogenic basis of ALS was observed in three sALS, with co-occurrence of intermediate-length repeat expansions inATXN2 and a rare/novel variant inDCTN1 andSETX genes. Additionally, molecular dynamics and biochemical functional analysis of an angiogenin variant (R21G) identified from our cohort demonstrated loss of ribonucleolytic and nuclear translocation activities. Our findings suggest that rare variants could be potentially pathogenic and functional studies are warranted to decisively establish the pathogenic mechanisms associated with them.
Source: Neurogenetics - Category: Genetics & Stem Cells Source Type: research