A Novel Missense Mutation in FLT4 Causes Autosomal Recessive Hereditary Lymphedema.

BACKGROUND: Primary lymphedema covers around 10% of all lymphedema cases. Most cases segregate as an autosomal dominant trait and rarely manifest autosomal recessive inheritance. Our research aimed to map and ultimately to hunt the mutation that causes hereditary lymphedema in an extended consanguineous Muslim family consisting of several affected individuals. METHODS AND RESULTS: We attempted molecular diagnosis by applying homozygosity mapping and whole genome linkage analysis. A candidate locus of 2.3 Mb located on chromosome 5q35.3 was identified, yielding an overall LOD score of 3.18. This locus has been previously linked to congenital lymphedema, namely by the FLT4 gene. Mutations in FLT4 that were previously described in Muslim-Israeli families were discarded as culprit using sequence analysis. Sanger sequencing the gene revealed a novel missense variant in exon 28 (NM_182925.4: c.3704C>G; p.Ser1235Cys). This variant has perfect segregation within the extended family and was not previously reported in either common or pathogenic variants databases. CONCLUSIONS: Our mutation is the first reported pathogenic variant located outside the tyrosine kinase domains of the VEGFR3 receptor, and the second to portray autosomal recessive inheritance. The homozygous substitution of serine by cysteine at position 1235 affects protein tyrosine kinase activity, possibly through a null effect mechanism rather than a negative dominant effect. Our variant is associated with a mild phenotype, possibly reflecting some residual receptor activity, most probably attributed to the variant's location beyond the TK domains.

BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study.

BRCA mutation carriers were reported to display a skewed distribution of FMR1 genotypes, predominantly within the low normal range (CGG repeat number <26). This observation led to the interpretation that BRCA1/2 mutations are embryo-lethal, unless rescued by 'low FMR1 alleles'. We undertook to re-explore the distribution of FMR1 alleles subdivided into low, normal and high (<26, 26-34, and >34 CGG repeats, respectively) subgenotypes, on a cohort of 125 Ashkenazi women, carriers of a BRCA1/2 founder mutation. Ashkenazi healthy females (n=368), tested in the frame of the Israeli screening population program, served as controls. BRCA1/2 carriers and controls demonstrated a comparable and non-skewed FMR1 subgenotype distribution. Taken together, using a homogeneous ethnic group of Ashkenazi BRCA1/2 mutation carriers, we could not confirm the reported association between FMR1 low genotypes and BRCA1/2 mutations. The notion that BRCA1/2 mutations are embryo-lethal unless rescued by the low FMR1 subgenotypes is hereby refuted.