Screening and identification of a novel FHL2 mutation by whole exome sequencing in twins with familial Waldenström macroglobulinemia

Abstract

BACKGROUND: Waldenström macroglobulinemia (WM) is a rare chronic B-cell lymphoma. Familial clustering of WM has been observed over the years. However, little is known about the contribution of inherited genetic variants to familial WM cases. METHODS: The authors performed whole exome sequencing (WES) of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Bioinformatics analysis of public biological databases was used to identify the most relevant familial WM candidate from WES. Transcript expression and protein levels of the familial WM candidate were evaluated in the WM patient and 2 unaffected members of the kindred. RESULTS: Among the 10 shared candidate mutations in the twins, the authors identified a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) as a familial WM-associated mutation. FHL2 appeared to be connected with reported signaling pathways and disease-driving genes such as IL6 and HCK in WM. In addition, the authors found reduced FHL2 messenger RNA and protein expression in peripheral blood samples from the patient with WM in comparison with the healthy siblings. CONCLUSIONS: Taken together, these findings indicate that an FHL2 g226a mutation may play an important role in familial WM, and they provide new screening possibilities for familial cases.

Hematologic secondary malignancies among 102 Chinese patients with Waldenstrom’s macroglobulinemia: a single-center case experience and literature review

“…However, our study was conducted in the Chinese population in the time frame of 2003 to 2023, and the treatment regimen changed from traditional chemotherapy to regimens dominated by new agents such as rituximab, bortezomib, and BTKi. Our earlier work found that WM is characterized by familial co-morbidity, especially in first-degree relatives ( 18 ). We followed up on these patients and found that the proportion of hematologic SMs was not high, but the survival of this subgroup of patients was significantly lower than that of sporadic WM.…”