Hereditary Lymphedema Research Articles

Cross-sectional analysis for lymphedema epidemiology in South Korea by HIRA data: An observational study.

Lymphedema is known to affect as many as 140 to 250 million people worldwide. Approximately 99% of lymphedemas are secondary cases after lymphadenectomy, radiation, or parasite infection. There has been no accurate estimate of the lymphedema population size in South Korea. This study aimed to quantify the epidemiology of lymphedema in South Korea and analyze the clinical characteristics of patients with lymphedema using a nationwide database. This large-scale cross-sectional study included patients who received one of the following three diagnostic codes - Q82.0 (hereditary lymphedema), I97.2 (breast cancer-related lymphedema), and I89.0 (unclassified lymphedema) from the Korean Health Insurance Review and Assessment service between January 2019 and July 2022 at tertiary hospitals, general hospitals, or other hospitals. The demographics of the lymphedema population, medication use, and medical characteristics were identified. Over the last 4 years, the annual incidence of lymphedema has steadily increased and peaked in 2021 with the number 1.85 out of 1000. Of all patients, 81% were located in the upper extremity, and 10.6% had previous cancer. Most patients were diagnosed in general hospitals (53.2%), at orthopedic surgery department (41.9%). On average, lymphedema patients spent 70.17 US dollar for medication and hospitalized for 16.9 days annually after diagnosis. Commonly prescribed medications were Entelon® (Vitis vinifera seed extract) (66.9%), steroids (40.5%), non-steroidal anti-inflammatory drugs (26.5%) and diuretics (21.8%). Only 5.7% of patients received surgery and 19.2% received herbal medicine. This is the first study in South Korea to quantify demographic and medical characteristics of lymphedema patients. These results will contribute to a comprehensive understanding of lymphedema diagnosis and treatment in our nation.

FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms.

Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. The distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. The phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. In this study, we show that FLT4 variants identified in patients with TOF, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wild-type (WT) FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of WT human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms.

The VASCERN PPL working group patient pathway for primary and paediatric lymphoedema

Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production and leads to swelling associated with tissue changes (skin thickening, fat deposition). Its main common complication is the increased risk of developing cellulitis/erysipelas in the affected area, which can worsen the lymphatic function and can be the cause of raised morbidity of the patient if not treated correctly/urgently. The term primary lymphoedema covers a group of rare conditions caused by abnormal functioning and/or development of the lymphatic system. It covers a highly heterogeneous group of conditions. An accurate diagnosis of primary lymphoedema is crucial for the implementation of an optimal treatment plan and management, as well as to reduce the risk of worsening. Patient care is diverse across Europe, and national specialised centres and networks are not available everywhere. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) gathers the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. There are six different working groups in VASCERN, which focus on arterial diseases, hereditary haemorrhagic telangiectasia, neurovascular diseases, lymphoedema and vascular anomalies. The working group Paediatric and Primary Lymphedema (PPL WG) gathers and shares knowledge and expertise in the diagnosis and management of adults and children with primary and paediatric lymphoedema. The members of PPL WG have worked together to produce this opinion statement reflecting strategies on how to approach patients with primary and paediatric lymphoedema. The objective of this patient pathway is to improve patient care by reducing the time to diagnosis, define the best management and follow-up strategies and avoid overuse of resources. Therefore, the patient pathway describes the clinical evaluation and investigations that lead to a clinical diagnosis, the genetic testing, differential diagnosis, the management and treatment options and the patient follow up at expert and local centres. Also, the importance of the patient group participation in the PPL WG is discussed.

Molecular Analysis of the First Reported Hereditary Lymphedema-distichiasis Case in Bangladesh

Lymphedema–distichiasis syndrome (LD, OMIM 153400) is hereditary primary lymphedema with autosomal dominant nature of inheritance and variable expression. LD is characterized by late childhood or pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes (distichiasis) arising from the meibomian glands. Among the molecular reasons behind this condition are the mutations in the FOXC2 gene, a forkhead transcription factor, that plays a role in the formation of lymphatic and vascular systems. In this study, we report the first case of LD from Bangladesh with classical lymphedema–distichiasis syndrome with an eight-base-pair deletion in the FOXC2 gene. ClinVar accession code for this deletion is RCV000007679.3. FOXC2 protein is 501 amino acids long. This deletion of 8 bp (ACGCCGCC) causes frameshift of codons after amino acid number 304. The frameshift creates an altered truncated protein with 154 new amino acids after codon 304. We assume that these changes in the protein may affect its function contributing to the disease manifestations. Further research may confirm these assumptions. J. Bangladesh Acad. Sci. 47(2); 205-213: December 2023

A Practical Approach to the Diagnosis of Lymphedema: A Narrative Review.

Lymphedema often presents as progressive, unremitting swelling and skin changes that are extremely distressing to patients. Hereditary lymphedema (HL) constitutes a type of primary lymphedema that is passed down through generations. The primary aims of this narrative review are to illustrate a framework to distinguish lymphedema from other causes of swelling and to differentiate the hereditary lymphedemas from each other. A literature search was undertaken using relevant search terms. The articles were evaluated to generate a diagnostic algorithm to approach the swelling of an extremity using clinical and laboratory data. First, the stemmer sign should be evaluated. If it is negative, other causes should be considered. History and additional physical exam findings suggest either a primary or secondary cause of lymph-edema. The hereditary lymphedemas have been classified by age of onset and then stratified by clinical criteria and genetic testing.

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

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.

The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases.

Vascular endothelial growth factor receptors (VEGFRs) are part of the evolutionarily conserved VEGF signalling pathways that regulate the development and maintenance of the body’s cardiovascular and lymphovascular systems. VEGFR3, encoded by the FLT4 gene, has an indispensable and well-characterized function in development and establishment of the lymphatic system. Autosomal dominant VEGFR3 mutations, that prevent the receptor functioning as a homodimer, cause one of the major forms of hereditary primary lymphoedema; Milroy disease. Recently, we and others have shown that FLT4 variants, distinct to those observed in Milroy disease cases, predispose individuals to Tetralogy of Fallot, the most common cyanotic congenital heart disease, demonstrating a novel function for VEGFR3 in early cardiac development. Here, we examine the familiar and emerging roles of VEGFR3 in the development of both lymphovascular and cardiovascular systems, respectively, compare how distinct genetic variants in FLT4 lead to two disparate human conditions, and highlight the research still required to fully understand this multifaceted receptor.

Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family.

A second multigeneration family with hereditary lymphedema (LE) secondary to a variant in the planar polarity gene, CELSR1, is described. Dominant inheritance of the variant was discovered using whole-exome sequencing and confirmed by Sanger sequencing. In contrast to heterozygous males, all heterozygous females showed LE during physical examination albeit variable in severity and age of onset. Lymphscintigraphy in affected females showed previously undescribed lymphatic abnormalities consistent with lymphangiectasia, valve dysfunction, and thoracic duct reflux.

Increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants.

A whole exome sequencing approach was recently used to detect a CELSR1 truncating variant associated with lymphedema in a large pedigree. Since this first report, no other similar associations have been reported in the literature. Here, we present the genetic results of 95 probands tested using a next generation sequencing panel that covered all known lymphedema-associated genes, including CELSR1. Five out of 95 probands (5.3%) were found to carry novel loss-of-function variants in CELSR1. Family segregation studies were possible in four out of five probands and showed possible sex-specific differences: CELSR1 variants showed almost complete penetrance in females and were associated with early-onset lymphedema, whereas in males they showed incomplete penetrance and were associated with late onset of the condition. Since the percentage of lymphedema patients carrying CELSR1 variants is not negligible, we do not hesitate to recommend including this gene in routine genetic testing.

Rare genetic variants potentially involved in ovarian hyperstimulation syndrome.

We aim to investigate whether there is a genetic predisposition in women who developed ovarian hyperstimulation syndrome (OHSS) after GnRH antagonist protocol with GnRH agonist trigger and freeze-all approach. Four patients with OHSS after GnRH agonist trigger and freeze-all approach were gathered from the worldwide patient population. These patients were analyzed through Whole Exome Sequencing. In this study known causes of OHSS were investigated and new causes present in at least two individuals were searched for. In the first part of the study, we evaluated the presence of mutations in genes already known to be involved in OHSS. In PGR and TP53, heterozygous alterations were detected. PGR is predicted to be involved in progesterone resistance with a recessive inheritance pattern and is, therefore, not considered as being causal. The consequences of the variant detected in TP53 currently remain unknown. In part 2 of the study, we assessed the clinical significance of variants in genes previously not linked to OHSS. We especially focused on genes with variants present in ≥ 2 patients. Two patients have variants in the FLT4 gene. Mutations in this gene are linked to hereditary lymphedema, but no link to OHSS has been described. Defining a genetic predisposition for OHSS is essential in view of prevention. In this study, a potential link between the FLT4 gene and OHSS has been suggested. Future functional studies are essential to define a more precise involvement of the detected variants in the development of OHSS.

Hamartomas and malformations of the liver.

Hamartomas and malformations of the liver are rare and can lead to diagnostic challenges. Most present as mass lesions that can mimic true neoplasms of the liver on imaging and sometimes on histology, one example being focal nodular hyperplasia. The primary cell type in the hamartomas and malformations can be biliary, vascular, or hepatic. Biliary lesions include bile duct hamartomas and simple liver cysts. Other cystic malformations include the ciliated hepatic foregut cysts and mesothelial cysts. Vascular malformations include telangiectasias, arteriovenous malformations, and hereditary lymphedema. Malformations composed primarily of hepatocytes include accessory lobes and focal nodular hyperplasia. All of these entities are discussed, with a focus on the diagnostic histological findings.

A novel mutation in the conserved sequence of vascular endothelial growth factor receptor 3 leads to primary lymphoedema

ObjectiveTo investigate whether lymphoedema in a Chinese family showed the hereditary and clinical characteristics of Milroy disease, an autosomal dominant form of congenital lymphoedema, typically characterized by chronic lower limb tissue swelling due to abnormal lymphatic vasculature development, and to perform mutational analyses of vascular endothelial growth factor receptor (VEGFR)3.MethodsIndividuals from a three-generation family affected by congenital lymphoedema were clinically assessed for Milroy disease. Mutation analysis of VEGFR3 was performed using DNA from family members and healthy controls.ResultsOut of 20 family members, eight were diagnosed with hereditary lymphoedema. Mutation analyses revealed a novel mutation site for c.3163 G>A, resulting in a p.1055D>N mutation in the second tyrosine kinase domain of VEGFR3, which was present in affected individuals only (absent in all unaffected family members and 130 healthy controls). Computed functional analyses showed the mutation may lead to structural alterations with a probability of 0.99999 of being disease causing.ConclusionA novel mutation associated with Milroy disease was identified in a Chinese family, expanding our knowledge of VEGFR3 gene function and providing a potential molecular target for treating hereditary lymphoedema.

Ultrasound- Guided Laser- Mediated Thermal Angioplasty of Occluded Artery Accompanied by Protoporphyrin IX– Loaded Microbubbles- Mediated Sonodynamic Therapy

The transcription factor SOX18 has been shown to play a role in the development of hair, blood and lymphatic vessels. Mutations in SOX18 result in hereditary lymphedema, with the unique clinical association of hypotrichosis and telangiectasia (HLTS). Some patients present with additional disease features which may be explained by the location of SOX18 mutation. We report a patient with hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) confirmed by detection of a novel mutation in the SOX18 gene. Few cases of HTLS have been reported in the literature. We reviewed all cases reported to date to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome for appropriate management and genetic counseling.

Primary lymphedema and other lymphatic anomalies are associated with 22q11.2 deletion syndrome

BackgroundLymphedema is an abnormal accumulation of interstitial fluid within the tissues. Primary lymphedema is caused by aberrant lymphangiogenesis and it has been historically classified based on age at presentation. Although most cases are sporadic, primary lymphedema may be familial or present in association with chromosomal abnormalities and syndromic disorders. To the best of our knowledge, primary lymphedema has never been described in patients with 22q11.2 deletion syndrome. Methods and resultsWe identified 4 patients with 22q11.2 deletion syndrome and primary lymphedema via our International 22q11.2 Deletion Syndrome Consortium. All patients underwent comprehensive clinical, laboratory and imaging assessments to rule out other causes of lymphedema. All patients had de novo typical deletions and family histories were negative for lymphedema. ConclusionsWe report the novel association of primary lymphedema with 22q11.2 deletion syndrome. Importantly, animal models demonstrated Tbx1 playing a critical role in lymphangiogenesis by reducing Vegfr3 expression in lymphatic endothelial cells. Moreover, the VEGFR3 pathway is essential for lymphangiogenesis with mutations identified in hereditary primary lymphedema. Accordingly, our findings provide a new insight into understanding cellular mechanisms of lymphangiogenesis disorders.

Further delineation of the SOX18-related Hypotrichosis, Lymphedema, Telangiectasia syndrome (HTLS)

The transcription factor SOX18 has been shown to play a role in the development of hair, blood and lymphatic vessels. Mutations in SOX18 result in hereditary lymphedema, with the unique clinical association of hypotrichosis and telangiectasia (HLTS). Some patients present with additional disease features which may be explained by the location of SOX18 mutation. We report a patient with hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) confirmed by detection of a novel mutation in the SOX18 gene. Few cases of HTLS have been reported in the literature. We reviewed all cases reported to date to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome for appropriate management and genetic counseling.

In silico analysis of single nucleotide polymorphisms (SNPs) in human FOXC2 gene.

Introduction: Lymphedema is an abnormal accumulation of interstitial fluid, due to inefficient uptake and reduced flow, leading to swelling and disability, mostly in the extremities. Hereditary lymphedema usually occurs as an autosomal dominant trait with allelic heterogeneity. Methods: We identified single nucleotide polymorphisms (SNPs) in the FOXC2 gene using dbSNP, analyzed their effect on the resulting protein using VEP and Biomart, modelled the resulting protein using Project HOPE, identified gene - gene interactions using GeneMANIA and predicted miRNAs affected and the resulting effects of SNPs in the 5' and 3' regions using PolymiRTS. Results: We identified 473 SNPs - 429 were nsSNPs and 44 SNPs were in the 5' and 3' UTRs. In total, 2 SNPs - rs121909106 and rs121909107 - have deleterious effects on the resulting protein, and a 3D model confirmed those effects. The gene - gene interaction network showed the involvement of FOXC2 protein in the development of the lymphatic system. hsa-miR-6886-5p, hsa-miRS-6886-5p, hsa-miR-6720-3p, which were affected by the SNPs rs201118690, rs6413505, rs201914560, respectively, were the most important miRNAs affected, due to their high conservation score. Conclusions: rs121909106 and rs121909107 were predicted to have the most harmful effects, while hsa-miR-6886-5p, hsa-miR-6886-5p and hsa-miR-6720-3p were predicted to be the most important miRNAs affected. Computational biology tools have advantages and disadvantages, and the results they provide are predictions that require confirmation using methods such as functional studies.

It is All in My Genes: A Case Report of Recurrent Pleural Effusion

SESSION TITLE: Pulmonary Manifestations of Systemic Disease 3 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Pleural effusion is the excessive accumulation of fluid in the pleural space which develops when there is imbalance between fluid formation and fluid removal by lymphatics. CASE PRESENTATION: A 39 year old Yemeni born male with comorbidities of hereditary lymphedema, bilateral hearing loss, left sided pleural effusion status post video assisted thoracoscopic pleurodesis, pericardial effusion status post pericardial window 22 years ago, presented with dyspnea on exertion and right sided back pain for 1 week. Significant family history of consanguinity in his parents and first degree relatives. His sister also had bilateral pleurodesis and pericardial window for similar presentation, but his brother and other cousins only had lymphedema of bilateral lower extremities. Physical examination showed bilateral upper and lower extremity 2+ non-pitting edema, diminished breath sounds over right lungs field with dullness to percussion. Labs were unremarkable. Non-contrast CT Chest showed a large loculated right pleural effusion with compressive atelectasis. Patient underwent right VATS, decortication and talc pleurodesis with improvement in aeration. Pleural fluid analysis revealed lymphocyte predominant exudative effusion, negative cultures for bacteria, fungi, and TB, negative for malignant cells on cytology. Pleural biopsy showed chronic pleuritis with focal mesothelial proliferation and atypia. Patient was successfully discharged home. DISCUSSION: Hereditary lymphedema is an uncommon genetic defect in lymphatic system development, classified by age of onset as- 1) Congenital 2) Lymphedema praecox 3) Lymphedema tarda. Usual manifestations are lymphedema of extremities (lower limbs more commonly affected than upper), sometimes lymphedema involving other areas of body such as face, trunk and larynx. Commonly associated with recurrent cellulitis, yellow nails and hearing loss. In rare instances, patients may develop fluid collection in serous cavities such as pericardial/pleural effusion and ascites.[1] Our patient developed lymphedema at age 4 in his legs, eventually involving his arms. By age 18, he underwent left VATS/pleurodesis and pericardial window. He suffered bilateral hearing loss by age 34. His full sister has the same spectrum of disease but symptoms began at birth. CONCLUSIONS: In addition to pooling of multiple affected cases in this single family tree, lack of clinical, radiological or laboratory evidence of infection and malignancy, we can conclude that etiology of recurrent pleural effusion in our patient is one of the manifestations of lymphedema praecox.[2] Reference #1: http://www.atsjournals.org/doi/abs/10.1164/arrd.1978.117.3.595 Reference #2: http://pubs.rsna.org/doi/pdf/10.1148/82.2.246 DISCLOSURE: The following authors have nothing to disclose: Sandi Khin, Sapan Patel, Keerthana Keshava No Product/Research Disclosure Information

In silico analysis of single nucleotide polymorphisms (SNPs) in human FOXC2 gene

Introduction: Lymphedema is an abnormal accumulation of interstitial fluid, due to inefficient uptake and reduced flow, leading to swelling and disability, mostly in the extremities. Hereditary lymphedema usually occurs as an autosomal dominant trait with allelic heterogeneity. Methods: We identified single nucleotide polymorphisms (SNPs) in the FOXC2 gene using dbSNP, analyzed their effect on the resulting protein using VEP and Biomart, modelled the resulting protein using Project HOPE, identified gene – gene interactions using GeneMANIA and predicted miRNAs affected and the resulting effects of SNPs in the 5’ and 3’ regions using PolymiRTS. Results: We identified 473 SNPs - 429 were nsSNPs and 44 SNPs were in the 5’ and 3’ UTRs. In total, 2 SNPs - rs121909106 and rs121909107 - have deleterious effects on the resulting protein, and a 3D model confirmed those effects. The gene – gene interaction network showed the involvement of FOXC2 protein in the development of the lymphatic system. hsa-miR-6886-5p, hsa-miRS-6886-5p, hsa-miR-6720-3p, which were affected by the SNPs rs201118690, rs6413505, rs201914560, respectively, were the most important miRNAs affected, due to their high conservation score. Conclusions: rs121909106 and rs121909107 were predicted to have the most harmful effects, while hsa-miR-6886-5p, hsa-miR-6886-5p and hsa-miR-6720-3p were predicted to be the most important miRNAs affected. Computational biology tools have advantages and disadvantages, and the results they provide are predictions that require confirmation using methods such as functional studies.

In silico analysis of single nucleotide polymorphisms (SNPs) in human FOXC2 gene.

Introduction: Lymphedema is abnormal accumulation of interstitial fluid, due to inefficient uptake and reduced flow, leading to swelling and disability, mostly in the extremities. Hereditary lymphedema usually occurs as an autosomal dominant trait with allelic heterogeneity. Methods: We identified single nucleotide polymorphisms (SNPs) in the FOXC2 gene using dbSNP, analyzed their effect on the resulting protein using VEP and Biomart, modelled the resulting protein using Project HOPE, identified gene - gene interactions using GeneMANIA and predicted miRNAs affected and the resulting effects of SNPs in the 5' and 3' regions using PolymiRTS. Results: We identified 448 SNPs - 429 were nsSNPs and 44 SNPs were in the 5' and 3' UTRs. In total, 2 SNPs have deleterious effects on the resulting protein, and a 3D model confirmed those effects. The gene - gene interaction network showed the involvement of FOXC2 protein in the development of the lymphatic system. hsa-miR-6886-5p, hsa-miRS-6886-5p , hsa-miR-6720-3p, which were affected by the SNPs rs201118690, rs6413505, rs201914560, respectively, were the most important miRNAs affected, due to their high conservation score. Conclusions: rs121909106 and rs121909107 were predicted to have the most harmful effects, while hsa-miR-6886-5p, hsa-miR-6886-5p and hsa-miR-6720-3p were predicted to be the most important miRNAs affected. Computational biology tools have advantages and disadvantages, and the results they provide are predictions that require confirmation.

Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.

Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients' erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema.