Genetic analysis of ALS cases in the isolated island population of Malta

Borg, Rebecca; Wismayer, Maia Farrugia; Bonavia, Karl; Wismayer, Andrew Farrugia; Vella, Malcolm; Vugt, Joke J.F.A. van; Kenna, Brendan; Kenna, Kevin P.; Vassallo, Neville; Veldink, Jan H.; Cauchi, Ruben J.

doi:10.1038/s41431-020-00767-9

Cited by 19 publications

(11 citation statements)

References 66 publications

(88 reference statements)

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“…As similarly argued recently by Borg et al. ( 45 ), identifying such isolates for study has the potential to expand captured rare, community-specific disease variation and aid genetic disease research.…”

Section: Discussionmentioning

confidence: 76%

Revealing the recent demographic history of Europe via haplotype sharing in the UK Biobank

Gilbert

Shanmugam

Cavalleri

2022

Proc. Natl. Acad. Sci. U.S.A.

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Haplotype-based analyses have recently been leveraged to interrogate the fine-scale structure in specific geographic regions, notably in Europe, although an equivalent haplotype-based understanding across the whole of Europe with these tools is lacking. Furthermore, study of identity-by-descent (IBD) sharing in a large sample of haplotypes across Europe would allow a direct comparison between different demographic histories of different regions. The UK Biobank (UKBB) is a population-scale dataset of genotype and phenotype data collected from the United Kingdom, with established sampling of worldwide ancestries. The exact content of these non-UK ancestries is largely uncharacterized, where study could highlight valuable intracontinental ancestry references with deep phenotyping within the UKBB. In this context, we sought to investigate the sample of European ancestry captured in the UKBB. We studied the haplotypes of 5,500 UKBB individuals with a European birthplace; investigated the population structure and demographic history in Europe, showing in parallel the variety of footprints of demographic history in different genetic regions around Europe; and expand knowledge of the genetic landscape of the east and southeast of Europe. Providing an updated map of European genetics, we leverage IBD-segment sharing to explore the extent of population isolation and size across the continent. In addition to building and expanding upon previous knowledge in Europe, our results show the UKBB as a source of diverse ancestries beyond Britain. These worldwide ancestries sampled in the UKBB may complement and inform researchers interested in specific communities or regions not limited to Britain.

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Section: Discussionmentioning

confidence: 76%

Revealing the recent demographic history of Europe via haplotype sharing in the UK Biobank

Gilbert

Shanmugam

Cavalleri

2022

Proc. Natl. Acad. Sci. U.S.A.

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“…This was lower than that in the present study and might be due to the different screening criteria used. In other studies of the genetic spectrum and variability in ALS patients, researchers found several ERBB4 variants, such as p.Met322Lys ( 25 ), Glu69Val, Arg103His ( 26 , 27 ), p.Gly1272Arg, p.His374Gln and p.Met1059Thr, and the p.Gly1272Arg variant was a probable pathogenic variant ( 28 ).…”

Section: Discussionmentioning

confidence: 98%

Analysis of ERBB4 Variants in Amyotrophic Lateral Sclerosis Within a Chinese Cohort

Wang

Liu

et al. 2022

Front. Neurol.

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ERBB4 is related to amyotrophic lateral sclerosis (ALS) in patients with a family history and is thought to cause ALS-19. We screened 448 ALS patients, including 364 sporadic ALS (sALS) and 84 familial ALS (fALS) patients with ERBB4 variants, in a Chinese cohort. In total, 12 missense variants were identified in this study. Of these, 3 (p.Arg106His, p.Gln164Pro, and p.Val212Leu) were absent from the in-house healthy control cohort and population databases and predicted to be likely pathogenic. Genetic burden analysis did not reveal an increase in damaging variants of the ERBB4 gene. We considered that most of the missense variants in ERBB4 were not pathogenic, but certain variants, such as p.Arg106His, p.Gln164Pro, and p.Val212Leu, were likely pathogenic. The phenotype of these three patients carrying ERBB4 variants revealed the typical clinical manifestations of ALS without cognitive dysfunction. We concluded that ERBB4 likely pathogenic variants account for ~0.67% of ALS patients in China. It is necessary to interpret the relationship between the disease and variants carefully for ALS patients with ERBB4 gene variants.

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“…Likewise, allelic interaction may determine a phenotype different than the expected for ATXN2 intermediate alleles in ALS and full CAG expansions in SCA2. This notion, of allelic interaction, is reinforced by appearance of late onset SCA2 resulting from homozygous 31/31CAG, and a case ALS with cognitive decline and 28/28CAG in homozygous state [ 28 , 29 ].…”

Section: Spinocerebellar Ataxia 2 Mutagenesis and Founder Effectsmentioning

confidence: 99%

Ataxin-2 gene: a powerful modulator of neurological disorders

Laffita-Mesa

Paucar

Svenningsson

2021

Current Opinion in Neurology

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Purpose of review To provide an update on the role of Ataxin-2 gene ( ATXN2) in health and neurological diseases. Recent findings There is a growing complexity emerging on the role of ATXN2 and its variants in association with SCA2 and several other neurological diseases. Polymorphisms and intermediate alleles in ATXN2 establish this gene as a powerful modulator of neurological diseases including lethal neurodegenerative conditions such as motor neuron disease, spinocerebellar ataxia 3 (SCA3), and peripheral nerve disease such as familial amyloidosis polyneuropathy. This role is in fact far wider than the previously described for polymorphism in the prion protein ( PRNP ) gene. Positive data from antisense oligo therapy in a murine model of SCA2 suggest that similar approaches may be feasible in humans SCA2 patients. Summary ATXN2 is one of the few genes where a single gene causes several diseases and/or modifies several and disparate neurological disorders. Hence, understanding mutagenesis, genetic variants, and biological functions will help managing SCA2, and several human diseases connected with dysfunctional pathways in the brain, innate immunity, autophagy, cellular, lipid, and RNA metabolism.

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Genetic analysis of ALS cases in the isolated island population of Malta

Cited by 19 publications

References 66 publications

Revealing the recent demographic history of Europe via haplotype sharing in the UK Biobank

Revealing the recent demographic history of Europe via haplotype sharing in the UK Biobank

Analysis of ERBB4 Variants in Amyotrophic Lateral Sclerosis Within a Chinese Cohort

Ataxin-2 gene: a powerful modulator of neurological disorders

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