New structural variations responsible for Charcot-Marie-Tooth disease: The first two large KIF5A deletions detected by CovCopCan software

Pyromali, Ioanna; Perani, Alexandre; Nizou, Angélique; Benslimane, Nesrine; Derouault, Paco; Bourthoumieu, Sylvie; Fradin, Mélanie; Solé, Guilhem; Duval, Fanny; Gomes, Constantin; Favreau, Fréderic; Sturtz, Franck; Magdelaine, Corinne; Lia, Anne‐Sophie

doi:10.1016/j.csbj.2021.07.037

Cited by 2 publications

(1 citation statement)

References 31 publications

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“…Additionally, this type of recently developed software is not being employed systematically in routine analysis of NGS data. In order to improve patients’ diagnoses, we perform SV-research analysis in patients suffering from peripheral neuropathies using the CovCopCan software, and so far, we have detected pathogenic SVs in CMT patients [ 23 , 24 ] and in patients suffering from spastic ataxia of Charlevoix-Saguenay [ 17 ]. Moreover, SV research analysis has contributed to improving early diagnosis for patients presenting with inherited peripheral neuropathies [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

The First Large Deletion of ATL3 Identified in a Patient Presenting with a Sensory Polyneuropathy

et al. 2023

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Hereditary sensory neuropathies (HSN) are a heterogenous group of sensory neuropathies. Mutations in ATL3 have been described in patients presenting with hereditary sensory neuropathy IF (HSN1F), a subtype of HSN. Herein, by analyzing targeted-NGS data of a patient presenting with sensory neuropathy symptoms using the CovCopCan bioinformatic tool, we discovered the presence of a deletion of around 3kb in ATL3 from Chr11:63,401,422 to Chr11:63,398,182. This deletion affects ATL3 exons 11 and 12 and could lead to the mutation c.(1036-861_1539+329del), p.(Ala346_Gln513del). In addition, an analysis of the breakpoints’ sequences revealed the presence of Alu transposable elements at the position of the breakpoints, which pointed to a possible erroneous recombination event following a non-allelic-homologous-recombination mechanism in this area. Moreover, electronic microscopy analysis of the patient’s nerve biopsy revealed a severe rarefaction of the myelinated fibers, a demyelinating–remyelinating process, and an abnormal aspect of the endoplasmic reticulum. These findings suggest that this structural variation could potentially be responsible for the HSN symptoms of the patient. Research of structural variations in ATL3 in numerous other patients presenting similar symptoms should be broadly investigated in order to improve patients’ diagnoses.

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Section: Discussionmentioning

confidence: 99%

The First Large Deletion of ATL3 Identified in a Patient Presenting with a Sensory Polyneuropathy

et al. 2023

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From Negative to Positive Diagnosis: Structural Variation Could Be the Second Mutation You Are Looking for in a Recessive Autosomal Gene

Pyromali

Benslimane

Favreau

et al. 2022

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Next-generation sequencing (NGS) allows the detection of plentiful mutations increasing the rate of patients getting a positive diagnosis. However, while single-nucleotide variants (SNVs) or small indels can be easily detected, structural variations (SVs) such as copy number variants (CNVs) are often not researched. In Charcot–Marie–Tooth disease (CMT), the most common hereditary peripheral neuropathy, the PMP22-duplication was the first variation detected. Since then, more than 90 other genes have been associated with CMT, with point mutations or small indels mostly described. Herein, we present a personalized approach we performed to obtain a positive diagnosis of a patient suffering from demyelinating CMT. His NGS data were aligned to the human reference sequence but also studied using the CovCopCan software, designed to detect large CNVs. This approach allowed the detection of only one mutation in SH3TC2, the frequent p.Arg954*, while SH3TC2 is known to be responsible for autosomal recessive demyelinating CMT forms. Interestingly, by modifying the standard CovCopCan use, we detected the second mutation of this patient corresponding to a 922 bp deletion in SH3TC2 (Chr5:148,390,609-Chr5:148,389,687), including only one exon (exon 14). This highlights that SVs, different from PMP22 duplication, can be responsible for peripheral neuropathy and should be searched systematically. This approach could also be employed to improve the diagnosis of all inherited diseases.

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New structural variations responsible for Charcot-Marie-Tooth disease: The first two large KIF5A deletions detected by CovCopCan software

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Cited by 2 publications

References 31 publications

The First Large Deletion of ATL3 Identified in a Patient Presenting with a Sensory Polyneuropathy

The First Large Deletion of ATL3 Identified in a Patient Presenting with a Sensory Polyneuropathy

From Negative to Positive Diagnosis: Structural Variation Could Be the Second Mutation You Are Looking for in a Recessive Autosomal Gene

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