Mapping of Primary Congenital Lymphedema to the 5q35.3 Region

• Published in: American journal of human genetics Vol. 64; no. 2; pp. 547 - 555
• Main Authors: Evans, Alison L., Brice, Glen, Sotirova, Vihra, Mortimer, Peter, Beninson, Joseph, Burnand, Kevin, Rosbotham, Jane, Child, Anne, Sarfarazi, Mansoor
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.02.1999; University of Chicago Press
• Subjects: Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Chromosome 5q35.3; Chromosome Mapping; Chromosomes, Human, Pair 5; Diseases of the lymphatic vessels; Female; Humans; Lymphedema - congenital; Lymphedema - genetics; Lymphedema - physiopathology; Lymphedema, early onset; Lymphedema, hereditary I; Male; Medical sciences; Milroy disease; Nonne-Milroy lymphedema; Pedigree; Primary congenital lymphedema; Primary congenital lymphedema; Milroy disease; Chromosome 5q35.3; Lymphedema, early onset; Nonne-Milroy lymphedema; Lymphedema, hereditary I; Genetic mapping; Human; Linkage; Family study; Cardiovascular disease; Chromosome B5; Congenital disease; Genetic determinism; Lymphatic vessel disease; Genetic disease; Gene; Lymphedema; Autosomal character; Dominant character; Locus; Haplotype
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/302248

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.