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Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly

A Correction to this article was published on 03 June 2022

This article has been updated


Central conducting lymphatic anomaly (CCLA) is a heterogenous disorder caused by disruption of central lymphatic flow that may result in dilation or leakage of central lymphatic channels. There is also a paucity of known genetic diagnoses associated with CCLA. We hypothesized that specific genetic syndromes would have distinct lymphatic patterns and this would allow us to more precisely define CCLA. As a first step toward “precision lymphology”, we defined the genetic conditions associated with CCLA by performing a retrospective cohort study. Individuals receiving care through the Jill and Mark Fishman Center for Lymphatic Disorders at the Children’s Hospital of Philadelphia between 2016 and 2019 were included if they had a lymphangiogram and clinical genetic testing performed and consented to a clinical registry. In our cohort of 115 participants, 26% received a molecular diagnosis from standard genetic evaluation. The most common genetic etiologies were germline and mosaic RASopathies, chromosomal abnormalities including Trisomy 21 and 22q11.2 deletion syndrome, and PIEZO1-related lymphatic dysplasia. Next, we analyzed the dynamic contrast magnetic resonance lymphangiograms and found that individuals with germline and mosaic RASopathies, mosaic KRASopathies, PIEZO1-related lymphatic dysplasia, and Trisomy 21 had distinct central lymphatic flow phenotypes. Our research expands the genetic conditions associated with CCLA and genotype-lymphatic phenotype correlations. Future descriptions of CCLA should include both genotype (if known) and phenotype to provide more information about disease (gene-CCLA). This should be considered for updated classifications of CCLA by the International Society of Vascular Anomalies.

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Fig. 1: CONSORT diagram.
Fig. 2: The clinical phenotype of participants in the confirmed category.
Fig. 3: Representative imaging findings based on genotype.

Data availability

The data that support this study are available in the tables and Supplementary Tables. Additional data is not available due to privacy restrictions.

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The authors thank the patients, their families, and the other clinicians that have helped care for the individuals in this study. We thank Lymphatic Center, CAG and CVAP team members for their insightful comments and discussion.


Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR001880 (SES). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research reported in the publication was supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania (SES), The Children’s Hospital of Philadelphia Comprehensive Vascular Anomalies Frontier Program (HH), The Children’s Hospital of Philadelphia K-readiness grant (SES), Uplifting Athletes and the Lymphangiomatosis Gorham’s Disease Alliance (SES).

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Conceptualization: YD, SES; Data curation: ML, CS, YD, SES; Formal Analysis: ML, CS, DL, SES; Funding acquisition: YD, SES; Investigation: ML, CS, DMB, DL, NR, EP, CS, EHZ, YD, SES; Methodology: ML, SS; Project administration: ML, YD; Supervision: YD, SES; Validation: ML, CS; Visualization: ML, CS, YD, SES; Writing (original draft): ML, SES; Writing (review & editing): ML, CS, DL, HH, YD, SES.

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Correspondence to Sarah E. Sheppard.

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Competing interests

HH and The Children’s Hospital of Philadelphia are equity holders in Nobias Therapeutics Inc., developing MEK inhibitor therapy for complex lymphatic anomalies. Other authors declare no competing interests.

Ethics approval and consent to participate

The Children’s Hospital of Philadelphia Institutional Review Board approved a registry and biorepository study (PI YD). Informed consent was obtained from all participants as required by the IRB.

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Liu, M., Smith, C.L., Biko, D.M. et al. Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly. Eur J Hum Genet (2022).

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