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Targeted next-generation sequencing study in familial ALS-FTD Portuguese patients negative for C9orf72 HRE

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with clinical and etiological heterogeneity and a complex genetic contribution. Clinical, neuropathological, and genetic evidence revealed that ALS and frontotemporal dementia (FTD) are in part of a single disease continuum. Genetic causes have been identified in sporadic (SALS) and familial patients (FALS) and the recurrent genetic factor underlying ALS and FTD is the C9orf72 hexanucleotide repeat expansion (HRE). However, in our population, the concomitance of ALS and FTD cannot be explained by C9orf72 HRE in many FALS and SALS cases. Our aim is to further understand the genetic basis of ALS in Portuguese patients. 34 patients with FALS or SALS-FTD, negative for C9orf72 HRE, were screened for rare variants in a panel of 29 relevant genes by next-generation sequencing. We detected 15 variants in 11 genes, one classified as pathogenic in TARDBP, two as likely pathogenic in TARDBP and PRPH, and the others as variants of unknown significance (VUS). Gene variants, including VUS, were found in 41.2% FALS patients and 40% SALS-FTD. In most patients, no potential pathogenic variants were found. Our results emphasize the need to enhance the efforts to unravel the genetic architecture of ALS-FTD.

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Funding

This project was supported by FTC—Fundação para a Ciência e Tecnologia—through project “Comprehensive evaluation of circulating MicroRNA as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis”—PTDC/MEC-NEU/31195/2017.

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Authors and Affiliations

  1. Instituto de Medicina Molecular and Institute of Physiology, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1648-028, Lisbon, Portugal

    Marta Gromicho, Ana Catarina Pronto-Laborinho & Mamede de Carvalho

  2. GenoMed-Diagnósticos de Medicina Molecular SA, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    Ana Margarida Coutinho, Rita Raposeiro, Joana Tavares & Diana Antunes

  3. Medical Genetics Department, Hospital de Dona Estefânia, Centro Hospitalar Lisboa Central, Lisbon, Portugal

    Diana Antunes

  4. Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal

    Mamede de Carvalho

Authors
  1. Marta Gromicho
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  2. Ana Margarida Coutinho
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  3. Ana Catarina Pronto-Laborinho
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  4. Rita Raposeiro
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  5. Joana Tavares
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  6. Diana Antunes
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  7. Mamede de Carvalho
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Contributions

Conceptualization, MG and MdC; methodology, ACPL and JT; software, MG and JT; validation, DA; formal analysis, MG, AMC, and RR; data curation, MG, AMC, RR, and DA; writing—original draft preparation, MG; writing—review and editing, MG and MdC; supervision, MdC.

Corresponding author

Correspondence to Marta Gromicho.

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The authors declare that they have no conflict of interest.

Ethics approval

This project was approved by the Local Ethics Committee (ID number 215/15). The study conformed to the standards defined in the latest revision of the Declaration of Helsinki. All patients and controls signed a written informed consent. Databases were properly treated for privacy.

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All listed authors have approved the manuscript before submission, including the names and order of authors.

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Gromicho, M., Coutinho, A.M., Pronto-Laborinho, A.C. et al. Targeted next-generation sequencing study in familial ALS-FTD Portuguese patients negative for C9orf72 HRE. J Neurol 267, 3578–3592 (2020). https://doi.org/10.1007/s00415-020-10042-y

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  • DOI: https://doi.org/10.1007/s00415-020-10042-y

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