Genotype Phenotype characterisation, Imaging profile and novel genetic mutations from a large cohort of Frontotemporal Dementia from India

Abstract

AbstractBackgroundDegenerative dementia like Frontotemporal dementia (FTD) are complex heterogeneous disorders with variable phenotypes, patterns of atrophy and pathogenicity. Advanced genetic studies from India are sparse and earlier techniques mostly reported negative results. Current study aims to evaluate the clinical, radiological and genetic profile of FTD/FTD overlap syndromes, to perform whole exome sequencing and to explore genotype phenotype correlations.MethodSubjects with dementia fulfilling standard criteria’s for FTD/FTD Overlap and AD were recruited from Dept. of Neurology, NIMHANS, India Demography, pedigree analysis, clinical, cognitive and neuropsychological evaluation and blood sampling for genetic analysis by next generation sequencing and MRI as per ADNI protocol were performed. RT‐PCR was done for analysing c9orf.Results133 FTD/FTD overlap were recruited. Mean age at onset was 56 ± 9.8 years in FTD There were 87 men and 75 women. Family history was documented in 43%. 42% had family history in first degree relatives, 11% had history in second degree and 4% in third degree relatives. Mean ACE scores were 43.8± 24.7. Frontotemporal atrophy was noted in 90% in MRI (n = 115). 41% had Grade 1 (mild) global cortical atrophy score .MRI also revealed characteristic features like diffusion restriction, white matter lesions (CSF1R) basal ganglia calcification with bone cysts(TYROBP) and Corpus callosal atrophy(TREM2)11 novel gene mutations including one each of CSF1R, TREM2, TYROBP, SQSTM1, GRN, MAPT, PSEN2 and four cases of C9orf were detected (Pathogenic in 11 and Variant of unknown significance in 26), out of the 100 samples sequenced and analysed (ACMG guidelines). VUS like GBA, PANK2, PLAG26, PRNP, LRRK2, DCNT etc. were also identified. Sanger validation confirmed the pathogenic mutations. Novel variants of CSF1R, TREM2 and TYROBP, primary microgliopathy as causative genes are being first time described from India. SQSTM1 presented as bvFTD without ALS overlap, GRN as non‐fluent aphasia, MAPT as bvFTD and PSEN2 as non‐fluent PPA and two patients with C9orf presented as bvFTD and two others as FTD‐ALS.ConclusionGenotype‐phenotype correlations along with neuroimaging and pedigree analysis has aided in early diagnosis, prognostication and novel and unique genetics causes shedding light on underlying FTD mechanism from our cohort.