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Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family.

ABSTRACT: Frontotemporal dementia (FTD) is the second-most common young-onset dementia. Variants in the TMEM106B gene have been proposed as modifiers of FTD disease risk, especially in progranulin (GRN) mutation carriers. A patient in their 50s presented to our clinic with behavioral variant FTD (bvFTD). Genetic testing revealed the disease-causing variant c.349 + 1G > C in GRN. Family testing revealed that the mutation was inherited from an asymptomatic parent in their 80s and that the sibling also carries the mutation. Genetic analyses showed that the asymptomatic parent and sibling carry two copies of the protective TMEM106B haplotype (defined as c.554C > G, p.Thr185Ser), whereas the patient is heterozygous. This case report illustrates that combining TMEM106B genotyping with GRN mutation screening may provide more appropriate genetic counseling on disease risk in GRN families. Both the parent and sibling were counseled to have a significantly reduced risk for symptomatic disease. Implementing TMEM106B genotyping may also promote the collection of biosamples for research studies to improve our understanding of the risk-and disease-modifying effect of this important modifier gene.

SUBMITTER: Perneel J

PROVIDER: S-EPMC10106611 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family.

Perneel Jolien J Manoochehri Masood M Huey Edward D ED Rademakers Rosa R Goldman Jill J

Frontiers in neurology 20230403

Frontotemporal dementia (FTD) is the second-most common young-onset dementia. Variants in the TMEM106B gene have been proposed as modifiers of FTD disease risk, especially in progranulin (GRN) mutation carriers. A patient in their 50s presented to our clinic with behavioral variant FTD (bvFTD). Genetic testing revealed the disease-causing variant c.349 + 1G > C in GRN. Family testing revealed that the mutation was inherited from an asymptomatic parent in their 80s and that t ...[more]

PMID: 37077569

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Project description:Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.

Dataset Information

Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family.

Publications

Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family.

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