Abstract:The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173… Show more
“…However, these genes still await further evidences to confirm their role. Furthermore, a more recent study [ 127 ] rejected the assumption that de novo variants result in a significant portion of ALS cases.…”
Section: Applying the Acmg Standards And Guidelines For The Interpmentioning
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.
“…However, these genes still await further evidences to confirm their role. Furthermore, a more recent study [ 127 ] rejected the assumption that de novo variants result in a significant portion of ALS cases.…”
Section: Applying the Acmg Standards And Guidelines For The Interpmentioning
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.
“…In vitro functional evidenceSteinberg et al 2015 [162]Amyotrophic lateral sclerosisSporadic ALS, no history of ALS, even if an ALS associated mutation was found in a known gene46.1 years(26–59)44 c WES (Roche NimbleGen SeqCap EZ Human Exome Library kits, Illumina)0.39Functional gene annotation meta-analysis with Chesi et al (DAVID): enrichment in genes related to transcription regulation CHRM1? Hit twice (Chesi et al [37] + Steinberg et al [162]) no functional analysesVan Doormaal et al 2017 [173]Amyotrophic lateral sclerosisSporadic ALS, prescreening of C9ORF72 ± SOD1, FUS, and TARDBP NA82 d WES (Roche NimbleGen SeqCap EZ Human Exome Library kits, Illumina, n = 61) or WGS (Complete Genomics, n = 21)0.84Functional gene annotation (DAVID), protein–protein interactions (DAPPLE), meta-analysis with Steinberg et al [162] and Chesi et al [37]: enrichment in phosphoproteins, no increased interactionNone a Including one proband with a PSEN1 DNM and one proband with an APP de novo duplication b Including 20 quads (trios + one unaffected sib pair)—one trio was removed after quality assessment c Including 4 probands with a pathogenic mutation in a known gene, inherited from an asymptomatic parent d Including 1 proband with a pathogenic C9ORF72 repeat expansion, inherited from an asymptomatic parent…”
Section: De Novo Mutations In Known Autosomal-dominant Genesmentioning
confidence: 99%
“…This study design was originally applied to sporadic early-onset neurodevelopmental disorders and revealed a high genetic heterogeneity with many different genes affected by DNMs [42, 44, 69]. Although the application of the trio study design to sporadic AOND is limited by the access to parental biological samples, recent successful applications were published on Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) [37, 58, 84, 148, 162, 173]. Fig.…”
The genetic underpinnings of the most common adult-onset neurodegenerative disorders (AOND) are complex in majority of the cases. In some families, however, the disease can be inherited in a Mendelian fashion as an autosomal-dominant trait. Next to that, patients carrying mutations in the same disease genes have been reported despite a negative family history. Although challenging to demonstrate due to the late onset of the disease in most cases, the occurrence of de novo mutations can explain this sporadic presentation, as demonstrated for severe neurodevelopmental disorders. Exome or genome sequencing of patient-parent trios allows a hypothesis-free study of the role of de novo mutations in AOND and the discovery of novel disease genes. Another hypothesis that may explain a proportion of sporadic AOND cases is the occurrence of a de novo mutation after the fertilization of the oocyte (post-zygotic mutation) or even as a late-somatic mutation, restricted to the brain. Such somatic mutation hypothesis, that can be tested with the use of novel sequencing technologies, is fully compatible with the seeding and spreading mechanisms of the pathological proteins identified in most of these disorders. We review here the current knowledge and future perspectives on de novo mutations in known and novel candidate genes identified in the most common AONDs such as Alzheimer's disease, Parkinson's disease, the frontotemporal lobar degeneration spectrum and Prion disorders. Also, we review the first lessons learned from recent genomic studies of control and diseased brains and the challenges which remain to be addressed.
“…It is difficult to determine with certainty whether DNMs in genes not previously implicated in disease are causal since they may be unique to that individual. Patterns and rates of DNMs in ALS patients do not appear to differ from the general population as was noted in 82 new patient–parent trios when combined with datasets of all previously published ALS trios (173 trios in total) ( van Doormaal et al , 2017 ). In general, these studies suggest that DNMs may account for rare cases of ALS but do not appear to play a major role in disease pathogenesis.…”
The genetic underpinnings of late-onset degenerative disease have typically been determined by screening families for the segregation of genetic variants with the disease trait in affected, but not unaffected, individuals. However, instances of intrafamilial etiological heterogeneity, where pathogenic variants in a culprit gene are not shared among all affected family members, continue to emerge and confound gene-discovery and genetic counseling efforts. Discordant intrafamilial cases lacking a mutation shared by other affected family members are described as disease phenocopies. This description often results in an over-simplified acceptance of an environmental cause of disease in the phenocopy cases, while the role of intrafamilial genetic heterogeneity, shared de novo mutations (DNMs) or epigenetic aberrations in such families is often ignored. On a related note, it is now evident that the same disease-associated variant can be present in individuals exhibiting clinically distinct phenotypes, thereby genetically uniting seemingly unrelated syndromes to form a spectrum of disease. Herein, we discuss the intricacies of determining complex degenerative disease etiology and suggest alternative mechanisms of disease transmission that may account for the apparent missing heritability of disease.
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