1 / 21

Unraveling ALS Genetics: Current Insights and Future Trends

Explore the latest in ALS genetics, from human genome basics to discovery approaches and key ALS genes, shedding light on familial and sporadic ALS and the complex landscape of ALS genetics research.

marlenej
Download Presentation

Unraveling ALS Genetics: Current Insights and Future Trends

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Overview of ALS GeneticsParts of what’s known and a glimpse of what’s next… Patrick Dion, Ph.D. Neurology and Neurosurgery McGill University

  2. Human Genome Basics • 3 billions base pairs. • Contains protein-coding and noncoding DNA. • 19,000-20,000 protein-coding genes (2% of the genome). • Exomes refers to the 2% coding DNA share. • Noncoding is associated with regulation of expression, chromosome architecture and epigenetic regulation. • First sequencing draft completed in 2001. • Several thousands genomes have now been sequenced. • Available through various databases (e.g. 1kGP, ExaC, EVS). • Regardless of race we are 99.9% identical at the genome level.

  3. Human Genome Basics • Distinctive markers exist all across the genome. • [Large] RFLP, tandem repeat, Copy Number Variants (CNVs) • [Small] Single nucleotide polymorphisms (SNPs). • SNPs are common variants found in >1% of the population at 1,000 bp across. • When in coding regions SNPs can be synonymous or nonsynonymous. • Distinction between SNPs and single nucleotide variants (SNVs).

  4. Discovery Approaches • Classical linkage analysis • Candidate genes association • Genome Wide Association Study (GWAS) • Use of common variants to identify regions shared by affected. • Whole Exome Sequencing (WES) • Seeks to filter rare coding variants to identify to identify deleterious ones. • No need for controls except when population specific. • Whole Genome Sequencing (WGS) • Seeks to filter all variants (coding and not coding) • WES and WGS data can also be used to conduct association studies using common variants and rare ones (e.g. Minor Allele Frequency < 1%)

  5. Variants filtering of WES and WGS

  6. FALS and SALS • Overall ALS is the most common rare disease (2/100,00). • FALS (familial) • 5-10% of cases of ALS • Primarily autosomal dominant (AD) segregation of definite, probable or possible individuals. • SALS(sporadic) • No family history • Clinically indistinguishable • Except age of onset and sex distribution • This classification should not overshadow the fact that FALS and SALS DO share common genetic causes. • Moreover environmental/stochastic factors can affect genetically susceptible individuals.

  7. Just how many ALS genes are there? • http://alsod.iop.kcl.ac.uk/home.aspx • Updated once a year. • Between the discovery of the first causative gene (SOD1) in 1993 and now,126 genes were “linked” to ALS. • [+] Classify the genes according to phenotype, geographical distribution and method of identification. • [-] Includes > 50% of genes for which associations are either weak and/or were never replicated in independent studies. • Nonetheless a valuable and objective online to use assessment tool to consult about the causal nature of specific variants. • The risk linked to ALS genes can be classified according to multiple factors.

  8. High Risk Genes

  9. Superoxide Dismutase-1 SOD1 [ALS1] • Originally found using Classical linkage analysis and FALS. • Accounts for ~20% of FALS forms (2% of SALS). • >160 mutations identified all over SOD1. • All dominant except for D90A and D96N, recessive in some cases • Some mutations affect survival time: • A4V rapid progression D90A slow progression • Some affect disease onset: • G37R with early onset • Most mutations trigger a shift of the folding equilibrium toward poorly structured SOD monomers. • A great number of mechanisms are proposed to be involved, however, distinguishing cause from effect and identifying the critical processes remains challenging

  10. TAR DNA Binding ProteinTARDBP (TDP-43) [ALS10] • [Candidate gene approach] • In 2008 the gene was screened for mutations as its product was a prominent product of ubiquitinated cytoplasmic inclusions in the CNS tissues of FTD and ALS. • Accounts for ~4% of FALS forms (<1 % of SALS). • > 47 Missense and one truncating variants. • All variants are dominants. • Pathogenic variants are mostly in the C-terminus which is involved in RNA binding and splicing.

  11. Fused in SarcomaFUS[ALS6] • [Candidate gene approach and locus approaches] (2009) • Accounts for ~4% of FALS forms (<1 % of SALS). • Autosomal dominant and recessive. • Age of onset younger (< 40yrs with cases during teens). • Faster progression than TARDBP and SOD1 cases • > 50 Missense and one truncating variants. • All variants are dominants. • Pathogenic variants are mostly in the C-terminus.

  12. Chromosome 9 open reading frame C9orf72[ALS-FTD] • [GWAS and locus approaches] (2011) • Accounts for ~40% of European descent familial ALS-FTD cases (10 % of Asians) and 7% of SALS. • Large intronic repeat expansion (GGGGCC or G4C2). • >30 repeats pathogenic, 15-30 not very pathogenic but recently observed to be with ATXN2 intermediate CAG expansion. • Both gain and loss of functions are under consideration. • Multiple pathogenic avenues.. • RNA foci and sequestration of RNA binding components. • Non-ATG (RAN) translation of repeat derived dipeptide accumulation in the CNS (GR > PR > GA > AP > GP). • Dysregulation of its potential DENN Rab-GEFs activity on membrane trafficking. • Disrupts of nucleocytoplasmic transport of mRNA.

  13. Low Risk Genes

  14. Percentage of ALS genetically explained Nat Neurosci. 2014 Jan; 17(1): 17–23.

  15. New genes 2015 and up * * * * *Aggregation tests termed as burden tests collapse information for multiple genetic variants into a single genetic score and test for association between this score and a trait. A simple approach summarizes genotype information by comparing the number of minor alleles (˂ 1%) across all variants in the sequencing data of multiple cases and controls.

  16. Growing percentage of SALS genetically explained 17 % Nat Neurosci. 2014 Jan; 17(1): 17–23. Neurology 2017;89:226-233

  17. A rapidly increasing number of ALS genes Bettencourt & Houlden, Nat Neuroscience 2015

  18. Rate of ALS gene Discovery >100 ALS genes? C21ORF2 UNC13A MOBP TIA1 SCFD1 ANXA11 CCNF 2017 Rate of new gene discovery has reached a plateau despite increased sequencing efforts

  19. Rate of gene discovery • “Plateau” Stage • Several candidate genes without strong evidence • Functional relevance unknown • Limit reached for current technologies • Require larger cohorts to detect small effect sizes • Deep phenotyping and extreme phenotypes • New directions: • Large consortia (MinE) • Whole genome sequencing • Rare and small structural variants • Epigenetics

  20. Other themes tested for ALS Genetics • Oligogenicity • Possibility that ALS is caused by two (or more) variants concurrently that would not independently cause disease. • Studies have observed patients with multiple mutations in “causal” genes. • e.g. C9orf72 expansion with an OPTN mutation of unknown pathogenicity • Does severity of disease increase with more ALS mutations? • De novo mutations • Mutations can occur in germinal cells, not present in either parent • Sporadic ALS patients have no family history, but could pass new mutations to children? • De novo isnot commonly observed in genetic studies, not a common cause of ALS

  21. Thank you! patrick.a.dion@mcgill.ca

More Related