Polydactyly and genes

Phadke, Shubha R.; Sankar, V.H.

doi:10.1007/s12098-010-0033-1

Cited by 11 publications

(11 citation statements)

References 25 publications

(19 reference statements)

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“…Polydactyly, one of the most common congenital hand/foot malformations encountered in clinical genetics [ 1 , 2 ], can occur as an isolated entity or as part of pleiotropic developmental anomaly syndromes [ 3 ]. Post-axial polydactyly is far more common than pre-axial and central polydactyly; occasionally, concomitant syndactyly is seen with some forms of polydactyly [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

A novel GLI3 mutation affecting the zinc finger domain leads to preaxial-postaxial polydactyly-syndactyly complex

2014

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BackgroundPolydactyly is a highly common congenital limb defect. Extra digits may appear as an isolated anomaly or as a part of a syndrome. Mutations in GLI3 have been shown to cause Greig cephalopolysyndactyly, Pallister-Hall syndrome and non-syndromic polydactyly. Genotype-phenotype correlation studies of GLI3 mutations suggest a model by which mutations in the zinc-finger domain (ZFD) of GLI3 likely lead to syndromic polydactyly. Here we describe a rare case of autosomal dominant heterozygous missense mutation in the ZFD of GLI3 leading to a variable polydactyly-syndactyly complex.Case presentationA large Jewish Moroccan family presented with apparently autosomal dominant heredity of bilateral thumb polydactyly in hands and feet combined with post-axial polydactyly type B or type A. Syndactyly was evident in most patients’ hands and feet. Apart from head circumference beyond 90th percentile in some of the affected individuals, none had craniofacial dysmorphism. A novel GLI3 c.1802A > G (p.His601Arg) mutation was found in all affected individuals.ConclusionWe demonstrate that a mutation in the ZFD domain of GLI3 leads to phenotypic variability, including an isolated limb phenotype. Thus, the variability in phenotypes caused by mutations in this master developmental regulator is more profound than has been previously suggested.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0110-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A novel GLI3 mutation affecting the zinc finger domain leads to preaxial-postaxial polydactyly-syndactyly complex

2014

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“…However, malformations affecting the limbs, more specifically the number of digits with which an infant is born, are among the most frequent congenital defects recorded in humans, occurring as often as 1 in 1000 live births. Currently, there are about 221 syndromes described with polydactyly and 120 syndromes with oligodactyly [2]. Despite this wide prevalence of limb abnormalities, to date only ∼84 genes have been associated with syndromes that include limb defects, 15 of which have described polydactyly [2].…”

Section: Introductionmentioning

confidence: 99%

“…Currently, there are about 221 syndromes described with polydactyly and 120 syndromes with oligodactyly [2]. Despite this wide prevalence of limb abnormalities, to date only ∼84 genes have been associated with syndromes that include limb defects, 15 of which have described polydactyly [2]. Similarly, the sequential and tightly interconnected cellular events that lead to the establishment of each individual tissue type, as well as the three-dimensional molecular interplay within the vertebrate limb are not yet fully understood [3].…”

Section: Introductionmentioning

confidence: 99%

Global Gene Expression Analysis of Murine Limb Development

et al. 2011

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Detailed information about stage-specific changes in gene expression is crucial for understanding the gene regulatory networks underlying development and the various signal transduction pathways contributing to morphogenesis. Here we describe the global gene expression dynamics during early murine limb development, when cartilage, tendons, muscle, joints, vasculature and nerves are specified and the musculoskeletal system of limbs is established. We used whole-genome microarrays to identify genes with differential expression at 5 stages of limb development (E9.5 to 13.5), during fore- and hind-limb patterning. We found that the onset of limb formation is characterized by an up-regulation of transcription factors, which is followed by a massive activation of genes during E10.5 and E11.5 which levels off at later time points. Among the 3520 genes identified as significantly up-regulated in the limb, we find ∼30% to be novel, dramatically expanding the repertoire of candidate genes likely to function in the limb. Hierarchical and stage-specific clustering identified expression profiles that are likely to correlate with functional programs during limb development and further characterization of these transcripts will provide new insights into specific tissue patterning processes. Here, we provide for the first time a comprehensive analysis of developmentally regulated genes during murine limb development, and provide some novel insights into the expression dynamics governing limb morphogenesis.

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“…According to the position of the extra digit, polydactyly has been classified into postaxial polydactyly (PAP), mesoaxial, and preaxial (Malik, ). This defect is also associated with at least 221 syndromes according to the London dysmorphology database (Phadke & Sankar, ), covering 146 genes (Umair et al, ) and can be a hallmark for a group of syndromes such as for ciliopathies. For this group of diseases, in addition to skeletal malformations such as PAP, the phenotypic spectrum can associate retinal degeneration, obesity, kidney dysfunction, and sometimes intellectual disability as observed in the classical Bardet–Biedl syndrome (BBS; MIM# 209900) for which 22 genes have been identified.…”

Section: Introductionmentioning

confidence: 99%

NovelIQCEvariations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish

et al. 2019

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Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high‐genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole‐exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients’ fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog‐signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.

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Polydactyly and genes

Cited by 11 publications

References 25 publications

A novel GLI3 mutation affecting the zinc finger domain leads to preaxial-postaxial polydactyly-syndactyly complex

A novel GLI3 mutation affecting the zinc finger domain leads to preaxial-postaxial polydactyly-syndactyly complex

Global Gene Expression Analysis of Murine Limb Development

NovelIQCEvariations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish

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