Lymphatic Malformation 6: Comprehensive Disease-Characteristics Report

Executive summary

Lymphatic malformation 6 (LM6) is a rare Mendelian disorder of lymphatic development caused principally by biallelic loss-of-function variants in PIEZO1, which encodes a mechanically activated, calcium-permeable cation channel. It is best understood clinically as PIEZO1-related generalized lymphatic dysplasia (GLD). The characteristic spectrum comprises prenatal nonimmune hydrops fetalis, pleural or pericardial effusions, chylothorax, ascites, pulmonary or intestinal lymphangiectasia, and congenital or later-onset generalized lymphedema. Disease severity is highly variable, ranging from fetal death to transient prenatal edema followed by childhood- or adult-onset lymphatic disease. Founding human studies were published independently in September 2015 by Fotiou et al. and Lukacs et al. (PMIDs indexed for the disease association include 26333996 and 26387913). (OpenTargets Search: lymphatic malformation 6, iyer2020lymphaticvalvesand pages 15-17, fotiou2015novelmutationsin pages 1-2)

The strongest recent mechanistic advance is the 2024 demonstration that PIEZO1 activation in lymphatic endothelial cells induces ANGPT2 exocytosis, ADAM17-mediated TIE1 shedding, TIE/PI3K/AKT activation, and FOXO1 nuclear export. This complements earlier evidence that PIEZO1 controls lymphatic-valve morphogenesis, lymphatic sprouting, and vessel maintenance. No approved PIEZO1-directed treatment exists; small-molecule PIEZO1 agonism with Yoda1 remains preclinical. (du2024themechanosensorychannel pages 1-2, choi2022piezo1regulatedmechanotransductioncontrols pages 1-3, ludlow2023smallmoleculefunctionalrescue pages 14-16)

The following table summarizes the principal evidence and ontology-ready annotations.

Table: This compact table organizes the key human, in vitro, mouse, and trial evidence for PIEZO1-related lymphatic malformation 6. It highlights the founding 2015 cohorts, recent mechanistic advances, and the important distinction between preclinical Yoda1 rescue and non-genotype-specific lymphatic-malformation trials.

1. Disease information

Definition and identifiers

• Preferred name: Lymphatic malformation 6.
• Core clinical designation: PIEZO1-related generalized lymphatic dysplasia.
• MONDO: MONDO:0014797.
• OMIM: 616843.
• Causal gene: PIEZO1, Ensembl ENSG00000103335; approved name piezo type mechanosensitive ion channel component 1 (Er blood group). OpenTargets identifies PIEZO1 as the sole associated target, supported by five evidence records and multiple disease-defining publications. (OpenTargets Search: lymphatic malformation 6)
• Common synonyms: generalized lymphatic dysplasia with nonimmune hydrops fetalis; PIEZO1-related generalized lymphatic dysplasia; congenital lymphatic dysplasia; hereditary lymphedema due to PIEZO1 deficiency; Fotiou generalized lymphatic dysplasia.
• Classification: congenital primary lymphatic anomaly; autosomal-recessive Mendelian disease.

No unique disease-specific ICD-10, ICD-11, or MeSH code was established in the retrieved evidence. Coding therefore generally relies on broader categories for congenital lymphatic malformation, primary lymphedema, hydrops fetalis, or chylous effusion. The evidence summarized here is principally aggregated disease-level information derived from published families and experimental studies, not individual EHR data.

Defining abstract quotations

Fotiou et al. defined GLD as “a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions.” They further reported “homozygous and compound heterozygous mutations in PIEZO1, resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis.” Published September 2015; DOI: https://doi.org/10.1038/ncomms9085; PMID 26333996. (OpenTargets Search: lymphatic malformation 6, fotiou2015novelmutationsin pages 1-2)

Lukacs et al. reported: “Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 … in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia.” Published September 2015; DOI: https://doi.org/10.1038/ncomms9329; PMID 26387913. (OpenTargets Search: lymphatic malformation 6, iyer2020lymphaticvalvesand pages 15-17)

2. Etiology

Causal factors and genetic risk

The established cause is biallelic pathogenic or likely pathogenic PIEZO1 variation, usually homozygous or compound heterozygous, producing absent protein, defective membrane trafficking, or impaired mechanically activated channel function. Reported classes include nonsense, canonical splice-site, frameshift/deletion, and missense variants. Ten variants were initially identified across six families; an independently reported sibling pair carried a splice/truncating allele and a missense allele. (iyer2020lymphaticvalvesand pages 15-17, fotiou2015novelmutationsin pages 1-2, cheng2025piezo1variantimplications pages 3-4)

Important genotype distinction:

1. Biallelic PIEZO1 loss of function causes LM6/GLD.
2. Heterozygous PIEZO1 gain-of-function variants more commonly cause autosomal-dominant dehydrated hereditary stomatocytosis, sometimes accompanied by perinatal edema or hydrops. These allelic disorders should not be conflated. (iyer2020lymphaticvalvesand pages 15-17, ludlow2023smallmoleculefunctionalrescue pages 5-8)

Family history, parental consanguinity, and carriage of a pathogenic allele in each parent increase reproductive risk. A pseudo-dominant pedigree can occur when an affected homozygous person and a heterozygous carrier have affected children, as reported for the I2270T allele in a consanguineous family. (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 14-16)

Environmental, infectious, and lifestyle factors

No reproducible toxin, radiation, infectious, dietary, smoking, alcohol, occupational, or other environmental cause has been demonstrated. There is likewise no established environmental protective factor or validated gene–environment interaction. Mechanical forces are essential physiological signals sensed by PIEZO1, but they are part of the molecular mechanism—not an avoidable environmental exposure.

No genetic protective allele has been validated for LM6. Variable residual PIEZO1 activity may modify severity, but this remains a genotype–function hypothesis rather than a clinically validated protective factor.

3. Phenotypes

The phenotype is multisystemic and markedly variable. Reliable disease-specific percentages are unavailable because published cohorts are small.

• Nonimmune hydrops fetalis — HP:0001561: prenatal sign, often detected in the second or third trimester; ranges from transient to lethal. One founding-family fetus died at 34 weeks, whereas hydrops resolved after birth in some survivors. (fotiou2015novelmutationsin pages 1-2, fotiou2015novelmutationsin pages 2-3)
• Pleural effusion — HP:0002202; chylothorax — HP:0010318: prenatal, neonatal, childhood, or adult manifestation; may be bilateral and persistent. In a recent family, bilateral hydrothoraces were detected at 19 weeks; another patient developed bilateral chylothoraces in the third decade. (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 41-45)
• Pericardial effusion — HP:0001698: systemic lymphatic manifestation; CT documentation accompanied bilateral chylothorax in one recent proband. (ludlow2023smallmoleculefunctionalrescue pages 41-45)
• Ascites — HP:0001744: prenatal or postnatal fluid accumulation resulting from defective lymphatic drainage. (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 5-8)
• Generalized/peripheral lymphedema — HP:0001789: congenital or delayed onset, affecting all four limbs, face, and sometimes genitalia. Some founding-cohort survivors developed edema around 6–9 years, whereas recent families expand onset into adulthood. (ludlow2023smallmoleculefunctionalrescue pages 8-10, fotiou2015novelmutationsin pages 2-3, ludlow2023smallmoleculefunctionalrescue pages 5-8)
• Facial edema/facial dysmorphism — suggested HP:0000978: secondary to chronic lymphatic swelling; may impair appearance, oral function, and psychosocial well-being. (fotiou2015novelmutationsin pages 1-2)
• Lymphangiectasia — HP:0001733: intestinal or pulmonary; may lead to respiratory morbidity, protein loss, nutritional problems, and recurrent effusions. (choi2022piezo1regulatedmechanotransductioncontrols pages 10-12, fotiou2015novelmutationsin pages 1-2)
• Polyhydramnios — HP:0002023: reported in antenatally affected pregnancies. (ludlow2023smallmoleculefunctionalrescue pages 8-10)
• Recurrent cellulitis: two founding-cohort patients had severe recurrent facial cellulitis, a complication of chronic edema and impaired local barrier/immune function. (fotiou2015novelmutationsin pages 2-3)
• Subtle erythrocyte abnormalities: stomatocytes or spherocytes were reported in some affected people and carriers, but these are inconsistent and are not diagnostic of LM6. (fotiou2015novelmutationsin pages 2-3)

Quality-of-life studies specific to LM6 were not retrieved. Expected burdens include chronic swelling, disfigurement, restricted mobility, recurrent infection, dyspnea from thoracic effusions, repeated drainage or hospitalization, and psychosocial effects. These impacts are clinically plausible but have not been quantified with EQ-5D, SF-36, or a disease-specific instrument in a sufficiently large LM6 cohort.

4. Genetic and molecular information

PIEZO1 encodes a large trimeric mechanosensitive ion channel that increases membrane permeability to calcium and other cations in response to membrane tension, stretch, and fluid shear. Disease-associated LM6 alleles generally reduce mechanosensitivity or channel abundance. (du2024themechanosensorychannel pages 1-2, iyer2020lymphaticvalvesand pages 15-17)

Reported variants in retrieved studies include truncating alleles p.E755X, p.E1630X, and p.Q2228X, splice donor c.3796+1G>A, and recent missense substitutions E829V, G1978D, I2270T, and R2335Q. The 2015 study also documented another splice-site allele, c.1669+1G>A. Exact transcript-dependent HGVS normalization should be verified against the current MANE transcript before database ingestion. (fotiou2015novelmutationsin pages 1-2, fotiou2015novelmutationsin pages 2-3, ludlow2023smallmoleculefunctionalrescue pages 41-45)

The early variants segregated with disease; most were absent from dbSNP, 1000 Genomes, and 900 controls, while two had reported minor-allele frequencies of approximately 0.0002. The four 2023 missense alleles were absent or ultra-rare in gnomAD, with no homozygotes reported. (fotiou2015novelmutationsin pages 1-2, ludlow2023smallmoleculefunctionalrescue pages 41-45)

Functional consequences include exon skipping or intron retention, premature truncation, reduced/absent protein, impaired surface trafficking, and channels that reach the membrane but have markedly reduced mechanosensitivity. In 2023 assays, the missense channels exhibited approximately 65–90% lower calcium signaling than wild type; I2270T produced no detectable stretch-activated current under the tested conditions. Yoda1 restored activity in several mutant channels. (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 14-16)

No validated modifier gene, disease-specific methylation signature, recurrent chromosomal abnormality, or somatic mosaic mechanism has been established. The disorder is primarily a germline single-gene disease.

5. Environmental information

Environmental toxins, pollution, radiation, infection, diet, exercise, smoking, and alcohol have no established etiological role. Infection can occur secondarily as cellulitis in chronically edematous tissue but is not the primary cause. Lifestyle measures may reduce secondary lymphedema complications but cannot correct PIEZO1 deficiency.

6. Mechanism and pathophysiology

Causal chain

Biallelic PIEZO1 loss of function → deficient lymphatic endothelial sensing of shear/stretch → reduced calcium-dependent mechanotransduction → disturbed valve-gene regulation, endothelial rearrangement, sprouting, and vessel maintenance → valve paucity/regression and malformed lymphatic networks → lymph reflux or failed drainage → fetal effusions/hydrops, lymphangiectasia, chylothorax, ascites, and chronic lymphedema. Human genetics establishes the upstream cause; cell and mouse studies establish the intervening mechanism. (du2024themechanosensorychannel pages 1-2, choi2019piezo1incorporatesmechanical pages 2-4, choi2022piezo1regulatedmechanotransductioncontrols pages 1-3, iyer2020lymphaticvalvesand pages 15-17, fotiou2015novelmutationsin pages 1-2)

Principal pathways

1. Valve morphogenesis: Piezo1 detects oscillatory shear stress in lymphatic endothelial cells. Conditional deletion suppresses valve formation in newborn mice; adult deletion causes substantial valve degeneration. Knockdown prevents flow-induced expression of valve genes, whereas overexpression or Yoda1 activation promotes valve-gene expression. (choi2019piezo1incorporatesmechanical pages 2-4, choi2019piezo1incorporatesmechanical pages 1-2)
2. Cytoskeletal and junctional remodeling: endothelial Piezo1 knockout impairs valve-leaflet protrusion, collective migration, actin polymerization, and remodeling of VE-cadherin-positive junctions. Knockout mice have markedly fewer lymphatic valves, pleural effusions, and postnatal death. (iyer2020lymphaticvalvesand pages 15-17)
3. PIEZO1–ORAI1–KLF2/DTX/NOTCH axis: flow-activated PIEZO1 lies upstream of ORAI1-dependent calcium signaling and regulates KLF2, DTX1, DTX3L, and NOTCH1. Loss causes embryonic sprouting defects and adult lymphatic regression; Dtx3L expression can rescue aspects of the knockout phenotype. (choi2022piezo1regulatedmechanotransductioncontrols pages 10-12, choi2022piezo1regulatedmechanotransductioncontrols pages 1-3)
4. 2024 ANGPT2/TIE/PI3K/AKT/FOXO1 advance: PIEZO1 activation triggers ANGPT2 exocytosis, ADAM17-dependent TIE1 ectodomain shedding, increased TIE/PI3K/AKT signaling, and FOXO1 nuclear export. It regulates lymphedema-associated valve genes including FOXC2, GATA2, GJA4, and ITGA9. Published May 2024; DOI: https://doi.org/10.1172/JCI176577. (du2024themechanosensorychannel pages 1-2)

Suggested annotations include GO:0034405 response to fluid shear stress, GO:0001946 lymphangiogenesis, calcium-ion transport/signaling, actin-cytoskeleton organization, cell–cell junction organization, and PI3K/AKT signaling. The principal cell is the lymphatic endothelial cell; use the current Cell Ontology identifier after release-specific validation. No robust LM6-specific metabolomic, lipidomic, proteomic, epigenomic, single-cell, spatial-transcriptomic, or multi-omic patient signature has been validated.

7. Anatomical structures affected

The primary lesion is distributed throughout the lymphatic vasculature, especially collecting vessels, intraluminal lymphatic valves, and lymphovenous drainage structures. Suggested anatomy annotations are UBERON:0005409 lymphatic vessel, lymphatic capillary, collecting lymphatic vessel, lymphatic valve, and lymphatic endothelium.

Secondary sites include subcutaneous connective tissue of all limbs and face; pleural and pericardial cavities; lungs; intestinal lymphatics; abdominal/peritoneal cavity; and occasionally genital tissue. Disease is typically generalized and often asymmetric in severity rather than strictly unilateral. At the subcellular level, PIEZO1 is a plasma-membrane channel, although intracellular channel pools were suggested by calcium-release experiments. (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 5-8)

8. Temporal development

Onset may be antenatal, congenital, childhood, or—less commonly—adult. Prenatal disease is chronic developmental rather than an acute acquired process. Hydrops may remit spontaneously around birth, but remission does not ensure cure: edema and systemic lymphatic complications can recur years later. Founding survivors developed lymphedema at approximately 6–9 years; a recent family included adult-onset bilateral chylothoraces in the 30s. (ludlow2023smallmoleculefunctionalrescue pages 8-10, fotiou2015novelmutationsin pages 2-3, cheng2025piezo1variantimplications pages 3-4)

There is no validated staging system. A pragmatic course is: prenatal effusions/hydrops; neonatal stabilization or death; latent/partially resolved interval in some survivors; then chronic lymphedema, lymphangiectasia, recurrent effusions, or infections. The disease is generally lifelong even if individual fluid collections resolve.

9. Inheritance and population

Inheritance is predominantly autosomal recessive, with variable expressivity and incompletely defined penetrance. For two confirmed carrier parents, standard Mendelian counseling predicts a 25% affected, 50% carrier, and 25% unaffected/noncarrier probability for each pregnancy. Pseudo-dominant inheritance can occur in consanguineous pedigrees. Germline mosaicism has not been established but cannot be excluded in apparently de novo recurrence. No founder allele, carrier frequency, ethnic enrichment, sex bias, anticipation, or geographic concentration is established. (fotiou2015novelmutationsin pages 1-2, ludlow2023smallmoleculefunctionalrescue pages 14-16)

Disease-specific prevalence and incidence are unknown. A broad estimate of approximately 1 in 6,000 was mentioned for generalized lymphatic dysplasia in a 2023 preprint, but it should not be used as an established LM6 prevalence because the denominator and molecular ascertainment were not disease-specific. (ludlow2023smallmoleculefunctionalrescue pages 5-8)

10. Diagnostics

Clinical and imaging assessment

Prenatal ultrasound should evaluate skin edema, ascites, pleural/pericardial effusions, hydrothorax, placental edema, and polyhydramnios. Postnatal assessment may include ultrasound, echocardiography, chest radiography/CT or MRI, lymphoscintigraphy, and—where available—dynamic contrast MR lymphangiography to define central lymphatic flow. Lymphoscintigraphy was consistently abnormal in four founding-cohort patients. (fotiou2015novelmutationsin pages 2-3)

Laboratory evaluation is mainly directed toward complications: CBC and blood film; hemolysis indices where stomatocytosis is suspected; albumin, total protein, immunoglobulins and lymphocyte counts for intestinal lymph loss; electrolytes; and pleural-fluid triglycerides/chylomicrons for chylothorax. No validated circulating LM6 biomarker exists.

Genetic testing algorithm

1. Confirm a generalized congenital lymphatic phenotype and exclude immune, cardiac, chromosomal, infectious, hematologic, and structural causes of hydrops.
2. Use a primary-lymphedema/generalized lymphatic-anomaly panel that includes PIEZO1 and relevant differential genes such as PIEZO2, EPHB4, RASA1, ANGPT2, TIE1, FLT4, CCBE1, FAT4, ADAMTS3, FOXC2, GATA2, PTPN14, and PIK3CA.
3. If negative, perform trio WES or WGS; WGS is useful for deep intronic, structural, and poorly captured variants.
4. Confirm candidate PIEZO1 variants by segregation analysis. For missense VUS, functional channel assays may be decisive because surface-localized protein can still lack mechanical activity. (iyer2020lymphaticvalvesand pages 15-17, ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 41-45)

CMA or karyotyping is appropriate in fetal hydrops with multiple anomalies but does not specifically diagnose LM6. FISH, mitochondrial testing, and repeat-expansion testing are not routine LM6 investigations.

Differential diagnoses include PIK3CA-related lymphatic malformations, Hennekam lymphangiectasia-lymphedema syndrome, hereditary lymphedema caused by FLT4 or FOXC2, EPHB4-related lymphatic-related hydrops, RASopathies, Turner syndrome, congenital infection, fetal anemia, cardiac disease, and heterozygous PIEZO1-associated dehydrated hereditary stomatocytosis.

11. Outcome and prognosis

Prognosis is variable. Severe prenatal disease can cause miscarriage, stillbirth, or neonatal death; one reported fetus died at 34 weeks. Survivors may have complete early resolution of hydrops yet later develop chronic generalized lymphedema, recurrent cellulitis, respiratory compromise, chylothorax, pericardial effusion, ascites, or intestinal protein loss. No reliable five- or ten-year survival estimate, life-expectancy figure, validated prognostic score, or molecular prognostic biomarker exists. (fotiou2015novelmutationsin pages 1-2, fotiou2015novelmutationsin pages 2-3, cheng2025piezo1variantimplications pages 3-4)

Residual channel function, extent of thoracic/intestinal involvement, persistence of prenatal effusions, and ability to control chyle loss are plausible prognostic factors, but they have not been validated in a sufficiently large prospective cohort.

12. Treatment

There is no approved disease-modifying or PIEZO1-genotype-specific therapy. Management should be coordinated through a multidisciplinary vascular-anomalies/primary-lymphedema team.

• Lymphedema care: compression garments or bandaging, skin care, exercise, manual lymphatic drainage where appropriate, weight optimization, rapid treatment of cellulitis, and physical/occupational therapy.
• Effusions and chylothorax: respiratory support, drainage when clinically required, nutritional management with low long-chain-fat/high-medium-chain-triglyceride feeding or parenteral nutrition, and individualized lymphatic interventional procedures.
• Surgery/intervention: pleurodesis, thoracic-duct or abnormal-channel embolization, lymphovenous procedures, or debulking may be considered according to anatomy and severity; no LM6-specific response rate is established.
• Sirolimus/rapamycin: used for complicated lymphatic anomalies generally, but no controlled evidence establishes efficacy specifically for biallelic PIEZO1 LM6.
• Alpelisib: appropriate only for proven PIK3CA-driven disease; it is not mechanistically indicated solely by a PIEZO1 diagnosis.

Current non-genotype-specific studies include NCT06673290 (sirolimus, recruiting, n=150), NCT03243019 (rapamycin, recruiting, n=28), NCT06239480 (topical rapamycin, phase 3, active-not-recruiting, n=51), NCT05948943 (alpelisib for PIK3CA-mutant malformations, recruiting, n=232), and completed NCT00975819 (sirolimus in complicated vascular anomalies, n=61). None should be represented as an LM6-specific trial. (OpenTargets Search: lymphatic malformation 6)

Experimental PIEZO1 agonism

Yoda1 accelerated valve formation, promoted lymphatic sprouting, reduced postsurgical lymphedema in mice, and rescued several mechanically insensitive human mutant channels in vitro. The 2023 study stated that “The potential to pharmacologically overcome the loss of force sensing was demonstrated.” This is promising precision-therapy evidence but remains preclinical; systemic PIEZO1 activation could affect erythrocytes and other vascular tissues and requires rigorous safety evaluation. DOI: https://doi.org/10.1101/2023.08.01.23292554. (choi2022piezo1regulatedmechanotransductioncontrols pages 1-3, ludlow2023smallmoleculefunctionalrescue pages 14-16, ludlow2023smallmoleculefunctionalrescue pages 5-8)

Suggested NCIT annotations include Genetic Counseling, Supportive Care, Lymphedema Therapy, Compression Therapy, Sirolimus, Alpelisib, Pleurodesis, and Clinical Trial; exact NCIT identifiers should be release-validated.

13. Prevention

No primary lifestyle or environmental prevention exists. The principal preventive strategy is genetic counseling with cascade testing of relatives, partner testing where appropriate, and discussion of prenatal diagnosis or preimplantation genetic testing when familial pathogenic variants are known. Prenatal molecular testing should be accompanied by serial ultrasound because severity is variable even within families.

Secondary prevention comprises early recognition of fetal effusions, anticipatory delivery planning at a tertiary center, and surveillance for recurrent pleural/pericardial effusion, intestinal lymph loss, and progressive edema. Tertiary prevention includes compression, meticulous skin care, prompt treatment of cellulitis, nutritional management of chyle loss, vaccination according to routine schedules, and rehabilitation. No vaccine or prophylactic medication prevents LM6 itself.

14. Other species and natural disease

No well-established naturally occurring PIEZO1-LM6 counterpart in companion animals, livestock, or wildlife was retrieved, and there is no zoonotic or transmissible component. PIEZO1 and lymphatic-valve mechanobiology are evolutionarily conserved. Zebrafish possess lymphatic valves and are useful for comparative developmental studies, but a validated natural zebrafish LM6 disease was not identified.

15. Model organisms

The strongest models are genetically engineered mice and cultured lymphatic endothelial cells.

• Tie2Cre;Piezo1 conditional knockout mice: endothelial loss causes pleural effusion, marked lymphatic-valve reduction, and postnatal death.
• Lyve1Cre;Piezo1 knockout mice: lymphatic/endothelial targeting confirms a valve requirement.
• Prox1-CreERT2 and Cdh5(PAC)-CreERT2 models: temporally controlled deletion demonstrates requirements in neonatal valve formation and adult valve maintenance.
• Lymphatic-specific embryonic/adult deletion models: reproduce sprouting defects, reduced branching, delayed valve formation, and adult vessel regression.
• Cultured human or mouse lymphatic endothelial cells: support shear-stress, calcium imaging, patch-clamp, trafficking, RNA-expression, and ANGPT2/TIE/FOXO1 pathway studies.
• Heterologous expression systems: determine whether individual human missense variants alter surface localization, mechanically activated current, calcium influx, or Yoda1 responsiveness. (du2024themechanosensorychannel pages 1-2, choi2019piezo1incorporatesmechanical pages 2-4, choi2022piezo1regulatedmechanotransductioncontrols pages 10-12, iyer2020lymphaticvalvesand pages 15-17, ludlow2023smallmoleculefunctionalrescue pages 8-10)

These models reproduce central mechanistic features but not the complete variability of human prenatal hydrops, multiorgan lymphangiectasia, or long-term treatment response. Consequently, Yoda1 rescue in cells or mice cannot yet be extrapolated to clinical efficacy.

Evidence limitations and curation recommendations

LM6 remains exceptionally rare, and most clinical evidence consists of small pedigrees and case reports. Phenotype frequencies, penetrance, prevalence, survival, quality of life, and treatment-response rates therefore remain uncertain. The 2023 functional-rescue report was retrieved as a medRxiv preprint and should be labeled accordingly. Ontology identifiers suggested above should be checked against current HPO, GO, CL, UBERON, NCIT, and HGNC releases before production ingestion. Most importantly, treatment evidence for broad lymphatic malformations should not be attributed automatically to PIEZO1-related LM6.

References

1. (OpenTargets Search: lymphatic malformation 6): Open Targets Query (lymphatic malformation 6, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (iyer2020lymphaticvalvesand pages 15-17): Drishya Iyer, Melanie Jannaway, Ying Yang, and Joshua P. Scallan. Lymphatic valves and lymph flow in cancer-related lymphedema. Cancers, 12:2297, Aug 2020. URL: https://doi.org/10.3390/cancers12082297, doi:10.3390/cancers12082297. This article has 50 citations.

3. (fotiou2015novelmutationsin pages 1-2): Elisavet Fotiou, Silvia Martin-Almedina, Michael A. Simpson, Shin Lin, Kristiana Gordon, Glen Brice, Giles Atton, Iona Jeffery, David C. Rees, Cyril Mignot, Julie Vogt, Tessa Homfray, Michael P. Snyder, Stanley G. Rockson, Steve Jeffery, Peter S. Mortimer, Sahar Mansour, and Pia Ostergaard. Novel mutations in piezo1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis. Nature Communications, Sep 2015. URL: https://doi.org/10.1038/ncomms9085, doi:10.1038/ncomms9085. This article has 380 citations and is from a highest quality peer-reviewed journal.

4. (du2024themechanosensorychannel pages 1-2): Jing Du, Pan Liu, Yalu Zhou, Sol Misener, Isha Sharma, Phoebe Leeaw, Benjamin R. Thomson, Jing Jin, and Susan E. Quaggin. The mechanosensory channel piezo1 functions upstream of angiopoietin/tie/foxo1 signaling in lymphatic development. The Journal of Clinical Investigation, May 2024. URL: https://doi.org/10.1172/jci176577, doi:10.1172/jci176577. This article has 33 citations.

5. (choi2022piezo1regulatedmechanotransductioncontrols pages 1-3): Dongwon Choi, Eunkyung Park, Roy P. Yu, Michael N. Cooper, Il-Taeg Cho, Joshua Choi, James Yu, Luping Zhao, Ji-Eun Irene Yum, Jin Suh Yu, Brandon Nakashima, Sunju Lee, Young Jin Seong, Wan Jiao, Chester J. Koh, Peter Baluk, Donald M. McDonald, Sindhu Saraswathy, Jong Y. Lee, Noo Li Jeon, Zhenqian Zhang, Alex S. Huang, Bin Zhou, Alex K. Wong, and Young-Kwon Hong. Piezo1-regulated mechanotransduction controls flow-activated lymphatic expansion. Circulation Research, Jul 2022. URL: https://doi.org/10.1161/circresaha.121.320565, doi:10.1161/circresaha.121.320565. This article has 115 citations and is from a highest quality peer-reviewed journal.

6. (ludlow2023smallmoleculefunctionalrescue pages 14-16): Melanie J Ludlow, Oleksandr V Povstyan, Deborah M Linley, Silvia Martin-Almedina, Charlotte Revill, Kevin Cuthbertson, Katie A Smith, Emily Fay, Elisavet Fotiou, Andrew Bush, Claire Hogg, Tobias Linden, Natalie B Tan, Susan M White, Esther Dempsey, Sahar Mansour, Gregory Parsonage, Antreas C Kalli, Richard Foster, Pia Ostergaard, and David J Beech. Small-molecule functional rescue of piezo1 channel variants associated with generalised lymphatic dysplasia. MedRxiv, Aug 2023. URL: https://doi.org/10.1101/2023.08.01.23292554, doi:10.1101/2023.08.01.23292554. This article has 5 citations.

7. (fotiou2015novelmutationsin pages 2-3): Elisavet Fotiou, Silvia Martin-Almedina, Michael A. Simpson, Shin Lin, Kristiana Gordon, Glen Brice, Giles Atton, Iona Jeffery, David C. Rees, Cyril Mignot, Julie Vogt, Tessa Homfray, Michael P. Snyder, Stanley G. Rockson, Steve Jeffery, Peter S. Mortimer, Sahar Mansour, and Pia Ostergaard. Novel mutations in piezo1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis. Nature Communications, Sep 2015. URL: https://doi.org/10.1038/ncomms9085, doi:10.1038/ncomms9085. This article has 380 citations and is from a highest quality peer-reviewed journal.

8. (ludlow2023smallmoleculefunctionalrescue pages 41-45): Melanie J Ludlow, Oleksandr V Povstyan, Deborah M Linley, Silvia Martin-Almedina, Charlotte Revill, Kevin Cuthbertson, Katie A Smith, Emily Fay, Elisavet Fotiou, Andrew Bush, Claire Hogg, Tobias Linden, Natalie B Tan, Susan M White, Esther Dempsey, Sahar Mansour, Gregory Parsonage, Antreas C Kalli, Richard Foster, Pia Ostergaard, and David J Beech. Small-molecule functional rescue of piezo1 channel variants associated with generalised lymphatic dysplasia. MedRxiv, Aug 2023. URL: https://doi.org/10.1101/2023.08.01.23292554, doi:10.1101/2023.08.01.23292554. This article has 5 citations.

9. (ludlow2023smallmoleculefunctionalrescue pages 5-8): Melanie J Ludlow, Oleksandr V Povstyan, Deborah M Linley, Silvia Martin-Almedina, Charlotte Revill, Kevin Cuthbertson, Katie A Smith, Emily Fay, Elisavet Fotiou, Andrew Bush, Claire Hogg, Tobias Linden, Natalie B Tan, Susan M White, Esther Dempsey, Sahar Mansour, Gregory Parsonage, Antreas C Kalli, Richard Foster, Pia Ostergaard, and David J Beech. Small-molecule functional rescue of piezo1 channel variants associated with generalised lymphatic dysplasia. MedRxiv, Aug 2023. URL: https://doi.org/10.1101/2023.08.01.23292554, doi:10.1101/2023.08.01.23292554. This article has 5 citations.

10. (ludlow2023smallmoleculefunctionalrescue pages 8-10): Melanie J Ludlow, Oleksandr V Povstyan, Deborah M Linley, Silvia Martin-Almedina, Charlotte Revill, Kevin Cuthbertson, Katie A Smith, Emily Fay, Elisavet Fotiou, Andrew Bush, Claire Hogg, Tobias Linden, Natalie B Tan, Susan M White, Esther Dempsey, Sahar Mansour, Gregory Parsonage, Antreas C Kalli, Richard Foster, Pia Ostergaard, and David J Beech. Small-molecule functional rescue of piezo1 channel variants associated with generalised lymphatic dysplasia. MedRxiv, Aug 2023. URL: https://doi.org/10.1101/2023.08.01.23292554, doi:10.1101/2023.08.01.23292554. This article has 5 citations.

11. (choi2019piezo1incorporatesmechanical pages 2-4): Dongwon Choi, Eunkyung Park, Eunson Jung, Boksik Cha, Somin Lee, James Yu, Paul M. Kim, Sunju Lee, Yeo Jin Hong, Chester J. Koh, Chang-Won Cho, Yifan Wu, Noo Li Jeon, Alex K. Wong, Laura Shin, S. Ram Kumar, Ivan Bermejo-Moreno, R. Sathish Srinivasan, Il-Taeg Cho, and Young-Kwon Hong. Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance. JCI insight, May 2019. URL: https://doi.org/10.1172/jci.insight.125068, doi:10.1172/jci.insight.125068. This article has 180 citations and is from a domain leading peer-reviewed journal.

12. (choi2019piezo1incorporatesmechanical pages 1-2): Dongwon Choi, Eunkyung Park, Eunson Jung, Boksik Cha, Somin Lee, James Yu, Paul M. Kim, Sunju Lee, Yeo Jin Hong, Chester J. Koh, Chang-Won Cho, Yifan Wu, Noo Li Jeon, Alex K. Wong, Laura Shin, S. Ram Kumar, Ivan Bermejo-Moreno, R. Sathish Srinivasan, Il-Taeg Cho, and Young-Kwon Hong. Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance. JCI insight, May 2019. URL: https://doi.org/10.1172/jci.insight.125068, doi:10.1172/jci.insight.125068. This article has 180 citations and is from a domain leading peer-reviewed journal.

13. (choi2022piezo1regulatedmechanotransductioncontrols pages 10-12): Dongwon Choi, Eunkyung Park, Roy P. Yu, Michael N. Cooper, Il-Taeg Cho, Joshua Choi, James Yu, Luping Zhao, Ji-Eun Irene Yum, Jin Suh Yu, Brandon Nakashima, Sunju Lee, Young Jin Seong, Wan Jiao, Chester J. Koh, Peter Baluk, Donald M. McDonald, Sindhu Saraswathy, Jong Y. Lee, Noo Li Jeon, Zhenqian Zhang, Alex S. Huang, Bin Zhou, Alex K. Wong, and Young-Kwon Hong. Piezo1-regulated mechanotransduction controls flow-activated lymphatic expansion. Circulation Research, Jul 2022. URL: https://doi.org/10.1161/circresaha.121.320565, doi:10.1161/circresaha.121.320565. This article has 115 citations and is from a highest quality peer-reviewed journal.

14. (cheng2025piezo1variantimplications pages 3-4): Chew W. Cheng, Sophie L. Earle, Oleksandr V. Povstyan, Chloe Randall, Katie A. Smith, Marjolaine Debant, Fraser L. Macrae, Daniel G. Beech, Anna McGrane, Fiona Bartoli, Eulashini Chuntharpursat-Bon, Richard M. Cubbon, Kathryn J. Griffin, Marc A. Bailey, Antreas C. Kalli, Lara C. Morley, Klaus K. Witte, and David J. Beech. Piezo1 variant implications for biological understanding and human health. Open Biology, Jul 2025. URL: https://doi.org/10.1098/rsob.240345, doi:10.1098/rsob.240345. This article has 11 citations and is from a peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.