A Framework For Large-Scale Reconstruction Of Extended Pedigrees To Facilitate Gene Discovery In ALS

Importance

With emerging gene-targeted therapies in amyotrophic lateral sclerosis (ALS), gene discoveries and genetic diagnoses provide a crucial path to treatment. Pathogenic variants with moderate effect or incomplete penetrance, however, remain unidentified in genome-wide association studies and can appear sporadic in small modern-day pedigrees. Lack of recognition of familial clustering of ALS limits opportunities for gene discovery, genetic diagnosis, risk counseling, and treatment.

Objective

To determine the power of automated reconstruction of extended pedigrees, integrating archive records and genetic relatedness, in gene-discovery studies.

Design

Retrospective observational study of Dutch ALS patients with the C9orf72 hexanucleotide repeat expansion (HRE), combining clinical family history, civil records, and genome-wide genotyping for relatedness and identity-by-descent (IBD) inference.

Setting

National, population-based ALS cohort from the Netherlands and digitized population archives enabling systematic reconstruction of extended pedigrees.

Participants

Individuals with ALS and a confirmed C9orf72 HRE. Participants must have provided a clinical family history and traceable Dutch ancestry documented in population archives.

Main Outcomes and Measures

The primary outcome was the proportion of C9orf72 HRE carriers with newly identified (distant) relatives with ALS compared with clinical family history. The secondary outcome was the precision of IBD-based methods to fine-map the C9orf72 HRE. Other outcomes included phenotypic similarities between distantly related patients.

Results

Among 238 C9orf72 HRE carriers, 91 could be included in one of 39 extended pedigrees dating back to ∼1800, with relationships up to the eighth degree of relatedness. Compared with clinical family history alone, our approach increased the number of identified relationships by 2.5- fold. Genome-wide IBD analysis revealed shared haplotypes encompassing the C9orf72 HRE in 97% of pedigrees by ≥7 meioses in 10.2-127.0 centimorgans total IBD shared.

Conclusions and Relevance

Large-scale interrogation of archives facilitates reconstruction of extended pedigrees for ALS patients carrying the C9orf72 HRE. This combined genealogical–genetic approach supports the reclassification of apparently sporadic cases, facilitates the discovery of new disease-causing variants in ALS, and is generalizable to other late-onset neurodegenerative diseases. We implemented the automated reconstruction and interactive visualization of extended pedigrees from genealogical records in an open-source software toolkit.

Key points

Question

How can extended pedigrees be leveraged to identify disease genes in a late-onset neurodegenerative disease such as ALS?

Findings

We built a pipeline to reconstruct extended pedigrees from large-scale genealogical data in archival records of ALS patients. We applied our methods to a cohort of patients carrying the C9orf72 repeat expansion. This identified 67 distant relationships, of which 38 (57%) could not be inferred from clinical family histories and were thus novel. In extended pedigrees connected by ≥7 meioses (N = 35), a single shared IBD segment with the C9orf72 repeat expansion was identified, spanning only 10.2-27.0 centimorgans.

Meaning

We provide a generalizable approach to reconstruct extended pedigrees, detecting small enough genomic regions for gene discovery in ALS and other late-onset neurodegenerative diseases.