Synpolydactyly: Clinical and molecular advances

Zentrum für Humangenetik, Philipps-Universität Marburg, Bahnhofstr. 7, Marburg, Germany.
Clinical Genetics (Impact Factor: 3.93). 03/2008; 73(2):113-20. DOI: 10.1111/j.1399-0004.2007.00935.x
Source: PubMed


Synpolydactyly (SPD) is a rare limb deformity showing a distinctive combination of syndactyly and polydactyly. Of the nine non-syndromic syndactylies, it is clinically and genetically one of the most heterogeneous malformation. SPD families may show clinical features consistent with the Temtamy and McKusick criteria as well as additional phenotypic variants, which vary from case to case. In certain instances, these variants predominate in a given family, while the typical SPD features remain less explicit. We have reviewed all the clinical variants occurring in well-documented SPD families. We conclude that typical SPD features can be delineated from minor clinical variants. Then, we propose to lump all the phenotypic variants, manifesting themselves in SPD families into three categories: (i) typical SPD features, (ii) minor variants, and (iii) unusual phenotypes. Next, we discuss the likely reasons for the occurrence of minor variants and the obvious lack of penetrance in SPD families. Finally, we show that for the SPD phenotype associated with HOXD13 mutations, a straightforward genotype-phenotype correlation is weak. Our lumping and splitting scheme for SPD phenotypic variants could be useful for the understanding of this interesting malformation.

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Available from: Sajid Malik, Jun 23, 2015
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    • "We re-examined the proposed genotype-phenotype correlation for HOXD13 (Figure 3 and Table 3). The polyalanine repeat expansions and frameshift deletion mutations usually give rise to typical SPD phenotypes, and the homeodomain missense mutation cluster for brachydactyly types [38]. Close genotype-phenotype correlations were also observed between different types of HOXD13-Syndactyly. "
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    ABSTRACT: Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. Its four subtypes (a, b, c, and d) are defined based on variable phenotypes, but the responsible gene is yet to be identified. SD1-a has been mapped to chromosome 3p21.31 and SD1-b to 2q34-q36. SD1-c and SD1-d are very rare and, to our knowledge, no gene loci have been identified. In two Chinese families with SD1-c, linkage and haplotype analyses mapped the disease locus to 2q31-2q32. Copy number variation (CNV) analysis, using array-based comparative genomic hybridization (array CGH), excluded the possibility of microdeletion or microduplication. Sequence analyses of related syndactyly genes in this region identified c.917G>A (p.R306Q) in the homeodomain of HOXD13 in family A. Analysis on family B identified the mutation c.916C>G (p.R306G) and therefore confirmed the genetic homogeneity. Luciferase assays indicated that these two mutations affected the transcriptional activation ability of HOXD13. The spectrum of HOXD13 mutations suggested a close genotype-phenotype correlation between the different types of HOXD13-Syndactyly. Overlaps of the various phenotypes were found both among and within families carrying the HOXD13 mutation. Mutations (p.R306Q and p.R306G) in the homeodomain of HOXD13 cause SD1-c. There are affinities between SD1-c and synpolydactyly. Different limb malformations due to distinct classes of HOXD13 mutations should be considered as a continuum of phenotypes and further classification of syndactyly should be done based on phenotype and genotype.
    PLoS ONE 05/2014; 9(5):e96192. DOI:10.1371/journal.pone.0096192 · 3.23 Impact Factor
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    • "limits the interpretation of the genotype-phenotype relationship. In addition to the clinical heterogeneity of SPD, the reduced penetrance may also compromise the genetic analysis and may have implications on the genetic counseling and risk estimation (Malik and Grzeschik, 2008). Moreover, due to the co-option of existing molecular pathways at different stages of development, it is not surprising that mutations causing limb malformations also affect the development of other organ systems (Wilkie, 2003; Scott et al., 2005). "
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    ABSTRACT: Synpolydactyly (SPD, OMIM 186000) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and between the fourth and fifth toes, with partial or complete digit duplication in the syndactylous web. The majority of these anomalies co-segregate with mutations in the HOXD13 gene, a homeobox transcription factor crucial for distal limb development. Different classes of HOXD13 mutations are involved in the pathogenesis of synpolydactyly, but an unequivocal genotype-phenotype correlation cannot always be achieved due to the clinical heterogeneity and reduced penetrance of SPD. All mutations identified so far mapped to the N-terminal polyalanine tract or to the C-terminal homeodomain of HOXD13, causing typical or atypical features of SPD respectively. However, mutations outside of these domains cause a broad variety of clinical features that complicate the differential diagnosis. The existing animal models that are currently used to study HOXD13 (mal)function are therefore instrumental in unraveling potential genotype-phenotype correlations. Both mouse- and chick-based approaches allow the in vivo study of the pathogenic mechanism by which HOXD13 mutations cause SPD phenotypes as well as help in identifying the transcriptional targets. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc.
    Developmental Dynamics 02/2014; 243(1). DOI:10.1002/dvdy.24037 · 2.38 Impact Factor
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    • "The proband showed bilateral webbing of the 3/4 fingers and clinodactyly of the fifth finger in both hands, but lacked the typical 4/5 toe webbing. Although clinodactyly has already been established as a feature of synpolydactyly at the milder end of its phenotypic spectrum [19]. Little has been reported about this phenotype in Chinese family. "
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    ABSTRACT: Human synpolydactyly (SPD), belonging to syndactyly (SD) II, is caused by mutations in homeobox d13 (HOXD13). Here, we describe the study of a two-generation Chinese family with a variant form of synpolydactyly. The sequence of the HOXD13 gene was analyzed. Luciferase assays were conducted to determine whether the mutation affected the function of the HOXD13 protein. We identified a novel c.659G>C (p.Gly220Ala) mutation outside the HOXD13 homeodomain responsible for the disease in this family. This mutation was not found in any of the unaffected family members and healthy control. Luciferase assays demonstrated that this mutation affected the transcriptional activation ability of HOXD13 (only approximately 84.7% of wild type, p<0.05). Phenotypes displayed by individuals carrying the novel mutation present additional features, such as fifth finger clinodactyly, which is not always associated with canonical SPD. This finding enhances our understanding about the phenotypic spectrum associated with HOXD13 mutations and advances our understanding of human limb development.
    Bone 08/2013; 57(1). DOI:10.1016/j.bone.2013.07.039 · 3.97 Impact Factor
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