Digenic Inheritance of a FOXC2 Mutation and Two PIEZO1 Mutations Underlies Congenital Lymphedema in a Multigeneration Family - 08/02/22

Doi : 10.1016/j.amjmed.2021.09.007

Debbie J. Mustacich, PhD ^a, Li-Wen Lai, PhD ^b, Michael J. Bernas, MS ^a,^{^{1
Full current address: TCU and UNTHS School of Medicine, 3500 Camp Bowie Blvd., Fort Worth, TX 76107.}}, Jazmine A. Jones, BS ^a, Reginald J. Myles, BS ^a, Phillip H. Kuo, MD, PhD ^c, Walter H. Williams, PhD, MD ^c, Charles L. Witte, MD ^a,^{^{2
Deceased.}}, Robert P. Erickson, MD ^d , Marlys Hearst Witte, MD ^a,^d,^⁎
^a Department of Surgery, University of Arizona College of Medicine, Tucson
^b Department of Pathology, University of Arizona College of Medicine, Tucson
^c Medical Imaging (Nuclear Medicine), University of Arizona College of Medicine, Tucson
^d Department of Pediatrics, University of Arizona College of Medicine, Tucson

^⁎Requests for reprints should be addressed to Marlys H. Witte, MD & Robert P. Erickson, MD, Departments of Surgery, Neurosurgery, & Pediatrics, University of Arizona College of Medicine, 1501 N. Campbell Avenue, PO Box 245200, Tucson, AZ 85724-5200.Departments of Surgery, Neurosurgery, & PediatricsUniversity of Arizona College of Medicine, 1501 N. Campbell Avenue, PO Box 245200, AZ 85724-5200Tucson

Abstract

Background

The lymphatic system is essential for maintaining the balance of interstitial fluid in tissues and for returning protein-rich fluids (lymph) to the bloodstream. Congenital lymphatic defects lead to accumulation of lymph in peripheral tissues and body cavities, termed primary lymphedema. To date, only a limited number of individual genes have been identified in association with primary lymphedema. However, variability of age of onset and severity of lymphatic abnormalities within some families suggests that multiple mutations or genes may be responsible, thus hampering efforts to identify individual associated genes.

Methods

Whole exome sequencing (WES) was performed in 4 members of a large multigeneration family with highly variable lymphedema and followed by Sanger sequencing for identified mutations in 34 additional family members. Genotypes were correlated with clinical and lymphangioscintigraphic phenotypes.

Results

WES uncovered 2 different mechanotransducer PIEZO1 mutations and one FOXC2 transcription factor mutation in various combinations. Sanger sequencing confirmed the presence/absence of the 3 variants in affected and unaffected family members and co-segregation of one or more variants with disease. Genetic profiles did not clearly correlate with the highly variable severity of lymphatic abnormalities.

Conclusions

WES in lymphedema families can uncover unexpected combinations of several lymphedema-associated mutations. These findings provide essential information for genetic counseling and reveal complex gene interactions in lymphatic developmental pathways. These can offer insights into the complex spectrum of clinical and lymphatic lymphedema phenotypes and potential targets for treatment.

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Keywords : Digenic inheritance, Familial lymphedema, FOXC2, Genotype-phenotype correlations, Jaundice, Lymphangioscintigraphy, PIEZO1

Plan

Introduction

Materials and Methods

	Funding: University of Arizona Translational Imaging Program Projects Stimulus (TIPPS) grant (MW, PK); National Institutes of Health/National Heart, Lung, and Blood Institute R25HL108837 (JJ, RM); and Arizona Disease Control Commission Contract ID No. 9-056 (RE, MW).
	Conflicts of Interest: None.
	Authorship: All authors had access to the data and a role in writing the final manuscript except CLW, who is deceased.