Clinical staging and genetic profiling of Korean patients with primary lymphedema using targeted gene sequencing

Abstract

Lymphedema is a progressive disease caused by lymphatic flow blockage in the lymphatic pathway. Primary (hereditary) lymphedema is caused by genetic mutations without secondary causes. We performed clinical profiling on Korean primary lymphedema patients based on their phenotypes using lymphoscintigraphy and made genetic diagnoses using a next-generation sequencing panel consisting of 60 genes known to be related to primary lymphedema and vascular anomalies. Of 27 patients included in this study, 14.8% of the patients had lymphedema of the upper extremities, 77.8% had lymphedema of the lower extremities and 7.4% had 4-limbs lymphedema. Based on the International Society of Lymphology staging, 14, 10, and 3 patients had stage 3, 2, and 1 lymphedema, respectively. Only one family was genetically confirmed to harbor likely pathogenic variants in CELSR1. The proband was carrying two likely pathogenic variants in CELSR1, while her symptomatic mother was confirmed to carry only one of the variants. Furthermore, two other variants of uncertain significance in CELSR1 were detected in other patients, making CELSR1 the most commonly altered gene in our study. The clinical and genetic profile of hereditary lymphedema reported here is the first such data series reported for South Korea.

A HGF Mutation in the Familial Case of Primary Lymphedema: A Report

“…For our analysis, we primarily searched for variants in the following list of genes associated with lymphedema and lymphatic disease [16]: ACVRL1, AKT1, ARAF, ARHGAP31, BRAF, CBL, CCBE1, CCM2, CELSR1, CTNNB1, DCHS1, ELMO2, ENG, EPHB4, FAT4, FGFR1, FLT4, FOXC2, GATA2, GDF2, GJC2, GLMN, GNA11, GNA14, GNAQ, HGF, HRAS, IDH1, IDH2, KIF11, KRAS, KRIT1, MAP2K1, MAP2K2, MAP3K1, MAP3K3, MAPK1, MAPK14, MAPK3, MET, MTOR, NRAS, PDCD10, PDGFRB, PIEZO1, PIK3CA, PTEN, PTPN11, PTPN14, RAF1, RASA1, RIT1, SHOC2, SMAD4, SOS1, SOX18, STAMBP, TEK, TP53, and VEGFC.…”

Lymphedema is associated with CELSR1 in Phelan–McDermid syndrome

“…22 In a case report of a 20-year-old woman with PMS due to a large deletion and lymphedema, the authors attribute the condition to loss of CELSR1. 23 Outside of the PMS literature, the evidence supporting the role of CELSR1 in lymphedema pathogenesis is supported by the finding of loss-of-function variants in CELSR1 were associated with primary lymphedema 24 and hereditary lymphedema. [25][26][27] According to gnomAD 28 CELSR1 has a pLI score of 1 indicating a gene most intolerant to truncating mutations.…”

Structure of the extracellular region of the adhesion GPCR CELSR1 reveals a compact module which regulates G protein-coupling

“…[27][28][29][30][31] CELSRs are also associated with lymphedema, Joubert syndrome, Tourette syndrome and leukemia. [32][33][34][35][36][37][38][39][40] From their N-termini, CELSRs have poorly conserved prodomains (PRO) with a putative furin cleavage site. Following PRO are nine cadherin repeats (CADH1-9) which take up ~ 40 % of the ECR mass, making CELSRs a unique CADH-containing subfamily of the aGPCRs.…”