JNNP: Family clustering effect in genetic screening of 235 French ALS families

Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease in adults.
neurodegenerative disease is characterized by sexual death of upper and lower motor neurons in the myeloid and spinal cord regions.
life after the onset of the disease was 36 months.
but after decades of research, pathophysiology is still not fully understood, but it is widely accepted around the world that environmental and genetic factors play a key role in the occurrence of disease.
first described familial amyotrophic lateral sclerosis (FALS) in 1850, but it was not until 1954 that family-form amyotrophic lateral sclerosis was officially accepted.
mutations in the superoxide dismification enzyme 1 (SOD1) gene in FALS were discovered in 1993, and more than 30 ALS-related pathogenic genes have been discovered in the past 30 years.
five variants of these genes are associated with a variety of pathological mechanisms, including neuro-inflammatory, excitable toxicity and defective axon transport, protein stabilization, autophagy, RNA metabolism, and mitochondrial abnormalities.
currently, FALS accounts for 5% to 10% of ALS cases, and four genes (C9orf72, SOD1, TARDBP, FUS) account for about 60% of FALS family and less than 10% of distributed ALS (SALS) cases.
Although the key role of genetics in ALS pathophysiology is widely accepted, many cases remain unspepepted due to the difficulty of determining the genetic mechanisms of a small number of ALS families and the complexity of mapping a clear correlation between genotypes and atypical ALS esotypes.
these complex situations will be studied using predictive tools that integrate esothic and family data and allow for targeted molecular biology screening.
the purpose of this study was to conduct a comprehensive analysis of the epidemiology, esotypes and genotypes of 235 French FALS families to determine whether family aggregation of ALS cases and disease esotypes were directly related to genotypes.
understanding of these relationships will help to develop targeted diagnostic methods that accelerate and improve personalized patient care.
recruited 235 white ALS patients with unrelated family cases at 19 AlS centres in France.
for each family, this paper collects the number of ALS cases, parental relationships between generations affected by ALS and other family ALS cases, and the number of men and women with ALS patients.
Taking into account the number of generations affected by ALS, the queue is divided into three subgroups: single generation (for single generation) when disease occurs in one generation, multigeneration (for multiple generations) when disease occurs in three generations.
the following clinical characteristics of all FALS pre-certificaters: date of birth, sex, age of onset, site of onset (refers to the first weak site), date of death or date of last update.
all patients agreed to DNA analysis.
to extract genomic DNA from the blood.
next-generation sequencing (NGS) analysis with all pre-emptors to study the following genomes: ALS2, ANG, CHCHD10, CHMP2B, DAO, DCTN1, DPYSL3, FIG4, FUS, GRN, MAPT, MATR3, NEF H, OPTN, PRPH, PSEN1, PSEN2, SETX, SIGMAR1, SOD1, SPG11, QSTM1, TAF15, TARDBP, TBK1, TREM2, TUBA4A, UBQLN2, VAPB and VCP.
use the GATK tool (V.3.4) to call variants, annotate with ANNOVAR software, and analyze coverage using Samtools (V.1.8).
selected 16 variants with a coverage of at least 30 times, allgene frequencies in 1,000 genome projects, and an accurate database of all populations was excluded.
used a 3130xl gene analyzer (ThermoFisher) to sequence and verify variants identified by NGS through Sanger sequencing.
the sex ratio was 0.93 (113/122), with an average age of 57.6±12.1 years, 69 cases of upper limb (30.3%) and 99 cases of lower extremities (43.4%).
range of 30.0±40.4 months, ranging from 5.0 to 221.0 months (n-149).
147 family (62.5%) included only 2 ALS patients.
125 cases (89 pairs of parents, 36 pairs of siblings) were first-class relatives and 22 cases (6 pairs of cousins, 16 pairs of uncles or grandparents) were second-class relatives.
The remaining 88 families involved 3 affected relatives (20.9 per cent), 4 affected relatives in 17 (7.2 per cent) families, 5 affected relatives in 8 (3.4 per cent) families, 4 6 affected relatives in each (1.7 per cent), 9 and 10 affected relatives in 3 (1.3 per cent) families and 7, 8, 11 and 15 affected relatives in one (0.4 per cent) family.
difference between the age of onset of falsity in two cases and at least three cases of FALS (t-test, p-lt;0.003).
the sex ratio (χ2 test, p-0.10), the site of onset (χ2-test, p-0.34) and the course of the disease (count rank test, p-0.66) were not different.
found abnormal amplification of G4C2 in the C9orf72 gene and/or genetic variation in another gene in 149 (63.4%) family (known FALS genes).
the remaining 86 cases (36.6%) of the FALS gene unknown group pre-empirators C9orf72 and NGS analysis was normal.
59 cases of NGS-identified variants, 34 cases of uncertain significant variation (VUS) and 39 cases of neutral variation (N).
of all candidate variants, only 11 of the 31 genes were observed to have 50 different harmful variants (online supplement table 1).
98 (41.7 per cent) of the 235 households in the united States were associated with C9orf72.
30 cases (12.8%) of the pre-certificates showed SOD1 mutations, 9 cases (3.8%) of the pre-certificates showed TARDBP mutations, and 7 cases (3.0%) of the pre-certificates showed FUS mutations.
the remaining mutation tBK1 (R440fs, E476fs), FIG4 (I41T, S787N), ALS2 (L238F, R1421fs), SETX (L1976F M2017I), DYSPL3 (I255V).
found in two pre-emptors that a mutation of DCTN1 (G601A), PFN1 (M114T) or SPG11 (G2317D) was found in one of the forefaids.
, it is suggested that in familial ALS, attention should be paid to the study of family and clinical esolysis in order to improve the level of molecular diagnosis.
can assume that observations in the ALS family may also be effective in other European and North American countries, and once confirmed, this study will change our clinical practice in FALS gene screening, as family aggregation in ALS cases determines the priority of some genetic analysis.
Corcia P, Camu W, Brulard C, et al Effect of familial clustering in the genetic screening of 235 French AL Families Journal of Neurology, Neurosurgery and Psython Published Online First: 06 January 2021. doi: 10.1136/jnnp-2020-3250 64MedSci Original Source: MedSci Original Copyright Notice: All text, images and audio and video materials on this website that indicate "Source: Mets Medicine" or "Source: MedSci Originals" are copyrighted by Mets Medical, are not authorized, may not be reproduced by any media, website or individual, and must be reproduced with the words "Source: Mets Medicine".
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