Hostname: page-component-cd9895bd7-fscjk Total loading time: 0 Render date: 2024-12-26T08:48:08.159Z Has data issue: false hasContentIssue false
  • English
  • Français

Advances in the molecular genetics of non-syndromic polydactyly

Published online by Cambridge University Press:  30 October 2015

Hao Deng ,
Ting Tan  and
Lamei Yuan
Hao Deng*
Affiliation:
Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Ting Tan
Affiliation:
Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Lamei Yuan
Affiliation:
Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
*
*Corresponding author: Hao Deng, MD, PhD, Professor of Center for Experimental Medicine and Professor of Neurology, Vice Director of Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, Chaina. E-mail: hdeng008@yahoo.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Polydactyly is one of the most common inherited limb abnormalities, characterised by supernumerary fingers or toes. It results from disturbances in the normal programme of the anterior–posterior axis of the developing limb, with diverse aetiology and variable inter- and intra-familial clinical features. Polydactyly can occur as an isolated disorder (non-syndromic polydactyly) or as a part of an anomaly syndrome (syndromic polydactyly). On the basis of the anatomic location of the duplicated digits, non-syndromic polydactyly is divided into three kinds, including preaxial polydactyly, axial polydactyly and postaxial polydactyly. Non-syndromic polydactyly frequently exhibits an autosomal dominant inheritance with variable penetrance. To date, in human, at least ten loci and four disease-causing genes, including the GLI3 gene, the ZNF141 gene, the MIPOL1 gene and the PITX1 gene, have been identified. In this paper, we review clinical features of non-syndromic polydactyly and summarise the recent progress in the molecular genetics, including loci and genes that are responsible for the disorder, the signalling pathways that these genetic factors are involved in, as well as animal models of the disorder. These progresses will improve our understanding of the complex disorder and have implications on genetic counselling such as prenatal diagnosis.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 17 , 2015 , e18
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Malik, S. (2014) Polydactyly: phenotypes, genetics and classification. Clinical Genetics 85, 203–212 Google Scholar
2. Zguricas, J. et al. (1999) Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9-cM region on chromosome 7q36. Journal of Medical Genetics 36, 32–40 Google Scholar
3. Schwabe, G.C. and Mundlos, S. (2004) Genetics of congenital hand anomalies. Handchirurgie Mikrochirurgie Plastische Chirurgie 36, 85–97 Google Scholar
4. Christensen, J.C. et al. (2011) Congenital polydactyly and polymetatarsalia: classification, genetics, and surgical correction. 1981. Journal of Foot and Ankle Surgery 50, 336–339 Google Scholar
5. de la Torre, J. and Simpson, R.L. (1998) Complete digital duplication: a case report and review of ulnar polydactyly. Annals of Plastic Surgery 40, 76–79 Google Scholar
6. Malik, S. et al. (2014) Clinical and descriptive genetic study of polydactyly: a Pakistani experience of 313 cases. Clinical Genetics 85, 482–486 CrossRefGoogle ScholarPubMed
7. Biesecker, L.G. (2011) Polydactyly: how many disorders and how many genes? 2010 update. Developmental Dynamics 240, 931–942 Google Scholar
8. Talamillo, A. et al. (2005) The developing limb and the control of the number of digits. Clinical Genetics 67, 143–153 Google Scholar
9. Materna-Kiryluk, A. et al. (2013) Epidemiology of isolated preaxial polydactyly type I: data from the Polish Registry of Congenital Malformations (PRCM). BMC Pediatrics 13, 26 Google Scholar
10. Haber, L.L. et al. (2007) Unique case of polydactyly and a new classification system. Journal of Pediatric Orthopedics 27, 326–328 Google Scholar
11. Phadke, S.R. and Sankar, V.H. (2010) Polydactyly and genes. Indian Journal of Pediatrics 77, 277–281 Google Scholar
12. Gillessen-Kaesbach, G. and Majewski, F. (1991) Bilateral complete polysyndactyly (type IV Haas). American Journal of Medical Genetics 38, 29–31 Google Scholar
13. Orioli, I.M. and Castilla, E.E. (1999) Thumb/hallux duplication and preaxial polydactyly type I. American Journal of Medical Genetics 82, 219–224 Google Scholar
14. Radhakrishna, U. et al. (1997) Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis. American Journal of Human Genetics 60, 597–604 Google Scholar
15. van der Zwaag, P.A. et al. (2010) An interstitial duplication of chromosome 13q31.3q32.1 further delineates the critical region for postaxial polydactyly type A2. European Journal of Medical Genetics 53, 45–49 Google Scholar
16. Zhao, H. et al. (2002) Postaxial polydactyly type A/B (PAP-A/B) is linked to chromosome 19p13.1-13.2 in a Chinese kindred. European Journal of Human Genetics 10, 162–166 CrossRefGoogle Scholar
17. Galjaard, R.J. et al. (2003) A new locus for postaxial polydactyly type A/B on chromosome 7q21-q34. European Journal of Human Genetics 11, 409–415 CrossRefGoogle ScholarPubMed
18. Mollica, F. et al. (1978) Autosomal recessive postaxial polydactyly type A in a Sicilian family. Journal of Medical Genetics 15, 212–216 Google Scholar
19. Mohan, J. (1969) Postaxial polydactyly in three Indian families. Journal of Medical Genetics 6, 196–200 Google Scholar
20. Kalsoom, U.E. et al. (2013) Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A. Journal of Medical Genetics 50, 47–53 Google Scholar
21. Chong, A.K. (2010) Common congenital hand conditions. Singapore Medical Journal 51, 965–971 Google Scholar
22. Guo, B. et al. (2013) Polydactyly: a review. Bulletin of the Hospital for Joint Disease 71, 17–23 Google Scholar
23. Bingle, G.J. and Niswander, J.D. (1975) Polydactyly in the American Indian. American Journal of Human Genetics 27, 91–99 Google Scholar
24. Woolf, C.M. and Myrianthopoulos, N.C. (1973) Polydactyly in American negroes and whites. American Journal of Human Genetics 25, 397–404 Google ScholarPubMed
25. Castilla, E. et al. (1973) Polydactyly: a genetic study in South America. American Journal of Human Genetics 25, 405–412 Google Scholar
26. Woolf, C.M. and Woolf, R.M. (1970) A genetic study of polydactyly in Utah. American Journal of Human Genetics 22, 75–88 Google ScholarPubMed
27. Semerci, C.N. et al. (2009) Homozygous feature of isolated triphalangeal thumb-preaxial polydactyly linked to 7q36: no phenotypic difference between homozygotes and heterozygotes. Clinical Genetics 76, 85–90 Google Scholar
28. Light, T.R. (1992) Treatment of preaxial polydactyly. Hand Clinics 8, 161–175 Google Scholar
29. Zhang, Z. et al. (2010) Preaxial polydactyly: interactions among ETV, TWIST1 and HAND2 control anterior-posterior patterning of the limb. Development 137, 3417–3426 Google Scholar
30. Heutink, P. et al. (1994) The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q. Nature Genetics 6, 287–292 CrossRefGoogle Scholar
31. Tsukurov, O. et al. (1994) A complex bilateral polysyndactyly disease locus maps to chromosome 7q36. Nature Genetics 6, 282–286 Google Scholar
32. Lettice, L.A. et al. (2002) Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proceedings of the National Academy of Sciences of the United States of America 99, 7548–7553 CrossRefGoogle ScholarPubMed
33. Lettice, L.A. et al. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Human Molecular Genetics 12, 1725–1735 Google Scholar
34. Gurnett, C.A. et al. (2007) Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly. American Journal of Medical Genetics. Part A 143A, 27–32 Google Scholar
35. Furniss, D. et al. (2008) A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. Human Molecular Genetics 17, 2417–2423 Google Scholar
36. Albuisson, J. et al. (2011) Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly. Clinical Genetics 79, 371–377 CrossRefGoogle ScholarPubMed
37. VanderMeer, J.E. et al. (2014) A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form. Human Mutation 35, 945–948 CrossRefGoogle Scholar
38. Li, H. et al. (2009) Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly. European Journal of Human Genetics 17, 604–610 Google Scholar
39. Klopocki, E. et al. (2008) A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. Journal of Medical Genetics 45, 370–375 Google Scholar
40. Balci, S. et al. (1999) Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome linked to chromosome 7q36. American Journal of Medical Genetics 87, 399–406 Google Scholar
41. Wang, Z.Q. et al. (2007) A single C to T transition in intron 5 of LMBR1 gene is associated with triphalangeal thumb-polysyndactyly syndrome in a Chinese family. Biochemical and Biophysical Research Communications 355, 312–317 Google Scholar
42. Farooq, M. et al. (2010) Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long-range cis-regulatory element ZRS. European Journal of Human Genetics 18, 733–736 CrossRefGoogle Scholar
43. Sun, M. et al. (2008) Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer. Journal of Medical Genetics 45, 589–595 Google Scholar
44. Wieczorek, D. et al. (2010) A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb. Human Mutation 31, 81–89 CrossRefGoogle ScholarPubMed
45. Norbnop, P. et al. (2014) ZRS 406>G mutation in patients with tibial hypoplasia, polydactyly and triphalangeal first fingers. Journal of Human Genetics 59, 467–470 Google Scholar
46. Wu, L. et al. (2009) A ZRS duplication causes syndactyly type IV with tibial hypoplasia. American Journal of Medical Genetics. Part A 149A, 816–818 Google Scholar
47. Atasu, M. (1976) Hereditary index finger polydactyly: phenotypic, radiological, dermatoglyphic, and genetic findings in a large family. Journal of Medical Genetics 13, 469–476 Google Scholar
48. Reynolds, J.F. et al. (1984) Preaxial polydactyly type 4: variability in a large kindred. Clinical Genetics 25, 267–272 Google Scholar
49. Radhakrishna, U. et al. (1999) The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. American Journal of Human Genetics 65, 645–655 CrossRefGoogle ScholarPubMed
50. Fujioka, H. et al. (2005) Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I. Clinical Genetics 67, 429–433 CrossRefGoogle ScholarPubMed
51. Tsai, L.P. et al. (2009) A novel microdeletion at chromosome 2q31.1-31.2 in a three-generation family presenting duplication of great toes with clinodactyly. Clinical Genetics 75, 449–456 CrossRefGoogle Scholar
52. Umm-e-Kalsoom, et al. (2012) Genetic mapping of an autosomal recessive postaxial polydactyly type A to chromosome 13q13.3-q21.2 and screening of the candidate genes. Human Genetics 131, 415–422 Google Scholar
53. Radhakrishna, U. et al. (1997) Mutation in GLI3 in postaxial polydactyly type A. Nature Genetics 17, 269–271 Google Scholar
54. Al-Qattan, M.M. (2012) A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. Clinical Genetics 82, 502–504 Google Scholar
55. Naruse, I. et al. (2010) Birth defects caused by mutations in human GLI3 and mouse Gli3 genes. Congenital Anomalies 50, 1–7 Google Scholar
56. Akarsu, A.N. et al. (1997) Mapping of the second locus of postaxial polydactyly type A (PAP-A2) to chromosome 13q21-q32. American Journal of Human Genetics 61(suppl.), A265 Google Scholar
57. Kondoh, S. et al. (2002) A novel gene is disrupted at a 14q13 breakpoint of t(2;14) in a patient with mirror-image polydactyly of hands and feet. Journal of Human Genetics 47, 136–139 Google Scholar
58. Klopocki, E. et al. (2012) Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. European Journal of Human Genetics 20, 705–708 CrossRefGoogle Scholar
59. Skoll, P.J. et al. (2000) Mirror foot. Plastic and Reconstructive Surgery 105, 2086–2088 Google Scholar
60. Lohan, S. et al. (2014) Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome. Clinical Genetics 86, 318–325 Google Scholar
61. Gurnett, C.A. et al. (2008) Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. American Journal of Human Genetics 83, 616–622 Google Scholar
62. Lanctot, C. et al. (1999) Hindlimb patterning and mandible development require the Ptx1 gene. Development 126, 1805–1810 CrossRefGoogle ScholarPubMed
63. Kjaer, K.W. et al. (2005) Male-to-male transmission in Laurin-Sandrow syndrome and exclusion of RARB and RARG. American Journal of Medical Genetics. Part A 137, 148–152 CrossRefGoogle ScholarPubMed
64. Rambaud-Cousson, A. et al. (1991) Syndactyly type IV/hexadactyly of feet associated with unilateral absence of the tibia. American Journal of Medical Genetics 40, 144–145 Google Scholar
65. Sato, D. et al. (2007) A syndactyly type IV locus maps to 7q36. Journal of Human Genetics 52, 561–564 Google Scholar
66. Zguricas, J. et al. (1998) Genetics of limb development and congenital hand malformations. Plastic and Reconstructive Surgery 101, 1126–1135 Google Scholar
67. Hill, R.E. (2007) How to make a zone of polarizing activity: insights into limb development via the abnormality preaxial polydactyly. Development Growth & Differentiation 49, 439–448 Google Scholar
68. Grzeschik, K.H. (2002) Human limb malformations; an approach to the molecular basis of development. International Journal of Developmental Biology 46, 983–991 Google Scholar
69. Maas, S.A. and Fallon, J.F. (2005) Single base pair change in the long-range Sonic hedgehog limb-specific enhancer is a genetic basis for preaxial polydactyly. Developmental Dynamics 232, 345–348.Google Scholar
70. Riddle, R.D. et al. (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416 Google Scholar
71. Johnson, R.L. and Tabin, C.J. (1997) Molecular models for vertebrate limb development. Cell 90, 979–990 CrossRefGoogle ScholarPubMed
72. Capdevila, J. and Izpisua, B.J. (2001) Patterning mechanisms controlling vertebrate limb development. Annual Review of Cell and Developmental Biology 17, 87–132 Google Scholar
73. Lettice, L.A. et al. (2008) Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Human Molecular Genetics 17, 978–985 Google Scholar
74. Sagai, T. et al. (2004) Phylogenetic conservation of a limb-specific, cis-acting regulator of Sonic hedgehog (Shh). Mammalian Genome 15, 23–34 Google Scholar
75. Masuya, H. et al. (2007) A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud. Genomics 89, 207–214 CrossRefGoogle Scholar
76. Park, K. et al. (2008) Canine polydactyl mutations with heterogeneous origin in the conserved intronic sequence of LMBR1. Genetics 179, 2163–2172 Google Scholar
77. Maas, S.A. and Fallon, J.F. (2004) Isolation of the chicken Lmbr1 coding sequence and characterization of its role during chick limb development. Developmental dynamics 229, 520–528 Google Scholar
78. Maas, S.A. et al. (2011) Identification of spontaneous mutations within the long-range limb-specific Sonic hedgehog enhancer (ZRS) that alter Sonic hedgehog expression in the chicken limb mutants oligozeugodactyly and silkie breed. Developmental Dynamics 240, 1212–1222 Google Scholar
79. Te, W.P. et al. (2002) Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science 298, 827–830 Google Scholar
80. Kraus, P. et al. (2001) Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Mechanisms of Development 100, 45–58 Google Scholar
81. Chiang, C. et al. (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 Google Scholar
82. Knudsen, T.B. and Kochhar, D.M. (2010) The Hemimelic extra toes mouse mutant: historical perspective on unraveling mechanisms of dysmorphogenesis. Birth Defects Research C, Embryo Today: Reviews 90, 155–162 Google Scholar
83. Hill, R.E. et al. (2003) Sonic hedgehog: restricted expression and limb dysmorphologies. Journal of Anatomy 202, 13–20 CrossRefGoogle ScholarPubMed
84. Sharpe, J. et al. (1999) Identification of sonic hedgehog as a candidate gene responsible for the polydactylous mouse mutant Sasquatch. Current Biology 9, 97–100 Google Scholar
85. Lee, J.D. et al. (2001) An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development. Developmental Biology 233, 122–136 Google Scholar
86. Crick, A.P. et al. (2003) Developmental mechanisms underlying polydactyly in the mouse mutant Doublefoot. Journal of Anatomy 202, 21–26 Google Scholar
87. Sharrocks, A.D. (2001) The ETS-domain transcription factor family. Nature Reviews. Molecular Cell Biology 2, 827–837 Google Scholar
88. Lettice, L.A. et al. (2012) Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Developmental Cell 22, 459–467 Google Scholar
89. O'Leary, D.A. et al. (2005) Identification and expression analysis of alternative transcripts of the mouse GA-binding protein (Gabp) subunits alpha and beta1. Gene 344, 79–92 Google Scholar
90. Rice, D.P. et al. (2010) Gli3Xt-J/Xt-J mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation. Human Molecular Genetics 19, 3457–3467 Google Scholar
91. Thien, H. and Ruther, U. (1999) The mouse mutation Pdn (Polydactyly Nagoya) is caused by the integration of a retrotransposon into the Gli3 gene. Mammalian Genome 10, 205–209 Google Scholar
92. Naruse, I. et al. (1997) Surgical manipulation of mammalian embryos in vitro. International Journal of Developmental Biology 41, 195–198 Google Scholar
93. Bose, J. et al. (2002) Pallister–Hall syndrome phenotype in mice mutant for Gli3. Human Molecular Genetics 11, 1129–1135 Google Scholar
94. Wang, C. et al. (2007) A hypermorphic mouse Gli3 allele results in a polydactylous limb phenotype. Developmental Dynamics 236, 769–776 Google Scholar
95. Wang, C. et al. (2007) The Shh-independent activator function of the full-length Gli3 protein and its role in vertebrate limb digit patterning. Developmental Biology 305, 460–469 Google Scholar
96. Matera, I. et al. (2008) A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Human Molecular Genetics 17, 2118–2131 Google Scholar
97. van der Hoeven, F. et al. (1993) Molecular linkage of the morphogenetic mutation add and the zinc finger gene Gli3. Mammalian Genome 4, 276–277 Google Scholar
98. Litingtung, Y. et al. (2002) Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature 418, 979–983 Google Scholar
99. Filges, I. et al. (2011) Fetal polydactyly: a study of 24 cases ascertained by prenatal sonography. Journal of Ultrasound in Medicine 30, 1021–1029 Google Scholar
100. Jamsheer, A. (2008) Genetic background of isolated forms of congenital malformations of the hand. Medycyna wieku rozwojowego 12, 729–737 Google ScholarPubMed