A novel mutation in CELSR1 is associated with hereditary lymphedema

Abstract

Background: Biological evidence reported in the literature supports the role of CELSR1 as being essential for valvular function in murine lymphatics. Yet thus far, there have been no variants in CELSR1 associated with lymphatic dysfunction in humans.

Case presentation: In this report, a rare early inactivating mutation in CELSR1 is found to be causal for non-syndromic, lower extremity lymphedema in a family across three generations. Near-infrared fluorescence lymphatic imaging shows that instead of being propelled within the lumen of well-defined lymphatic vessels, lymph moved in regions of both legs in an unusual fashion and within sheet-like structures.

Conclusion: CELSRI may be responsible for primary, non-syndromic lymphedema in humans.

Keywords: Near-infrared fluorescence imaging CELSR1; Planar polarity; Primary lymphedema; Whole exome sequencing.

Fig. 1

Montages of NIRFLI of the lower extremities of (a) the proband and (b) her mother. While the mother had well-defined lymphatics, she also had areas with dermal backflow as shown in the inset images of (b)

Fig. 2

Pedigree of the family showing members diagnosed with lymphedema (filled black), unknown phenotype (filled gray) and unaffected (open) subjects. Arrow indicates the proband. The small ‘s’ at the left top corner of the subjects indicates when the subject’s DNA was sequenced. A diagonal line indicates that the patient is deceased

Fig. 3

a Image from the Integrative genomics viewer, showing a 40 bp genomic region containing the variant. Each one of the samples is loaded into the panel. Each panel shows two windows, the top window displays the number of reads, and the allele fraction and the lower window show the alignments of the experimental reads. The bottom panel displays the transcripts with the open reading frames. b A cartoon representing the predicted protein structure of CELSR1 (uniprot id Q9NYQ6). An arrow represents the location of the mutation. The cartoon was inspired by the publication of Lei, et al., 2014 [30]