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Mapping of primary congenital lymphedema to the 5q35.3 region.

Primary lymphedema is a chronic tissue swelling, most frequently of the lower limbs, resulting from deficient lymphatic drainage. The variability of the affected phenotype, incomplete penetrance, lack of large families, and possible genetic heterogeneity have hampered the identification of causative genes until now. We carried out a genomewide search, using a four-generation North American family with dominantly inherited primary congenital lymphedema (PCL), otherwise known as "Milroy disease," or "hereditary lymphedema type I" (MIM 153100). Linkage to markers from the 5q35.3 region in this and four additional, British families was established. A minimum of 79 directly scorable haplotypes (37 affected) in five families conspicuously segregated with the most telomeric region of 5q35.3, thus suggesting a major locus for PCL in this vicinity. No recombination was observed with D5S408 (Z = 10.03) and D5S2006 (Z = 8.46) with a combined multipoint score of 16.55. While D5S2073 and WIAF-2213 defined the upper centromeric boundary, no recombinants were obtained for the last telomeric marker of D5S2006. Four unaffected subjects were identified as gene carriers and provided an estimated penetrance ratio of.84 for this condition. A few of the positionally mapped genes in the 5q35 region that may potentially be involved in the etiology of this condition are CANX, FGFR4, HK3, and hnRPH1.