The missense p.Trp7Arg mutation in GRN gene leads to progranulin haploinsufficiency

International audienceGRN null mutations are among the main genetic causes of frontotemporal dementia through progranulin haploinsufficiency. Most missense mutations are considered not pathogenic. The p.Trp7Arg substitution is localized within the signal peptide domain and no formal evidence for its pathogenicity has yet been provided. We identified the p.Trp7Arg substitution in 3 carriers with low plasma progranulin levels. This evidences that this missense mutation leads to functional haploinsufficiency and should thus be considered pathogenic. Assessing the pathogenicity of variants of unknown significance has significant implications for clinical practice, genetic counseling, and future therapeutic interventions

FXTAS: new insights and the need for revised diagnostic criteria

Fragile X-associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS

Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Non-amyloid Logopenic Variant

International audienceOBJECTIVE: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with progranulin (GRN) mutations, and study their neuroanatomical correlates. METHODS: PPA patients carrying GRN mutations (PPA-GRN) were selected amongst a national prospective research cohort of 1,696 frontotemporal dementia (FTD) patients, including 235 patients with PPA. All PPA patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and grey matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls, and sporadic PPA patients. RESULTS: Among the overall population of 235 patients, 45 (19%) carried GRN mutations. We studied 32 of these and showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (13, 41%), followed by non-fluent/agrammatic (nfvPPA: 9, 28%) and mixed forms (8, 25%). Semantic variant was rather rare (2, 6%). LvPPA patients, qualified as non-amyloid-lvPPA, presented canonical logopenic deficit. Seven out of 13 had a pure form, six showed subtle additional linguistic deficits not fitting criteria for mixed PPA, hence labelled as "logopenic-spectrum variant". GM atrophy primarily involved left posterior temporal gyrus, mirroring neuroanatomical changes of amyloid-positive-lvPPA. NfvPPA patients presented agrammatism (89%) rather than apraxia of speech (11%). CONCLUSIONS: This study shows that most frequent PPA variant associated with GRN mutations is non-amyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that language network may be affected at different levels. GRN testing is indicated for PPA patients, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

International audienceAbstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications