Lessons from a systematic review of family-based studies in ALS

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Amyotrophic Lateral Sclerosis (ALS) is genetically diverse, with numerous causal genes identified via family studies.
• Systematic review of family-based gene discovery studies highlighted unresolved genomic regions in five pedigrees.

Purpose of the Study:

• To re-evaluate previously identified unresolved genomic regions in ALS pedigrees.
• To assess the efficacy of family-based genetic studies in different pedigree structures.
• To propose novel strategies for identifying novel ALS genetic risk factors.

Main Methods:

• Systematic review of family-based gene discovery studies for ALS.
• Re-analysis of linkage in five ALS pedigrees.
• Utilizing large-scale genetic datasets for re-examination of unresolved regions.
• Comparative analysis of successful versus unsuccessful linkage in different pedigree types.

Main Results:

• Two pedigrees were resolved, identifying FUS and SYNE1 as causal genes.
• Three pedigrees remained linked to four unresolved regions, with no new ALS-causing variants found upon reanalysis.
• Successful gene discovery was associated with larger, multigenerational families, while complex or small pedigrees presented challenges.

Conclusions:

• Family-based genetic studies are effective for typical ALS pedigrees but have limitations in small or complex families.
• The rare-variant architecture of ALS necessitates innovative approaches.
• A 'super-pedigree' framework is proposed to aggregate extended families for enhanced power in discovering shared ALS genetic risk factors and advancing gene-based therapies.