Case Report: Early-Onset Behavioral Variant Frontotemporal Dementia in Patient With Retrotransposed Full-Length Transcript of Matrin-3 Variant 5

Abstract

Frontotemporal dementia (FTD) rarely occurs in individuals under the age of 30, and genetic causes of early-onset FTD are largely unknown. The current report follows a 27 year-old patient with no significant past medical history presenting with two years of progressive changes in behavior, rushed speech, verbal aggression, and social withdrawal. MRI and FDG-PET imaging of the brain revealed changes maximally in the frontal and temporal lobes, which along with the clinical features, are consistent with behavioral variant FTD. Next generation sequencing of a panel of 28 genes associated with dementia and amyotrophic lateral sclerosis (ALS) initially revealed a duplication of exon 15 in Matrin-3 (MATR3). Whole genome sequencing determined that this genetic anomaly was, in fact, a sequence corresponding with full-length MATR3 variant 5 inserted into chromosome 12, indicating retrotransposition from a messenger RNA intermediate. To our knowledge, this is a novel mutation of MATR3, as the majority of mutations in MATR3 linked to FTD-ALS are point mutations. Genomic DNA analysis revealed that this mutation is also present in one unaffected first-degree relative and one unaffected second-degree relative. This suggests that the mutation is either a disease-causing mutation with incomplete penetrance, which has been observed in heritable FTD, or a benign variant. Retrotransposons are not often implicated in neurodegenerative diseases; thus, it is crucial to clarify the potential role of this MATR3 variant 5 retrotransposition in early-onset FTD.

Keywords: Matrin 3; case report; frontotemporal dementia; retrotransposons; whole genome sequencing.

Figure 1

Brain MR images at age 27 (A) and 19 months later (B), with axial fluid attenuation inversion recovery (FLAIR) images (top and middle rows) and coronal T1-weighted images (bottom row). Note progression of the bilateral medial frontal, anterior temporal, and caudate head atrophy with the associated ventricular enlargement on the axial FLAIR images. The orbitofrontal as well as dorsomedial, anterior temporal, and caudate head atrophy are obvious on the coronal images. Images are in standard radiology orientation.

Figure 2

Statistical z-score maps of brain FDG-PET at age 27, with the degree of hypometabolism reflected by the color bar on the left; dark blue is within normal limits and red is maximally abnormal. Note the degree of hypometabolism is severe in the orbitofrontal and caudate regions, moderate in the frontotemporal regions (left slightly more so than right), and mild to moderate in the parietal and posterior cingulate regions.

Figure 3

Targeted PCR confirmed the MATR3V5 insertion in chromosome 12. (A) Diagram of chromosome 12 insertion site of MATR3 variant 5 and primers used for PCR. MATR3 gene sequence that codes for the matrin-3 protein isoform b is indicated in blue. (B) Patient (proband), parental, and grandparental genomic DNA were amplified by targeted PCR. Genomic DNA from the patient, parent 2, and grandparent 2 carried the mutation found in chromosome 12. A 1 kbp ladder was used in lanes 1 and 8. The expected product sizes were 1,457 bp for Assay 1 and 1,435 bp for Assay 2. Parent 1's genomic DNA was used for the negative control which lacked DNA polymerase.