TY - JOUR
T1 - Genetic analysis of ALS cases in the isolated island population of Malta
AU - Borg, Rebecca
AU - Farrugia Wismayer, Maia
AU - Bonavia, Karl
AU - Farrugia Wismayer, Andrew
AU - Vella, Malcolm
AU - van Vugt, Joke J F A
AU - Kenna, Brendan J
AU - Kenna, Kevin P
AU - Vassallo, Neville
AU - Veldink, Jan H
AU - Cauchi, Ruben J
N1 - Funding Information:
Funding This work was supported by the University of Malta Research Excellence Fund to RJC, and the Malta Council for Science & Technology Internationalisation Partnership Award to RJC. RB was supported by an EMBO short-term fellowship and by a Bjorn Formosa Scholarship for Advanced Research into ALS/MND funded by the non-profit organisation, ALS Malta Foundation, facilitated by the Research Trust (RIDT) of the University of Malta. ML was supported by an Endeavour Scholarship (Malta), part-financed by the EU—European Social Fund under Operational Programme II—Cohesion Policy 2014–2020, “Investing in human capital to create more opportunities and promote the well-being of society”.
Publisher Copyright:
© 2020, The Author(s).
PY - 2021/4
Y1 - 2021/4
N2 - Genetic isolates are compelling tools for mapping genes of inherited disorders. The archipelago of Malta, a sovereign microstate in the south of Europe is home to a geographically and culturally isolated population. Here, we investigate the epidemiology and genetic profile of Maltese patients with amyotrophic lateral sclerosis (ALS), identified throughout a 2-year window. Cases were largely male (66.7%) with a predominant spinal onset of symptoms (70.8%). Disease onset occurred around mid-age (median age: 64 years, men; 59.5 years, female); 12.5% had familial ALS (fALS). Annual incidence rate was 2.48 (95% CI 1.59-3.68) per 100,000 person-years. Male-to-female incidence ratio was 1.93:1. Prevalence was 3.44 (95% CI 2.01-5.52) cases per 100,000 inhabitants on 31st December 2018. Whole-genome sequencing allowed us to determine rare DNA variants that change the protein-coding sequence of ALS-associated genes. Interestingly, the Maltese ALS patient cohort was found to be negative for deleterious variants in C9orf72, SOD1, TARDBP or FUS genes, which are the most commonly mutated ALS genes globally. Nonetheless, ALS-associated repeat expansions were identified in ATXN2 and NIPA1. Variants predicted to be damaging were also detected in ALS2, DAO, DCTN1, ERBB4, SETX, SCFD1 and SPG11. A total of 40% of patients with sporadic ALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene, whilst the genetic cause of two thirds of fALS cases could not be pinpointed to known ALS genes or risk loci. This warrants further studies to elucidate novel genes that cause ALS in this unique population isolate.
AB - Genetic isolates are compelling tools for mapping genes of inherited disorders. The archipelago of Malta, a sovereign microstate in the south of Europe is home to a geographically and culturally isolated population. Here, we investigate the epidemiology and genetic profile of Maltese patients with amyotrophic lateral sclerosis (ALS), identified throughout a 2-year window. Cases were largely male (66.7%) with a predominant spinal onset of symptoms (70.8%). Disease onset occurred around mid-age (median age: 64 years, men; 59.5 years, female); 12.5% had familial ALS (fALS). Annual incidence rate was 2.48 (95% CI 1.59-3.68) per 100,000 person-years. Male-to-female incidence ratio was 1.93:1. Prevalence was 3.44 (95% CI 2.01-5.52) cases per 100,000 inhabitants on 31st December 2018. Whole-genome sequencing allowed us to determine rare DNA variants that change the protein-coding sequence of ALS-associated genes. Interestingly, the Maltese ALS patient cohort was found to be negative for deleterious variants in C9orf72, SOD1, TARDBP or FUS genes, which are the most commonly mutated ALS genes globally. Nonetheless, ALS-associated repeat expansions were identified in ATXN2 and NIPA1. Variants predicted to be damaging were also detected in ALS2, DAO, DCTN1, ERBB4, SETX, SCFD1 and SPG11. A total of 40% of patients with sporadic ALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene, whilst the genetic cause of two thirds of fALS cases could not be pinpointed to known ALS genes or risk loci. This warrants further studies to elucidate novel genes that cause ALS in this unique population isolate.
UR - https://www.scopus.com/pages/publications/85098875041
U2 - 10.1038/s41431-020-00767-9
DO - 10.1038/s41431-020-00767-9
M3 - Article
C2 - 33414559
SN - 1018-4813
VL - 29
SP - 604
EP - 614
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 4
ER -