Milroy Disease (Lymphedema Type I) via the FLT4 Gene

Lymph is a clear-to-white interstitial fluid comprised primarily of white blood cells, proteins, and lipids. The lymphatic system is a subset of the circulatory system with vessels and nodes that transport lymph throughout the body and includes the tonsils, adenoids, spleen, and thymus. The primary functions of the lymphatic system include ridding the body of infection and maintaining fluid balance. Improper lymphatic function can lead to lymph accumulation and swelling known as lymphedema. Lymphedema can result in infections and other complications including a form of lymphatic cancer called lymphangiosarcoma. Primary lymphedema is caused by pathologic development of the lymphatic system. Secondary lymphedema can arise from other conditions or disease treatments; most commonly from cancer and cancer treatments including lymphadenectomy (Gordon and Mortimer 2007; Warren et al. 2007). Milroy Disease (also known as Lymphedema Type I) is a type of primary lymphedema characterized by edema of the lower limbs (Brice et al. 2005). The swelling is typically bilateral, localized below the knee, and is often present at birth or develops in early infancy. Ultrasound showing in utero pleural effusions, lower limb swelling, and hydrops fetalis has also been used for prenatal diagnosis of Milroy disease (Daniel-Speigel et al. 2005; Ghalamkarpour et al. 2006). Other common features of Milroy disease include hydrocele in male patients, cellulitis, upslanting toenails, papillomas, and hyperkeratosis.

Milroy disease displays primarily autosomal dominant inheritance and is estimated to occur in 1:6000 births (Witte et al. 1998). At least two cases of apparent autosomal recessive inheritance have also been reported (Ghalamkarpour et al. 2009; Melikhan-Revzin et al. 2015). Variants in the FLT4 gene (also known as VEGFR3) are the only known cause of Milroy disease (Iljin et al. 2001; Evans et al. 2003; Brice et al. 2005). FLT4 encodes Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) a receptor tyrosine kinase found in lymphatic endothelial cells (Kaipainen et al. 1995). VEGFR3 is activated by the ligands VEGF-C and VEGF-D during lymphangiogenesis (Veikkola et al. 2001). Nearly all pathogenic variants are found in one of the two tyrosine kinase domains indicating the importance of these domains for VEGFR3 protein function during proper lymphatic system development (Ferrel et al. 1998, Evans et al. 2003; Ghalamkarpour et al. 2006). Pathogenic variants comprise mostly missense and nonsense variants, however at least one splice site variant and a few small deletions have also been reported. To date, no large deletions or duplications in the FLT4 gene have been reported in patients with Milroy disease. Penetrance of causative FLT4 variants appears to be 80-84% (Ferrell et al. 1998; Evans et al. 1999). At least one variant outside of the tyrosine kinase domains has been reported in patients with FLT4-related disorders that may have recessive inheritance (Melikhan-Revzin et al. 2015).

This test covers 100% of the coding region of the FLT4 gene. Variants in the FLT4 gene are the only known cause of Milroy disease. To date, pathogenic variants in 7 genes have been associated with disorders having lymphedema as a primary symptom, however, the extent to which each of the 7 known primary lymphedema genes contribute to the overall rate of primary lymphedema is unclear. Lymphedema is also a secondary symptom of many other disorders.

To date, no large deletions or duplications in the FLT4 gene have been reported in patients with Milroy disease.

This test provides full coverage of all coding exons of the FLT4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).