RARE VARIANTS IN LAMA5 GENE ASSOCIATED WITH FLT4 AND FOXC2 MUTATIONS IN PRIMARY LYMPHEDEMA MAY CONTRIBUTE TO SEVERITY

Abstract

Mutations in the Fms-related tyrosine
kinase 4 (FLT4) and forkhead box protein C2
(FOXC2) genes cause Milroy disease (MD)
and lymphedema-distichiasis syndrome (LDS),
respectively, but the mechanism underlying
disease pathology remains unclear. Applying
whole-exome sequencing to two families with
MD, one LDS family, and one sporadic LDS
case, we identified four rare variants in the
laminin subunit alpha-5 gene (LAMA5) in
subjects carrying novel and known missense
FLT4 mutations and a 7-bp duplication and
1-bp insertion in FOXC2. Phenotyping was
expanded in some individuals using magnetic
resonance lymphangiography, indiocyanine
green fluorescence lymphography, and
immunofluorescent lymphatic staining of skin
tissue. Skin lymphatic staining showed the
existence of dermal lymphatic vasculature in
the MD case. Significant lymphatic dysfunction
was observed in both MD and LDS
patients. In the MD patient, tortuous lymphatics
in the dorsum of the foot were slowly
enhanced on indocyanine green fluorescent
lymphography (ICG) imaging. Dilated lymph
collectors with disruption and lymph leakage
were observed in the familial LDS case on
magnetic resonance lymphangiography
(MRL). Numerous tortuous lymph collectors
were visualized along the entire length of
affected lower limbs on MRL imaging, and
retrograde lymph flow was observed in the
lymph collectors during ICG lymphography
in the isolated LDS case. The finding of rare
LAMA5 variants together with FLT4 and
FOXC2 mutations suggests that these
mutations may be co-responsible for these
disorders and most likely interfere with the
function of lymphatics. Further, larger studies
are needed to confirm these results.