scholarly journals Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

2020 ◽  
Vol 21 (9) ◽  
pp. 3346 ◽  
Author(s):  
Stefania Scarlino ◽  
Teuta Domi ◽  
Laura Pozzi ◽  
Alessandro Romano ◽  
Giovanni Battista Pipitone ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Rare Variants ◽  
Invasive Mechanical Ventilation ◽  
Progression Rate ◽  
Hereditary Neuropathy ◽  
Gene Variants ◽  
Motor Neuropathy ◽  
Next Generation ◽  
Sporadic Als ◽  
Generation Sequencing

Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2.

HADHA and HADHB gene associated phenotypes - Identification of rare variants in a patient cohort by Next Generation Sequencing

2019 ◽  
Vol 44 ◽  
pp. 14-20 ◽  
Author(s):  
Isabel Diebold ◽  
Ulrike Schön ◽  
Rita Horvath ◽  
Oliver Schwartz ◽  
Elke Holinski-Feder ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Rare Variants ◽  
Next Generation ◽  
Patient Cohort ◽  
Generation Sequencing

scholarly journals NEXT GENERATION SEQUENCING SHOULD BE PROPOSED TO EVERY WOMAN WITH “IDIOPATHIC” PREMATURE OVARIAN INSUFFICIENCY

2021 ◽  
Author(s):  
S Eskenazi ◽  
A Bachelot ◽  
J Hugon-Rodin ◽  
G Plu-Bureau ◽  
A Gompel ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Age At Onset ◽  
Ethnic Origin ◽  
Primary Objective ◽  
Primary Amenorrhea ◽  
Gene Variants ◽  
Next Generation ◽  
Ovarian Insufficiency ◽  
History Of ◽  
Generation Sequencing

Abstract Introduction Primary ovarian insufficiency (POI) affects 1% of women under 40 years old. POI is idiopathic in more than 70% of cases. Though many candidate genes have been identified in recent years, the prevalence and pathogenicity of abnormalities are still difficult to establish. Objectives Our primary objective was to evaluate the prevalence of gene variations in a large prospective multicentric POI cohort. Our secondary objective was to evaluate the correlation between phenotype and genotype. Patients and Methods Two hundred and sixty-nine well-phenotyped POI patients were screened for variants of 18 known POI genes (BMP15, DMC1, EIF2S2, FIGLA, FOXL2, FSHR, GDF9, GPR3, HFM1, LHX8, MSH5, NOBOX, NR5A1, PGRMC1, STAG3, XPNPEP2, BHLB and FSHB) by next generation sequencing (NGS). Abnormalities were classified as “variant” or “variant of unknown signification” (VUS) according to available functional tests or algorithms (SIFT, Polyphen-2, MutationTaster). Results One hundred and two patients (38%) were identified as having at least 1 genetic abnormality. Sixty-seven patients (25%) presented at least 1 variant. Forty eight patients presented at least 1 VUS (18%). Thirteen patients (5%) had combined abnormalities. NOBOX variants were the most common gene variants involved in POI (9%). Interestingly, we saw no significant differences in the previous family history of POI, ethnic origin, age at onset of POI, primary amenorrhea or secondary menstrual disturbances between the different genotypes. Conclusion In our study, a high percentage of patients presented gene variants detected by NGS analysis (38%). Every POI patient should undergo NGS analysis to improve medical cares of the patients.

scholarly journals ARIEL and AMELIA: Testing for an Accumulation of Rare Variants Using Next-Generation Sequencing Data

2012 ◽  
Vol 73 (2) ◽  
pp. 84-94 ◽  
Author(s):  
Jennifer L. Asimit ◽  
Aaron G. Day-Williams ◽  
Andrew P. Morris ◽  
Eleftheria Zeggini
Keyword(s):  
Next Generation Sequencing ◽  
Rare Variants ◽  
Next Generation Sequencing Data ◽  
Next Generation ◽  
Sequencing Data ◽  
Generation Sequencing

Identification of Rare Variants in Parkinson Disease Using Next-Generation Sequencing (S22.007)

Neurology ◽  
2012 ◽  
Vol 78 (Meeting Abstracts 1) ◽  
pp. S22.007-S22.007
Author(s):  
J. Vance ◽  
G. Bademci ◽  
K. Nuytemans ◽  
G. Beecham ◽  
Y. Edwards ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Parkinson Disease ◽  
Rare Variants ◽  
Next Generation ◽  
Generation Sequencing

scholarly journals Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation

BMJ Open ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. e021632 ◽  
Author(s):  
Juliette Bacquet ◽  
Tanya Stojkovic ◽  
Amandine Boyer ◽  
Nathalie Martini ◽  
Frédérique Audic ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Sanger Sequencing ◽  
Diagnostic Yield ◽  
Motor Neuropathy ◽  
Peripheral Neuropathies ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Generation Sequencing

PurposeInherited peripheral neuropathies (IPN) represent a large heterogenous group of hereditary diseases with more than 100 causative genes reported to date. In this context, targeted next-generation sequencing (NGS) offers the opportunity to screen all these genes with high efficiency in order to unravel the genetic basis of the disease. Here, we compare the diagnostic yield of targeted NGS with our previous gene by gene Sanger sequencing strategy. We also describe several novel likely pathogenic variants.Design and participantsWe have completed the targeted NGS of 81 IPN genes in a cohort of 123 unrelated patients affected with diverse forms of IPNs, mostly Charcot-Marie-Tooth disease (CMT): 23% CMT1, 52% CMT2, 9% distal hereditary motor neuropathy, 7% hereditary sensory and autonomic neuropathy and 6.5% intermediate CMT.ResultsWe have solved the molecular diagnosis in 49 of 123 patients (~40%). Among the identified variants, 26 variants were already reported in the literature. In our cohort, the most frequently mutated genes are respectively:MFN2,SH3TC2,GDAP1,NEFL,GAN,KIF5AandAARS. Panel-based NGS was more efficient in familial cases than in sporadic cases (diagnostic yield 49%vs19%, respectively). NGS-based search for copy number variations, allowed the identification of three duplications in three patients and raised the diagnostic yield to 41%. This yield is two times higher than the one obtained previously by gene Sanger sequencing screening. The impact of panel-based NGS screening is particularly important for demyelinating CMT (CMT1) subtypes, for which the success rate reached 87% (36% only for axonal CMT2).ConclusionNGS allowed to identify causal mutations in a shorter and cost-effective time. Actually, targeted NGS is a well-suited strategy for efficient molecular diagnosis of IPNs. However, NGS leads to the identification of numerous variants of unknown significance, which interpretation requires interdisciplinary collaborations between molecular geneticists, clinicians and (neuro)pathologists.

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