Gene3 diseases
MYD88
3 variant(s) documented across POEMS Syndrome, Schnitzler Syndrome, Waldenström's Macroglobulinemia
Found across diseases
POEMS Syndrome1 variant(s)
Schnitzler Syndrome1 variant(s)
Waldenström's Macroglobulinemia1 variant(s)
Variants
| Variant | Type | Frequency in disease | Significance | Also found in |
|---|---|---|---|---|
| Somatic mutations (including L265P) | somatic | Rare (identified in Chen et al. 2021 WES) | MYD88 mutations detected in some POEMS patients, though at lower frequency than in Waldenstrom macroglobulinemia (>90%). Drives NF-kB activation. Overlap with Waldenstrom and Schnitzler syndrome pathogenesis. | Waldenstrom macroglobulinemia (>90%); Schnitzler syndrome (~30%) |
| L265P (somatic) | somatic | ~30% of tested patients | The most significant genetic finding. Same mutation found in >90% of Waldenström's macroglobulinemia. Drives persistent NF-κB activation. | Waldenström's macroglobulinemia (>90%) |
| L265P (somatic) | somatic | >90% (up to 100% by AS-PCR) | Defining molecular hallmark of WM. Gain-of-function mutation causing constitutive Myddosome assembly, BTK activation, and NF-kB-driven B-cell survival. Discovered by Treon et al. 2012 via whole-genome sequencing. | Schnitzler syndrome (~30%); IgM-MGUS (~47%); DLBCL (ABC subtype) (~29%); Splenic marginal zone lymphoma (~6%) |
Clinical implications
Somatic mutations (including L265P)
May predict response to ibrutinib or other BTK inhibitors.
Testing: Allele-specific PCR, Whole-exome sequencing
L265P (somatic)
Supports shared pathogenic mechanism with WM. May predict response to ibrutinib.
Testing: allele-specific PCR, Sanger sequencing
L265P (somatic)
Predicts favourable response to ibrutinib. MYD88 wild-type patients have shorter survival and poor BTK inhibitor response. Required for molecular diagnosis per ECWM consensus.
Testing: allele-specific PCR (AS-PCR), Sanger sequencing, next-generation sequencing