An updated AL-base reveals ranked enrichment of immunoglobulin light chain variable genes in AL amyloidosis.

Abstract

Background: Each monoclonal antibody light chain associated with AL amyloidosis has a unique sequence. Defining how these sequences drive amyloid deposition could facilitate faster diagnosis and lead to new treatments.

Methods: Light chain sequences are collected in the AL-Base repository. Monoclonal sequences from AL amyloidosis, multiple myeloma and the healthy polyclonal immune repertoire were compared to identify differences in precursor gene use, mutation frequency and physicochemical properties.

Results: AL-Base now contains 2,200 monoclonal light chain sequences from AL amyloidosis and other plasma cell dyscrasias. Sixteen germline precursor genes were enriched in AL amyloidosis, relative to multiple myeloma and the polyclonal repertoire. Two genes, IGKV1-16 and IGLV1-36, were infrequently observed but highly enriched in AL amyloidosis. The number of mutations varied widely between light chains. AL-associated κ light chains harboured significantly more mutations compared to multiple myeloma and polyclonal sequences, whereas AL-associated λ light chains had fewer mutations. Machine learning tools designed to predict amyloid propensity were less accurate for new sequences than their original training data.

Conclusions: Rarely-observed light chain variable genes may carry a high risk of AL amyloidosis. New approaches are needed to define sequence-associated risk factors for AL amyloidosis. AL-Base is a foundational resource for such studies.