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

Primary lymphedema is a chronic tissue swelling, most frequently of the low er limbs, resulting from deficient lymphatic drainage. The variability of t he affected phenotype, incomplete penetrance, lack of large families, and p ossible genetic heterogeneity have hampered the identification of causative genes until now We carried out a genomewide search, using a four-generatio n North American family with dominantly inherited primary congenital lymphe dema (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 directl y scorable haplotypes (37 affected) in five families conspicuously segregat ed 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. Whil e D5S2073 and WIAF-2213 defined the upper centromeric boundary, no recombin ants were obtained for the last telomeric marker of D5S2006. Four unaffecte d subjects were identified as gene carriers and provided an estimated penet rance ratio of .84 for this condition. A few of the positionally mapped gen es in the 5q35 region that may potentially be involved in the etiology of t his condition are CANX, FGFR4, HK3, and hnRPH1.