Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis

McCann, Emma; Henden, Lyndal; Fifita, Jennifer A.; Zhang, Katharine Y.; Grima, Natalie; Bauer, Denis C.; Fat, Sandrine Chan Moi; Twine, Natalie A.; Pamphlett, Roger; Kiernan, Matthew C.; Rowe, Dominic B.; Williams, Kelly L.; Blair, Ian P.

doi:10.1136/jmedgenet-2020-106866

Cited by 64 publications

(76 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It suggests that the pathological process underlying the disease could exist from birth, but the accumulation of variants, toxic effects of proteins, and environmental factors are needed to trigger the disease [ 169 , 170 , 171 ]. Variants in some genes, such as SOD1 and C9orf72 , could have a more severe effect, while multiple variants in other genes with a lower impact are needed to exceed the threshold [ 172 , 173 , 174 , 175 , 176 ].…”

Section: The Complex Genetic Architecture Of Als and The Challengementioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

View full text Add to dashboard Cite

The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS.

show abstract

Section: The Complex Genetic Architecture Of Als and The Challengementioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

View full text Add to dashboard Cite

show abstract

“…Truseq PCR-free whole-genome sequencing (WGS) data from 609 SALS cases were used for genetic analysis (26). Custom UNIX scripts were applied to identify all variants in the SFPQ gene (NM_005066).…”

Section: Sfpq Variant Identificationmentioning

confidence: 99%

SFPQ intron retention, reduced expression and aggregate formation in central nervous system tissue are pathological features of amyotrophic lateral sclerosis

Hogan

Grima

Fifita

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Splicing factor proline and glutamine rich (SFPQ, also known as polypyrimidine tract-binding protein-associated-splicing factor, PSF) is a RNA-DNA binding protein with roles in key cellular pathways such as DNA transcription and repair, RNA processing and paraspeckle formation. Dysregulation of SFPQ is emerging as a common pathological feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Increased retention of SFPQ intron nine and nuclear loss of the protein have been linked to multiple genetic subtypes of ALS. Consequently, SFPQ dysregulation has been hypothesised to be a common pathological feature of this highly heterogeneous disease. Methods: This study provides a comprehensive assessment of SFPQ pathology in large ALS patient cohorts. SFPQ gene expression and intron nine retention were examined in multiple neuroanatomical regions and blood from ALS patients and control individuals using RNA sequencing (RNA-Seq) and quantitative PCR (RT-qPCR). SFPQ protein levels were assessed by immunoblotting of patient and control motor cortex and SFPQ expression pattern was examined by immunofluorescent staining of patient and control spinal cord sections. Finally, whole-genome sequencing data from a large cohort of sporadic ALS patients was analysed for genetic variation in SFPQ. Results: SFPQ intron nine retention was significantly increased in ALS patient motor cortex. Total SFPQ mRNA expression was significantly downregulated in ALS patient motor cortex but not ALS patient blood, indicating tissue specific SFPQ dysregulation. At the protein level, nuclear expression of SFPQ in both control and patient spinal motor neurons was highly variable and nuclear depletion of SFPQ was not a consistent feature in our ALS cohort. However, we did observe SFPQ-positive cytoplasmic ubiquitinated protein aggregates in ALS spinal motor neurons. In addition, our genetic screen of ALS patients identified two novel, and two rare sequence variants in SFPQ not previously reported in ALS. Conclusions: This study shows that dysregulation of SFPQ is a feature of ALS patient central nervous system tissue. These findings confirm SFPQ pathology as a feature of ALS and indicate that investigations into the functional consequences of this pathology will provide insight into the biology of ALS.

show abstract

“…Another recent report from an Australian sporadic ALS cohort found that one-third of patients carried a variant of interest and 7% carried two or more variants, which again was correlated with an earlier age of onset. 11 It has previously been reported that ALS is a six-step process, with genes, environment and time (in the form of ageing) contributing to disease development. 12 It was proposed that individuals with a genetic variant would require fewer steps than those without such variants.…”

Section: Introductionmentioning

confidence: 99%

Value of systematic genetic screening of patients with amyotrophic lateral sclerosis

Shepheard

Parker

Cooper‐Knock

et al. 2021

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

ObjectiveThe clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care.MethodsWe performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases.Results21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074).ConclusionsRoutine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.

show abstract

Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis

Cited by 64 publications

References 41 publications

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

SFPQ intron retention, reduced expression and aggregate formation in central nervous system tissue are pathological features of amyotrophic lateral sclerosis

Value of systematic genetic screening of patients with amyotrophic lateral sclerosis

Contact Info

Product

Resources

About