Patient: The early-onset semantic dementia phenotype with a family history of dementia and episodic memory deficit accompanied with profound semantic loss.
Problem: Due to the overlapping clinical presentations and neuropathology, clinical diagnosis of dementia is frequently challenging and inconclusive. The use of next-generation sequencing methods revealed the complex genomic nature of disease phenotypes, shifting the pathogenicity model from monogenic to oligogenic inheritance.
Solution: Identification of rare variants using the IntelliseqFlow platform. Two ready-to-use workflows were used for analyzing the sample: “WGS hereditary disorders ACMG report” and “WGS structural variants research analysis”.
Within the first workflow, fastq file quality was assessed with FastQC. Further, fastq files were aligned to Broad Institute Hg38 Human Reference Genome with GATK 4.0.3. Duplicate reads were removed with Picard and base quality Phred scores were recalibrated using GATK’s covariance recalibration. Variants were called using GATK best practices. Identified variants were assessed using the IntelliseqFlow annotation pipeline that implemented ACMG recommendations.
Within the second workflow, the structural variants were called with lumpy/smoove and annotated with duphold. Further, the structural variants were filtered with the following parameters: QUAL > 30, del_cov_max = 0.7, dup_cov_min = 1.3, min_snp_count = 4, het_max = 0.25.
Result: First report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. The results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.
The research was conducted by: Laboratory of Neurogenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences; Neurology Department, St. Adalbert Hospital; Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk; Laboratory of Pharmacogenomics, Department of Molecular Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences; Division of Nuclear Medicine, Faculty of Health Sciences, Medical University of Gdansk.Read the full story here: https://www.mdpi.com/2073-4425/12/11/1806/html.