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. 2024 Dec 16;272(1):64.
doi: 10.1007/s00415-024-12758-7.

Two novel variants in GRN: the relevance of CNV analysis and genetic screening in FTLD patients with a negative family history

Julie F H De Houwer  1 , Elise G P Dopper  1 , Ana Rajicic  1 , Renee van Buuren  1 , Marina Arcaro  2 , Daniela Galimberti  3   2 , Guido J Breedveld  4 , Martina Wilke  4 , Rick van Minkelen  4 , Lize C Jiskoot  1 , John C van Swieten  1 , Laura Donker Kaat #  4 , Harro Seelaar #  5
Affiliations

Two novel variants in GRN: the relevance of CNV analysis and genetic screening in FTLD patients with a negative family history

Julie F H De Houwer et al. J Neurol. .

Abstract

Background: Frontotemporal lobar degeneration (FTLD) is one of the leading causes of early onset dementia. Pathogenic variants in GRN have been reported to cause 5-25% of familial and 5% of sporadic FTLD. Here, we present two novel, likely pathogenic variants in GRN.

Methods: Four patients from four different families underwent whole exome sequencing (WES) with additional copy-number variance (CNV) analysis in a clinical setting. TMEM106B rs1990622 and rs3173615 SNPs and 3'UTR insertion were tested in one presymptomatic carrier. In three probands and one presymptomatic carrier, plasma progranulin (PGRN) levels were measured using a specific ELISA kit. In two probands, neuropathological diagnosis was established using current neuropathological criteria.

Results: Through CNV analysis on WES data, we identified a partial deletion, NM_002087.2 (GRN):c.1179 + 104_1536delinsCTGA, p.(?), in three patients with primary progressive aphasia and/or corticobasal syndrome. Haplotype analysis revealed a shared haplotype block, suggesting that the deletion represents a founder mutation. Additionally, we found a novel, missense variant, NM_002087.2 (GRN):c.23 T > A, p.(Val8Glu), in one proband with a negative family history. The proband's unaffected parent-in their 80 s-carried the same variant, yet was homozygous for the TMEM106B risk haplotype. The pathogenicity of both GRN variants was supported by typical neuropathological features and reduced PGRN levels.

Conclusion: We recommend a thorough genetic screening, including CNV analysis, for both familial and apparent sporadic FTLD patients. Furthermore, the presymptomatic carrier homozygous for the TMEM106B risk haplotype exemplifies the presence of other protective factors that modify disease onset and urges caution in genetic counselling based on the TMEM106B haplotype.

Keywords: CNV analysis; Frontotemporal dementia; Frontotemporal lobar degeneration; GRN; Missense mutation; Progranulin.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare that they have no conflict of interest. The authors did not receive support from any organization for the submitted work. Ethical approval: Studies involving human participants were reviewed and approved by the Medical Ethics Committees of the Erasmus University Medical Centre. The participants provided their written informed consent to participate in this study. Additional written informed consent was obtained for the publication of this study.

Figures

Fig. 1
Fig. 1
T1-weighted and T2 FLAIR MRI of the probands of family 1–4. a: family 1, III:1; b: family 2, III:1; c: family 3, III:1; d: family 4, III:1. Upper panel: T1-weighted MRI images of atrophy patterns. Lower panel: T2 FLAIR MRI images of white matter hyperintensities
Fig. 2
Fig. 2
Pedigree of family 1–4. a: family 1; b: family 2; b: family 3; d: family 4. Filled black symbols represent affected individuals. Deceased individuals are marked by a diagonal line. Numbers within the symbols represent additional unaffected relatives. Sex is masked for anonymity. Additional information underneath the symbols are the individual ID, clinical diagnosis, and age at death, respectively. Individuals who are known carriers are marked by + . Black arrow heads denote probands. Abbreviations: lvPPA = logopenic variant primary progressive aphasia; Dementia NOS = dementia not otherwise specified; bvFTD = behavioural variant frontotemporal dementia; AD = Alzheimer’s dementia; CBS = corticobasal syndrome; nfvPPA = non-fluent variant primary progressive aphasia; Figure was created using Biorender.com
Fig. 2
Fig. 2
Pedigree of family 1–4. a: family 1; b: family 2; b: family 3; d: family 4. Filled black symbols represent affected individuals. Deceased individuals are marked by a diagonal line. Numbers within the symbols represent additional unaffected relatives. Sex is masked for anonymity. Additional information underneath the symbols are the individual ID, clinical diagnosis, and age at death, respectively. Individuals who are known carriers are marked by + . Black arrow heads denote probands. Abbreviations: lvPPA = logopenic variant primary progressive aphasia; Dementia NOS = dementia not otherwise specified; bvFTD = behavioural variant frontotemporal dementia; AD = Alzheimer’s dementia; CBS = corticobasal syndrome; nfvPPA = non-fluent variant primary progressive aphasia; Figure was created using Biorender.com
Fig. 3
Fig. 3
Immunohistochemistry pTDP43 of the proband of family 1 (III:1). Grey matter of frontal cortex (a, b) with black arrow heads pointing to pTDP-43 immunoreactive short dystrophic neurites, white arrow heads to neuronal cytoplasmic inclusions, and grey matter of temporal cortex (c, d) with grey arrow pointing to lentiform neuronal intranuclear inclusion. Scale bars indicate 50 µm. Figure was created using QuPath and ImageJ
See this image and copyright information in PMC

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