The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort

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Abstract

A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4 of pedigrees had high family history, 6.5 medium, 15.4 low; 39 were apparent sporadic cases and 26.6 had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74) and decreased in other categories (medium: 15.4; low: 9.7; sporadic: 1.3). Mutation carriers with unknown family history (5.6) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4) in our cohort. An elevated proportion of FTLD patients belonging to "high risk" pedigrees asked for genetic counseling (42); requests decreased according to the estimated family risk (medium: 26.9; low: 17.7; sporadic: 5.1). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.

Original languageEnglish
Pages (from-to)753-760
Number of pages8
JournalJournal of Alzheimer's Disease
Volume61
Issue number2
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Frontotemporal Lobar Degeneration
Pedigree
Italy
Mutation Rate
Genetic Counseling
Mutation
Genetic Testing
Age of Onset
Genes
Phenotype

Keywords

  • C9orf72
  • frontotemporal lobar degeneration
  • genetic counseling
  • GRN
  • MAPT
  • mutation
  • pedigree

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

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title = "The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort",
abstract = "A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4 of pedigrees had high family history, 6.5 medium, 15.4 low; 39 were apparent sporadic cases and 26.6 had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74) and decreased in other categories (medium: 15.4; low: 9.7; sporadic: 1.3). Mutation carriers with unknown family history (5.6) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4) in our cohort. An elevated proportion of FTLD patients belonging to {"}high risk{"} pedigrees asked for genetic counseling (42); requests decreased according to the estimated family risk (medium: 26.9; low: 17.7; sporadic: 5.1). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.",
keywords = "C9orf72, frontotemporal lobar degeneration, genetic counseling, GRN, MAPT, mutation, pedigree",
author = "Silvia Fostinelli and Miriam Ciani and Roberta Zanardini and Orazio Zanetti and Giuliano Binetti and Roberta Ghidoni and Luisa Benussi",
year = "2017",
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T1 - The Heritability of Frontotemporal Lobar Degeneration

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AU - Fostinelli, Silvia

AU - Ciani, Miriam

AU - Zanardini, Roberta

AU - Zanetti, Orazio

AU - Binetti, Giuliano

AU - Ghidoni, Roberta

AU - Benussi, Luisa

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N2 - A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4 of pedigrees had high family history, 6.5 medium, 15.4 low; 39 were apparent sporadic cases and 26.6 had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74) and decreased in other categories (medium: 15.4; low: 9.7; sporadic: 1.3). Mutation carriers with unknown family history (5.6) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4) in our cohort. An elevated proportion of FTLD patients belonging to "high risk" pedigrees asked for genetic counseling (42); requests decreased according to the estimated family risk (medium: 26.9; low: 17.7; sporadic: 5.1). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.

AB - A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4 of pedigrees had high family history, 6.5 medium, 15.4 low; 39 were apparent sporadic cases and 26.6 had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74) and decreased in other categories (medium: 15.4; low: 9.7; sporadic: 1.3). Mutation carriers with unknown family history (5.6) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4) in our cohort. An elevated proportion of FTLD patients belonging to "high risk" pedigrees asked for genetic counseling (42); requests decreased according to the estimated family risk (medium: 26.9; low: 17.7; sporadic: 5.1). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.

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