Tibial hemimelia–polydactyly–five-fingered hand syndrome associated with a 404 G&gt;A mutation in a distant sonic hedgehog cis-regulator (ZRS)

Cho, Tae-Joon; Baek, Goo Hyun; Lee, Hey-Ran; Moon, Hyuk Joo; Yoo, Won Joon; Choi, In Ho

doi:10.1097/bpb.0b013e32835106b2

Cited by 24 publications

(19 citation statements)

References 12 publications

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“…The mutation may disrupt transcription factor binding sites and lead to limb malformation. Thus, our research is consistent with former reports suggesting that ZRS variation could lead to limb malformations [Sun et al, 2008;Cho et al, 2013].…”

Section: Discussionsupporting

confidence: 82%

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

Wu¹,

Guo

Fan³

et al. 2016

Cytogenet Genome Res

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Preaxial polydactyly (PPD; OMIM 603596), which is characterized as having supernumerary fingers, is an unusual congenital hand abnormality. Triphalangeal thumb (TPT; OMIM 190600) is identified by an extra phalangeal bone and is often found in association with PPD. When in combination, the disease is referred to as PPD type II (PPD II; OMIM 174500). Previous studies have demonstrated that variations in the zone of polarizing activity regulatory sequence (ZRS; chr7:156,583,796-156,584,569; hg19) region are associated with PPD II. In this study, our patient was diagnosed with PPD II, having bilateral thumb duplication and unilateral TPT (on the right hand). Further investigation of possible causative genes identified a de novo heterozygous ZRS mutation (ZRS 428T>A). This novel mutation was neither found in 200 normal controls nor reported in online databases. Moreover, the bioinformatics program Genomic Evolutionary Rate Profiling (GERP) revealed this site (ZRS428) to be evolutionarily highly conserved, and the 428T>A point mutation was predicted to be deleterious by MutationTaster. In conclusion, the affected individual shows bilateral thumb duplication, but unilateral TPT making this case special. Thus, our findings not only further support the important role of ZRS in limb morphogenesis and expand the spectrum of ZRS mutations, but also emphasize the significance of genetic diagnosis and counseling of families with digit number and identity alterations as well.

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Section: Discussionsupporting

confidence: 82%

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

Wu¹,

Guo

Fan³

et al. 2016

Cytogenet Genome Res

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“…Other manifestations included varying degree of syndactyly of digits, broad halluces, fused nail, bifid nail, sandal gap, and congenital talipes equinovarus. It is interesting to note that the nucleotide change reported here (G>T) is the third possible mutation of the 404th nucleotide of ZRS region with the other two variations (G>A and G>C) being reported earlier in three reports on four patients [Lettice et al, ; Wieczorek et al, ; Cho et al, ]. This suggests that this position is likely to be a mutational hotspot of ZRS.…”

Section: Discussionsupporting

confidence: 63%

“…These include Acheiropody (OMIM 200500), preaxial polydactyly type II (OMIM 174500), syndactyly type IV (OMIM 186200), triphalangeal thumb type II (OMIM 174500), triphalangeal thumb‐polysyndactyly syndrome (OMIM 174500) and Werner mesomelic syndrome (OMIM 188770). Werner mesomelia is characterized by abnormalities of hands and feet with mesomelia and is caused by mutations in a specific location (at position 404; G>A and G>C) of the ZRS region [Lettice et al, ; Wieczorek et al, ; Cho et al, ]. Here we report on a large family demonstrating autosomal dominant Werner mesomelia syndrome with a novel sequence variation (G>T) in the same position of ZRS and describe the intra‐familial variation in the limb phenotype.…”

Section: Introductionmentioning

confidence: 75%

A novel mutation (g.106737G>T) in zone of polarizing activity regulatory sequence (ZRS) causes variable limb phenotypes in Werner mesomelia

Girisha

Bidchol

Kamath

et al. 2014

American J of Med Genetics Pt A

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Werner mesomelia is characterized by a sequence variation in the specific region (position 404) of the enhancer ZRS of SHH. The phenotype comprises variable mesomelia, abnormalities of the thumb and great toe and supernumerary digits. We describe extensive variation in limb phenotype in a large family and report on a novel sequence variation NG_009240.1: g.106737G>T (traditional nomenclature: ZRS404G>T) in the ZRS within the LMBR1 gene. The newly recognized clinical features in this family include small thenar eminence, sandal gap, broad first metatarsals, mesoaxial polydactyly, and postaxial polydactyly. We provide information on 12 affected family members. We review the literature on how a sequence variation in ZRS may cause such diverse phenotypes.

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“…The anteroposterior patterning of the digits requires signalling from the zone of polarizing activity (ZPA), a group of mesenchymal cells localized at the posterior margin of the tetrapod limb bud. ZRS gain-of-function anomalies are responsible for limb malformations (the so-called ZRS-associated syndromes) (4), with phenotypic presentation ranging through preaxial polydactyly and/or triphalangeal thumbs [PPD2 (MIM 174500)] [reviewed in (5) (4,(10)(11)(12), PPD2 with radial deficiency (13) and some cases of Laurin-Sandrow syndrome (LSS [MIM 135750]) (14). A highly conserved cis-regulatory enhancer called the ZPA regulatory sequence [ZRS (MIM 605522)] lies within intron 5 of the LMBR1 gene on chromosome 7q36, which is located 1 megabase upstream of its target gene, SHH in human (2,3).…”

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confidence: 99%

Intrafamilial variability of ZRS‐associated syndrome: characterization of a mosaic ZRS mutation by pyrosequencing

et al. 2015

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During limb development, the spatio-temporal expression of sonic hedgehog (SHH) is driven by the Zone of polarizing activity Regulatory Sequence (ZRS), located 1 megabase upstream from SHH. Gain-of-function mutations of this enhancer, which cause ectopic expression of SHH, are known to be responsible for congenital limb malformations with variable expressivity, ranging from preaxial polydactyly or triphalangeal thumbs to polysyndactyly, which may also be associated with mesomelic deficiency. In this report, we describe a patient affected with mirror-image polydactyly of the four extremities and bilateral tibial deficiency. The proband's father had isolated preaxial polydactyly type II (PPD2). Using Sanger sequencing, a ZRS point mutation (NC_000007.14, g.156584153A>G, UCSC, Build hg.19) was only identified in the patient. However, pyrosequencing analysis enabled the detection of a 10% somatic mosaic in the blood and saliva from the father. To our knowledge, this is the first description of a ZRS mosaic mutation. This report highlights the complexity of genotype-phenotype correlation in ZRS-associated syndromes and the importance of detecting somatic mosaicism for accurate genetic counselling.

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Tibial hemimelia–polydactyly–five-fingered hand syndrome associated with a 404 G>A mutation in a distant sonic hedgehog cis-regulator (ZRS)

Cited by 24 publications

References 12 publications

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

A novel mutation (g.106737G>T) in zone of polarizing activity regulatory sequence (ZRS) causes variable limb phenotypes in Werner mesomelia

Intrafamilial variability of ZRS‐associated syndrome: characterization of a mosaic ZRS mutation by pyrosequencing

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