Am. J. Hum. Genet. 60:597-604, 1997 Mapping One Form of Autosomal Dominant Postaxial Polydactyly Type A to Chromosome 7pl 5-qi 1.23 by Linkage Analysis Uppala Radhakrishna,1 Jean-Louis Blouin,2 Hamid Mehenni,' Uday C. Patel,3 Manoj N. Patel,3 Jitendra V. Solanki,3 and Stylianos E. Antonarakis1'2 'Laboratory of Human Molecular Genetics, Department of Genetics and Microbiology, Geneva Medical School, and 2Division of Medical Genetics, Cantonal Hospital, Geneva; and 3Department of Animal Genetics and Breeding, Veterinary College, Anand, India Summary sal, and is usually functional. In postaxial polydactyly Postaxial polydactyly type-A (PAP-A) in humans is an type B (pedunculated postminimus), the extra digit is autosomal dominant trait characterized by an extra digit not well formed and is frequently in the form of a skin in the ulnar and/or fibular side of the upper and/or tag (Temtamy and McKusick 1969). The penetrance of lower extremities. The extra digit is well formed and type B has been estimated to be -65% (Scott-Emuakpor and Madueke 1976), while that of type A is much higher articulates with the fifth, or extra, metacarpal/metatar- and sal, and thus it is usually functional. In order to map the (Temtamy McKusick 1969; Castilla et al. 1973). gene responsible for PAP-A, we studied a five-generation Types A and B sometimes occur in the same pedigree Indian family of 37 individuals (15 of whom were af- (Sverdrup 1922; Odiorne 1943; Ventruto et al. 1980; A Kucheria et al. 1981). The occurrence of postaxial poly- fected). genomewide search with highly informative dactyly in the general population varies among different polymorphic markers on part of the pedigree showed racial groups and is 10 times more frequent in Blacks linkage between the PAP-A phenotype and markers on than in Caucasians (Frazier 1960). In Caucasians living chromosome 7p15-qll.23 (no crossovers were found in the United States, incidence figures vary from 1/3,300 with D7S526, D7S795, D7S528, D7S521, D7S691, to 1/630 live births and in African Americans from 1/ D7S667, D7S478, D7S1830, D7S803, D7S801, or 300 to 1/100 live births (Temtamy 1990). Postaxial ELN). The highest LOD score was obtained with marker polydactyly has also been reported as an autosomal re- D7S801 (Zmax = 4.21; 9 = 0). Haplotype analysis en- cessive trait (Mohan 1969; Cantu et al. 1974; Mollica abled the mapping ofthe PAP-A phenotype in this family et al. 1978) and in association with various syndromes between markers D7S2848 and D7S669. Analysis of (Merlob et al. 1981). Among the chromosomal abnor- additional families with PAP-A will narrow down the malities, postaxial polydactyly occurs in -75% of cases critical genomic region, facilitate positional cloning of with trisomy 13 (in particular 13q31-q34) (Lewandow- the PAP-A gene, and/or uncover potential genetic het- ski and Yunis 1977). erogeneity. The loci for a few other human polydactylies have been mapped. These include the synpolydactyly type II on chromosome 2q31 (Sarfarazi et al. 1995), complex Introduction bilateral polysyndactyly and triphalangeal thumb on 7q36 (Heutink et al. 1994; Tsukurov et al. 1994; Hing Postaxial polydactyly (MIM 174200) in humans is an et al. 1995; Radhakrishna et al. 1996), Greig cephalopo- autosomal dominant trait characterized by the presence lysyndactyly on 7pl3 (Brueton et al. 1988), and Ellis- of an extra finger and/or toe on the ulnar or fibular side van Creveld syndrome on 4pl6 (Polymeropoulos et al. of the hands and feet, respectively. Morphologically, 1996). Positional cloning and candidate gene analysis there exist two different types: In postaxial polydactyly experiments revealed that the gene responsible for the type A (PAP-A), the extra digit is rather well developed, Greig cephalopolysyndactyly is GLI3 (Vortkamp et al. articulates with the fifth, or extra, metacarpal/metatar- 1991), and that for synpolydactyly type II is HOXD13 (Muragaki et al. 1996). In order to map the locus associated with the PAP-A Received October 17, 1996; accepted for publication December 12, trait, we performed a genomewide search with geno- 1996. types of microsatellite polymorphic markers in members Address for correspondence and reprints: Prof. Stylianos E. Anto- of the Indian family UR004. narakis, Centre Medical Universitaire, 1 rue Michel Servet, CH-1211 Markers within chromo- Geneve, Switzerland. E-mail: [email protected] some 7p15-qll.23 showed no recombination with the © 1997 by The American Society of Human Genetics. All rights reserved. phenotype. The highest LOD score was obtained with 0002-9297/97/6003-0016$02.00 D7S801 (Zmax = 4.21; 0 = 0). 597 598 Am. J. Hum. Genet. 60:597-604, 1997 Subjects and Methods pedigree consists of a total of 37 individuals, with 6 affected males and 9 affected females with PAP. Figure Family UR004 2 shows this trait and radiograms in selected individuals. We studied an Indian family, UR004, with PAP-A, All 11 affected individuals examined showed extra post- from the Gujarat state in the western part of India (par- axial digits in both hands and feet (12 fingers and 12 tial pedigree is shown in fig. 1). This five-generation toes). These extra digits were well developed and similar 111=2 0- ML r- V1W IV-2 ~~~~IINV-3 77-oIVA IV-7 IVY IV-9 IV-10 DYS1808 2 5 2 3 1 2 3 1 4 2 5 2 5 D7S516 3 5 I I 3 4 1 2 3 I 2 1 2 D7817 3 2 4 ~~~~1 34 1 I 4 4 5 4 5 D7h2848 2 2 2 4 2 1 4 1 2 2 3 2 3 D7S526 3 4 1 3 2 3 3 2 1 1 3 1 3 D76795 3 2 5 ~~2 21 2 1 4 2 5 2 5 D78528 4 3 3 3 1 4 3 2 2 3 4 3 4 D7S521 4 2 1 1I 4 4 1 3 6 3 5 3 5 D7WS1 3 4 3 ~~2 4 5 2 1 3 2 1 2 1 D7I667 3 2 4 1 2 2 1 2 4 1 2 1 2 D7S478 1 2 1 2 3 3 2 1 1 2 1 2 D781830 1 1 4 ~~3 2 4 3 4 5 3 1 3 1 D7S83 2 3 1 4 4 4 4 2 4 4 4 4 4 D7S801 4 5 2 4 3 4 4 6 1 4 1 4 1 ELN 3 3 2 ~~3 1 3 3 1 3 3 1 3 1 D78669 2 4 2 5i 4 4 5 3 1 2 5 5 5 D7S2204 4 5 3 4I 4 6 4 3 1 3 2 4 2 D7S1797 3 I 23 2 2 1 3 1 3 1 F V-2 V-3 VA4 V-S V-S V-7 V-10 V-11 V-12 V-13 D7S1808 5 2) 2 2 5 2 3 3 2 4 I 4 5 43 D7S516 5 5 I 3 5 4 1 3 4 3 2 3 2 31 D7S817 2 3 4 3 2 4 1 3 4 4 1 4 5 4 D752848 2 2 2 2 2 1 4 2 1 2 2 2 3 2 D7S526 4 3 3 4 3 3 2 3 1 2 1 ,..,..... 1 D7S795 2 3 5 3 2 1 2 2 1 4 1 4 4 D76528 3 4 3 4 3 4 3 4 2 2 2 :. .;.. 2 D7S5211 2 4 1 4 2 4 1 4 4 6 3 6 6 D7869 4 3 3 3 4 5 2 4 5 3 1 3 2 3 D7S667 2 3 4 3 2 2 2 2 4 2 4 1 2 D7S478 2 1 1 I 2 3 2 3 3 1 I 1 2 1 D7S1830 1 1 4 I 1 4 3 2 4 5 4 3 4 D78803 3 3 1 2 3 4 4 4 4 4 2 4 4 2 S 5 2 4 5 4 4 4 3 1 6 4 6 ELN 3 3 2 3 3 3) 3 3 1 (3 I 31 3 1 4 4 (2 4) 2 4 S 4 4 1 3 3 I 3 I1 3 D7820 5 5 3 4 3 5 6 4 6 4 1 1 D7S1797 1 1 3 3 3 3 2 3 2 2 4 2 Figure 1 Partial pedigree of family UR004 with postaxial polydactyly (PAP-A). Only individuals studied are shown. Genotypes for selected polymorphic microsatellite markers on chromosome 7p15-qll.23 are shown. The order of the markers from top to bottom (from 7pter to 7qter) is that determined in the linkage maps of CHLC and Genfthon (see text). The order of pairs of markers D7S817/D7S2848 and D7S2204/D7S1797 could not be determined and is arbitrarily shown. Blackened symbols = individuals with polydactyly; empty symbols = unaffected individuals. Haplotypes of polymorphic markers could not be determined for individuals IV-9 and IV-10, because their parental genotypes were unknown. The phenotype-related haplotype is shown within a gray box; the "normal" haplotype is shown within an empty box. In individual V-12, recombination for markers in the lighter box could not be determined, because of parental homozygosity. The phase of genotypes in parenthesis could not be determined, because of parental heterozygosity for the same alleles. 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