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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Jun;64(6):1646–1654. doi: 10.1086/302403

Fine mapping of the split-hand/split-foot locus (SHFM3) at 10q24: evidence for anticipation and segregation distortion.

R S Ozen 1, B E Baysal 1, B Devlin 1, J E Farr 1, M Gorry 1, G D Ehrlich 1, C W Richard 1
PMCID: PMC1377907  PMID: 10330351

Abstract

Split-hand/split-foot malformation (SHFM, ectrodactyly, or lobster-claw deformity) is a human limb malformation characterized by aberrant development of central digital rays with absence of fingers and toes, a deep median cleft, and fusion of remaining digits. SHFM is clinically heterogeneous, presenting both in an isolated form and in combination with additional abnormalities affecting the tibia and/or other organ systems, including the genitourinary, craniofacial, and ectodermal structures. Three SHFM disease loci have been genetically mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 10q24 (SHFM3). We mapped data from a large Turkish family with isolated SHFM to chromosome 10q24 and have narrowed the SHFM3 region from 9 cM to an approximately 2-cM critical interval between genetic markers D10S1147 and D10S1240. In several instances we found evidence for a more severe phenotype in offspring of a mildly affected parent, suggesting anticipation. Finally, data from this family, combined with those from six other pedigrees, mapped to 10q24, demonstrate biased transmission of SHFM3 alleles from affected fathers to offspring. The degree of this segregation distortion is obvious in male offspring and is possibly of the same magnitude for female offspring.

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Selected References

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  1. Akarsu A. N., Stoilov I., Yilmaz E., Sayli B. S., Sarfarazi M. Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families. Hum Mol Genet. 1996 Jul;5(7):945–952. doi: 10.1093/hmg/5.7.945. [DOI] [PubMed] [Google Scholar]
  2. Baysal B. E., Farr J. E., Rubinstein W. S., Galus R. A., Johnson K. A., Aston C. E., Myers E. N., Johnson J. T., Carrau R., Kirkpatrick S. J. Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas, on chromosome 11q23. Am J Hum Genet. 1997 Jan;60(1):121–132. [PMC free article] [PubMed] [Google Scholar]
  3. Carey N., Johnson K., Nokelainen P., Peltonen L., Savontaus M. L., Juvonen V., Anvret M., Grandell U., Chotai K., Robertson E. Meiotic drive at the myotonic dystrophy locus? Nat Genet. 1994 Feb;6(2):117–118. doi: 10.1038/ng0294-117. [DOI] [PubMed] [Google Scholar]
  4. Chakraborty R., Stivers D. N., Deka R., Yu L. M., Shriver M. D., Ferrell R. E. Segregation distortion of the CTG repeats at the myotonic dystrophy locus. Am J Hum Genet. 1996 Jul;59(1):109–118. [PMC free article] [PubMed] [Google Scholar]
  5. Crackower M. A., Scherer S. W., Rommens J. M., Hui C. C., Poorkaj P., Soder S., Cobben J. M., Hudgins L., Evans J. P., Tsui L. C. Characterization of the split hand/split foot malformation locus SHFM1 at 7q21.3-q22.1 and analysis of a candidate gene for its expression during limb development. Hum Mol Genet. 1996 May;5(5):571–579. doi: 10.1093/hmg/5.5.571. [DOI] [PubMed] [Google Scholar]
  6. Emery A. E. A problem for genetic counselling - split hand deformity. Clin Genet. 1977 Aug;12(2):125–127. doi: 10.1111/j.1399-0004.1977.tb00914.x. [DOI] [PubMed] [Google Scholar]
  7. Evans K., Fryer A., Inglehearn C., Duvall-Young J., Whittaker J. L., Gregory C. Y., Butler R., Ebenezer N., Hunt D. M., Bhattacharya S. Genetic linkage of cone-rod retinal dystrophy to chromosome 19q and evidence for segregation distortion. Nat Genet. 1994 Feb;6(2):210–213. doi: 10.1038/ng0294-210. [DOI] [PubMed] [Google Scholar]
  8. Faiyaz ul Haque M., Uhlhaas S., Knapp M., Schüler H., Friedl W., Ahmad M., Propping P. Mapping of the gene for X-chromosomal split-hand/split-foot anomaly to Xq26-q26.1. Hum Genet. 1993 Mar;91(1):17–19. doi: 10.1007/BF00230215. [DOI] [PubMed] [Google Scholar]
  9. Freund C. L., Gregory-Evans C. Y., Furukawa T., Papaioannou M., Looser J., Ploder L., Bellingham J., Ng D., Herbrick J. A., Duncan A. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell. 1997 Nov 14;91(4):543–553. doi: 10.1016/s0092-8674(00)80440-7. [DOI] [PubMed] [Google Scholar]
  10. GRAHAM J. B., BADGLEY C. E. Split-hand with unusual complications. Am J Hum Genet. 1955 Mar;7(1):44–50. [PMC free article] [PubMed] [Google Scholar]
  11. Gemel J., Gorry M., Ehrlich G. D., MacArthur C. A. Structure and sequence of human FGF8. Genomics. 1996 Jul 1;35(1):253–257. doi: 10.1006/geno.1996.0349. [DOI] [PubMed] [Google Scholar]
  12. Gennarelli M., Dallapiccola B., Baiget M., Martorell L., Novelli G. Meiotic drive at the myotonic dystrophy locus. J Med Genet. 1994 Dec;31(12):980–980. doi: 10.1136/jmg.31.12.980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goodman F. R., Mundlos S., Muragaki Y., Donnai D., Giovannucci-Uzielli M. L., Lapi E., Majewski F., McGaughran J., McKeown C., Reardon W. Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7458–7463. doi: 10.1073/pnas.94.14.7458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gray I. C., Fallowfield J., Ford S., Nobile C., Volpi E. V., Spurr N. K. An integrated physical and genetic map spanning chromosome band 10q24. Genomics. 1997 Jul 1;43(1):85–88. doi: 10.1006/geno.1997.4809. [DOI] [PubMed] [Google Scholar]
  15. Gurrieri F., Prinos P., Tackels D., Kilpatrick M. W., Allanson J., Genuardi M., Vuckov A., Nanni L., Sangiorgi E., Garofalo G. A split hand-split foot (SHFM3) gene is located at 10q24-->25. Am J Med Genet. 1996 Apr 24;62(4):427–436. doi: 10.1002/(SICI)1096-8628(19960424)62:4<427::AID-AJMG16>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  16. Inglehearn C. F., Gregory C. Y. Meiotic drive at the myotonic dystrophy and the cone-rod dystrophy loci on chromosome 19q13.3. Am J Hum Genet. 1997 Jun;60(6):1562–1563. doi: 10.1016/S0002-9297(07)64255-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jagla K., Dollé P., Mattei M. G., Jagla T., Schuhbaur B., Dretzen G., Bellard F., Bellard M. Mouse Lbx1 and human LBX1 define a novel mammalian homeobox gene family related to the Drosophila lady bird genes. Mech Dev. 1995 Nov;53(3):345–356. doi: 10.1016/0925-4773(95)00450-5. [DOI] [PubMed] [Google Scholar]
  18. Jarvik G. P., Patton M. A., Homfray T., Evans J. P. Non-Mendelian transmission in a human developmental disorder: split hand/split foot. Am J Hum Genet. 1994 Oct;55(4):710–713. [PMC free article] [PubMed] [Google Scholar]
  19. Johnson K. R., Lane P. W., Ward-Bailey P., Davisson M. T. Mapping the mouse dactylaplasia mutation, Dac, and a gene that controls its expression, mdac. Genomics. 1995 Sep 20;29(2):457–464. doi: 10.1006/geno.1995.9981. [DOI] [PubMed] [Google Scholar]
  20. Johnson R. L., Tabin C. J. Molecular models for vertebrate limb development. Cell. 1997 Sep 19;90(6):979–990. doi: 10.1016/s0092-8674(00)80364-5. [DOI] [PubMed] [Google Scholar]
  21. Kengaku M., Capdevila J., Rodriguez-Esteban C., De La Peña J., Johnson R. L., Izpisúa Belmonte J. C., Tabin C. J. Distinct WNT pathways regulating AER formation and dorsoventral polarity in the chick limb bud. Science. 1998 May 22;280(5367):1274–1277. doi: 10.1126/science.280.5367.1274. [DOI] [PubMed] [Google Scholar]
  22. Lako M., Strachan T., Curtis A. R., Lindsay S. Isolation and characterization of WNT8B, a novel human Wnt gene that maps to 10q24. Genomics. 1996 Jul 15;35(2):386–388. doi: 10.1006/geno.1996.0374. [DOI] [PubMed] [Google Scholar]
  23. Leeflang E. P., McPeek M. S., Arnheim N. Analysis of meiotic segregation, using single-sperm typing: meiotic drive at the myotonic dystrophy locus. Am J Hum Genet. 1996 Oct;59(4):896–904. [PMC free article] [PubMed] [Google Scholar]
  24. Majewski E., Goecke T., Meinecke P. Ectrodactyly and absence (hypoplasia) of the tibia: are there dominant and recessive types? Am J Med Genet. 1996 May 3;63(1):185–189. doi: 10.1002/(SICI)1096-8628(19960503)63:1<185::AID-AJMG32>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  25. Munier F. L., Arabien L., Flodman P., Spence M. A., Pescia G., Rutz H. P., Murphree A. L. Putative non-Mendelian transmission of retinoblastoma in males: a phenotypic segregation analysis of 150 pedigrees. Hum Genet. 1994 Nov;94(5):484–490. doi: 10.1007/BF00211012. [DOI] [PubMed] [Google Scholar]
  26. Muragaki Y., Mundlos S., Upton J., Olsen B. R. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science. 1996 Apr 26;272(5261):548–551. doi: 10.1126/science.272.5261.548. [DOI] [PubMed] [Google Scholar]
  27. Nunes M. E., Schutt G., Kapur R. P., Luthardt F., Kukolich M., Byers P., Evans J. P. A second autosomal split hand/split foot locus maps to chromosome 10q24-q25. Hum Mol Genet. 1995 Nov;4(11):2165–2170. doi: 10.1093/hmg/4.11.2165. [DOI] [PubMed] [Google Scholar]
  28. Orioli I. M. Segregation distortion in the offspring of Afro-American fathers with postaxial polydactyly. Am J Hum Genet. 1995 May;56(5):1207–1211. [PMC free article] [PubMed] [Google Scholar]
  29. Raas-Rothschild A., Manouvrier S., Gonzales M., Farriaux J. P., Lyonnet S., Munnich A. Refined mapping of a gene for split hand-split foot malformation (SHFM3) on chromosome 10q25. J Med Genet. 1996 Dec;33(12):996–1001. doi: 10.1136/jmg.33.12.996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Raju K., Tang S., Dubé I. D., Kamel-Reid S., Bryce D. M., Breitman M. L. Characterization and developmental expression of Tlx-1, the murine homolog of HOX11. Mech Dev. 1993 Nov;44(1):51–64. doi: 10.1016/0925-4773(93)90016-q. [DOI] [PubMed] [Google Scholar]
  31. Ray A. K. Another case of split-foot mutation in two sibs. J Hered. 1970 Jul-Aug;61(4):169–170. doi: 10.1093/oxfordjournals.jhered.a108073. [DOI] [PubMed] [Google Scholar]
  32. Riess O., Epplen J. T., Amoiridis G., Przuntek H., Schöls L. Transmission distortion of the mutant alleles in spinocerebellar ataxia. Hum Genet. 1997 Feb;99(2):282–284. doi: 10.1007/s004390050355. [DOI] [PubMed] [Google Scholar]
  33. Roberts C. W., Sonder A. M., Lumsden A., Korsmeyer S. J. Development expression of Hox11 and specification of splenic cell fate. Am J Pathol. 1995 May;146(5):1089–1101. [PMC free article] [PubMed] [Google Scholar]
  34. STEVENSON A. C., JENNINGS L. M. Ectrodactyly--evidence in favour of a disturbed segregation in the offspring of affected males. Ann Hum Genet. 1960 Apr;24:89–96. doi: 10.1111/j.1469-1809.1959.tb01719.x. [DOI] [PubMed] [Google Scholar]
  35. Sanyanusin P., Schimmenti L. A., McNoe L. A., Ward T. A., Pierpont M. E., Sullivan M. J., Dobyns W. B., Eccles M. R. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nat Genet. 1995 Apr;9(4):358–364. doi: 10.1038/ng0495-358. [DOI] [PubMed] [Google Scholar]
  36. Scherer S. W., Poorkaj P., Allen T., Kim J., Geshuri D., Nunes M., Soder S., Stephens K., Pagon R. A., Patton M. A. Fine mapping of the autosomal dominant split hand/split foot locus on chromosome 7, band q21.3-q22.1. Am J Hum Genet. 1994 Jul;55(1):12–20. [PMC free article] [PubMed] [Google Scholar]
  37. Scherer S. W., Poorkaj P., Massa H., Soder S., Allen T., Nunes M., Geshuri D., Wong E., Belloni E., Little S. Physical mapping of the split hand/split foot locus on chromosome 7 and implication in syndromic ectrodactyly. Hum Mol Genet. 1994 Aug;3(8):1345–1354. doi: 10.1093/hmg/3.8.1345. [DOI] [PubMed] [Google Scholar]
  38. Scott M. P. Hox genes, arms and the man. Nat Genet. 1997 Feb;15(2):117–118. doi: 10.1038/ng0297-117. [DOI] [PubMed] [Google Scholar]
  39. Semina E. V., Reiter R. S., Murray J. C. Isolation of a new homeobox gene belonging to the Pitx/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum Mol Genet. 1997 Nov;6(12):2109–2116. doi: 10.1093/hmg/6.12.2109. [DOI] [PubMed] [Google Scholar]
  40. Seto M. L., Nunes M. E., MacArthur C. A., Cunningham M. L. Pathogenesis of ectrodactyly in the Dactylaplasia mouse: aberrant cell death of the apical ectodermal ridge. Teratology. 1997 Oct;56(4):262–270. doi: 10.1002/(SICI)1096-9926(199710)56:4<262::AID-TERA5>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  41. Shaw R. F., Glover R. A. Abnormal Segregation in Hereditary Renal Disease with Deafness. Am J Hum Genet. 1961 Mar;13(1 Pt 1):89–97. [PMC free article] [PubMed] [Google Scholar]
  42. Spranger M., Schapera J. Anomalous inheritance in a kindred with split hand, split foot malformation. Eur J Pediatr. 1988 Feb;147(2):202–205. doi: 10.1007/BF00442225. [DOI] [PubMed] [Google Scholar]
  43. Stadler H. S., Murray J. C., Leysens N. J., Goodfellow P. J., Solursh M. Phylogenetic conservation and physical mapping of members of the H6 homeobox gene family. Mamm Genome. 1995 Jun;6(6):383–388. doi: 10.1007/BF00355637. [DOI] [PubMed] [Google Scholar]
  44. Takiyama Y., Sakoe K., Soutome M., Namekawa M., Ogawa T., Nakano I., Igarashi S., Oyake M., Tanaka H., Tsuji S. Single sperm analysis of the CAG repeats in the gene for Machado-Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability. Hum Mol Genet. 1997 Jul;6(7):1063–1068. doi: 10.1093/hmg/6.7.1063. [DOI] [PubMed] [Google Scholar]
  45. Verma I. C., Joseph R., Bhargava S., Mehta S. Split-hand and split-foot deformity inherited as an autosomal recessive trait. Clin Genet. 1976 Jan;9(1):8–14. doi: 10.1111/j.1399-0004.1976.tb01543.x. [DOI] [PubMed] [Google Scholar]
  46. Wang W., Lufkin T. Assignment of the murine Hmx2 and Hmx3 homeobox genes to the distal region of mouse chromosome 7. Chromosome Res. 1997 Nov;5(7):501–502. doi: 10.1023/a:1018429316424. [DOI] [PubMed] [Google Scholar]
  47. Yamashita T., Agulnick A. D., Copeland N. G., Gilbert D. J., Jenkins N. A., Westphal H. Genomic structure and chromosomal localization of the mouse LIM domain-binding protein 1 gene, Ldb1. Genomics. 1998 Feb 15;48(1):87–92. doi: 10.1006/geno.1997.5163. [DOI] [PubMed] [Google Scholar]
  48. Zatz M., Cerqueira A., Vainzof M., Passos-Bueno M. R. Segregation distortion of the CTG repeats at the myotonic dystrophy (DM) locus: new data from Brazilian DM families. J Med Genet. 1997 Sep;34(9):790–791. doi: 10.1136/jmg.34.9.790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zlotogora J., Nubani N. Is there an autosomal recessive form of the split hand and split foot malformation? J Med Genet. 1989 Feb;26(2):138–140. doi: 10.1136/jmg.26.2.138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Zlotogora J. On the inheritance of the split hand/split foot malformation. Am J Med Genet. 1994 Oct 15;53(1):29–32. doi: 10.1002/ajmg.1320530107. [DOI] [PubMed] [Google Scholar]

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