Comprehensive molecular characterization of a heavy chain deposition disease case

Bender, Sébastien; Ayala, Maria Victoria; Javaugue, Vincent; Bonaud, Amélie; Cogné, Michel; Touchard, Guy; Jaccard, Arnaud; Bridoux, Frank; Sirac, Christophe

doi:10.3324/haematol.2018.196113

Cited by 9 publications

(6 citation statements)

References 14 publications

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“…Sequences were analyzed using FinchTV software and aligned with MultAlin (http://multalin.toulouse.inra.fr/multalin/), and the l VJ rearrangement was determined using the IMGT/V-QUEST tool (http://imgt.org/). [16][17][18] High-throughput sequencing on Illumina MiSeq sequencer…”

Section: Topo Cloning and Sequencingmentioning

confidence: 99%

Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Bender

Javaugue

Saintamand

et al. 2020

Blood

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Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystem disease resulting from an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear, but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected because of the highly restrictive usage of 2 λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations after PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in the case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (rapid amplification of cDNA ends-based repertoire sequencing [RACE-RepSeq]), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 83% of patients with POEMS syndrome, including some in whom BM tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ+ monoclonal PCs. Twenty-four (83%) of the 29 LC clonal sequences found were derived from the IGLV1-40 and IGLV1-44 germline genes, as well as 2 from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid, and specific tool to detect low-abundance PC clones in BM and assign them to POEMS syndrome, with all the consequences for therapeutic options.

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Section: Topo Cloning and Sequencingmentioning

confidence: 99%

Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Bender

Javaugue

Saintamand

et al. 2020

Blood

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“…Recently, immunofluorescence studies of bone marrow from HCDD patients revealed that clonal PC secrete both the pathogenic truncated HC and a non-toxic free LC. Although this LC does not deposit in tissues, it can be used as a surrogate marker of HC secretion and of the underlying clone activity [ 27 ]. A mouse model of HCDD has been generated by knock-in insertion of a human HC in the mouse kappa LC locus.…”

Section: Pathophysiologymentioning

confidence: 99%

Randall-Type Monoclonal Immunoglobulin Deposition Disease: New Insights into the Pathogenesis, Diagnosis and Management

et al. 2021

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Randall-type monoclonal immunoglobulin deposition disease (MIDD) is a rare disease that belongs to the spectrum of monoclonal gammopathy of renal significance (MGRS). Renal involvement is prominent in MIDD, but extra-renal manifestations can be present and may affect global prognosis. Recent data highlighted the central role of molecular characteristics of nephrotoxic monoclonal immunoglobulins in the pathophysiology of MIDD, and the importance of serum free light chain monitoring in the diagnosis and follow-up disease. Clone-targeted therapy is required to improve the overall and renal survival, and the achievement of a rapid and deep hematological response is the goal of therapy. This review will focus on the recent progress in the pathogenesis and management of this rare disease.

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“…Sequences were analyzed using FinchTV software and aligned with MultAlin (http://multalin.toulouse.inra.fr/multalin/) and the λ VJ rearrangement was determinated using IMGT/V-QUEST tool (http://imgt.org/). [15][16][17] High-Throughput sequencing on ROCHE 454 sequencer Transcripts were amplified using 5' RACE-PCR and consensus reverse primers hybridizing in λ constant exons as previously described 18,19 and sequenced on a 454 sequencer (Roche).…”

Section: Topo Cloning and Sequencingmentioning

confidence: 99%

Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Bender

Javaugue

Saintamand

et al. 2019

Preprint

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POEMS syndrome is a rare multisystem disease due to an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected, due to the highly restrictive usage of two λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations following PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (RACE-RepSeq), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 85% of patients with POEMS syndrome, including some in whom bone marrow tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ + monoclonal PCs. Twenty-four of the 30 LC clonal sequences found (80%) were derived from the IGLV1-40 and IGLV1-44 germline genes, two from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid and specific tool to detect low-abundance PC clones in BM, and assign them to POEMS syndrome, with all the consequences for therapeutic options hereby.

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Comprehensive molecular characterization of a heavy chain deposition disease case

Cited by 9 publications

References 14 publications

Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Randall-Type Monoclonal Immunoglobulin Deposition Disease: New Insights into the Pathogenesis, Diagnosis and Management

Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

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