Exploratory Whole-Genome Analysis in Familial Hemiplegic Migraine

Identifying rare genetic variants using a bioinformatics pipeline to investigate unexplained cases of familial hemiplegic migraine.

Abstract

Familial hemiplegic migraine (FHM) is a rare, monogenic subtype of migraine characterized by temporary weakness or paralysis on one side of the body. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A account for many cases, a substantial proportion of clinically diagnosed individuals lack mutations in these canonical genes. This study performed an exploratory whole-genome analysis of an individual with clinically diagnosed FHM to identify additional genetic contributors to the condition. 

Whole-genome sequencing data aligned to GRCh38 were analyzed using a bioinformatics pipeline based on Genome Analysis Toolkit (GATK) best-practice workflows. The pipeline included pre-processing, calling of single-nucleotide variants (SNVs) and small insertions/deletions (indels), and variant annotation. Variants on genes in a targeted gene panel of 6 genes and an expanded gene panel of over 220 genes associated with ion transport, neuronal excitability, and related neurological phenotypes were considered as candidates. Filtering was performed based on quality metrics, read depth, predicted functional impact, and population allele frequency.

No rare, high-impact variants were identified in canonical FHM genes. The application of the expanded gene panel identified 39 moderate or high-impact variants in candidate genes. After filtering and manual validation, a subset of variants in biologically relevant genes, including ATP13A5 and ATP8A1 were identified as potential candidates, although no definitive causal variant was identified. This study highlights both the potential and limitations of exploratory whole-genome analysis in rare disease.

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Key Findings

• No significant variants in canonical FHM genes
• Variant filtering narrowed >3.5 million variants down to 9 candidates
• Variants in two genes were biologically relevant candidates (ATP13A5 and ATP8A1)

Presentation

This presentation provides a full overview of the research question, methodology, and key findings.