Mutational screening of <i>GLI3, SHH, preZRS</i>, and <i>ZRS</i> in 102 Chinese children with nonsyndromic polydactyly

Xiang, Ying; Jiang, Limin; Wang, Bo; Xu, Yunlan; Cai, Haiqing; Fu, Qin

doi:10.1002/dvdy.24488

Cited by 17 publications

(17 citation statements)

References 53 publications

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“…Phenotypes observed in affected members of the present two families were similar to those reported previously in families inheriting PPD. However, a feature cutaneous syndactyly, reported previously, was not observed in affected members of our families.…”

Section: Discussioncontrasting

confidence: 62%

“…. However, a feature cutaneous syndactyly, reported previously,16,17 was not observed in affected members of our families.A previously published study has described mutations in the NEK1 causing in short-ribs associated with or without polydactyly syndrome (SRP type-II) 18. To further verify the non-polymorphic nature of the variant, it was crosschecked in 7000 in-house exome (IHG, Helmholtz, Munich, Germany), 130 exomes from unrelated members of the local population, and 215 ethnically matched controls.…”

contrasting

confidence: 52%

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Whole‐exome sequencing revealed a nonsense mutation in STKLD1 causing non‐syndromic pre‐axial polydactyly type A affecting only upper limb

et al. 2019

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Pre-axial polydactyly (PPD) is characterized by well-developed non-functional 1st digit (thumb) duplication in hands and/or feet. It is mostly inherited in autosomal dominant manner. In the present study, two families of Pakistani origin, demonstrating unilateral PPD type A, have been characterized at clinical and genetic levels. Whole-exome sequencing (WES) revealed a nonsense mutation (c.84C > A, p.Tyr28*) in the STKLD1, located on chromosome 9q34.2, in affected individuals of both the families. Our findings report the first direct involvement of the STKLD1 in the digit development and highlight the importance of inclusion of this gene for screening individuals presenting non-syndromic recessive PPD. K E Y W O R D S limb anomaly, nonsense variant, pre-axial polydactyly, serine-threonine kinase, STKLD1

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Section: Discussioncontrasting

confidence: 62%

contrasting

confidence: 52%

Whole‐exome sequencing revealed a nonsense mutation in STKLD1 causing non‐syndromic pre‐axial polydactyly type A affecting only upper limb

et al. 2019

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“…Genetic variants causative for such type of polydactyly were frequently found in the ZRS and pZRS regions located in intron 5 of LMBR1, FGFR1 as well as SHH in human (W ieczorek et al 2009; X iang et al 2017; H ovius 2018) and mice (HAJIHOSSEINI et al 2004). In our analysis, we confirmed the high conservation of ZRS and pZRS in cattle, but excluded polydactyly-associated variants in these regions and other polydactyly-related candidate genes reported for species other than cattle.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in mice and chicken affected with preaxial polydactyly verified altered regulatory functions of ZRS (M asuya et al 2007; M aas et al 2011). More than 20 different mutations in the ZRS and in the upstream sequence of the ZRS (pZRS) have been identified to be associated with polydactyly in human (L ettice et al 2003; G urnett et al 2007; F urniss et al 2008; S emerci et al 2009; W ieczorek et al 2009; F arooq et al 2010; A lbuisson et al 2011; AL-QATTAN et al 2012; L aurell et al 2012; V andermeer et al 2012; G irisha et al 2014; N orbnop et al 2014; V andermeer et al 2014; W u et al 2016; X iang et al 2017; H ovius 2018), dogs (P ark et al 2008), cats (L ettice et al 2008) and chicken (H uang et al 2006; D orshorst et al 2010; D unn et al 2011; J ohnson et al 2014) so far. In human, limb malformations caused by mutations located in this regulatory region represent a wide range of phenotypes (V andermeer and A hituv 2011).…”

Section: Introductionmentioning

confidence: 99%

De-novovariants inXIRP1associated with polydactyly and polysyndactyly in Holstein cattle

Braun

Hellige

Gerhauser

et al. 2019

Preprint

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Congenital polydactylous cattle are sporadically observed. Impairment of the limb patterning process due to altered control of the zone of polarizing activity (ZPA) was associated in several species with preaxial polydactyly and syndactyly. In cattle, the role of ZPA and other genes involved in limb patterning for polydactyly was not yet elucidated. Herein, we report on a preaxial type II polydactyly and a praeaxial type II+V polysyndactyly in two Holstein calves and screen whole genome sequencing data for associated variants. Using whole genome sequencing data of both affected calves did not show mutations in the candidate regions of ZRS and pZRS or in candidate genes associated with polydactyly, syndactyly and polysyndactyly in other species. Two indels, which are located inXIRP1within a common haplotype, were highly associated with the two phenotypes. Bioinformatic analyses retrieved an interaction betweenXIRP1andFGFR1, CTNNB1andCTNND1supporting a link between theXIRP1variants and embryonic limb patterning. The heterozygous haplotype was highly associated with the present polydactylous phenotypes due to dominant mode of inheritance with an incomplete penetrance in Holstein cattle.

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“…Research has found that more than 100 genes are associated with human polydactyly, including the GLI3 (GLI‐Kruppel Family Member 3; MIM 165240) and SHH (Sonic hedgehog; MIM 600725) genes, which are the most reported (Xiang et al, ). The SHH‐GLI3 pathway is essentially important during early development of different tissues, including the neural tube, craniofacial structure, and limbs (Motoyama, ).…”

Section: Introductionmentioning

confidence: 99%

Novel GLI3 variant causes Greig cephalopolysyndactyly syndrome in three generations of a Lithuanian family

Siavrienė

Mikštienė

Radzevičius

et al. 2019

Molec Gen & Gen Med

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Background Preaxial polydactyly type IV, also referred as polysyndactyly, has been described in a few syndromes. We present three generations of a family with preaxial polydactyly type IV and other clinical features of Greig cephalopolysyndactyly syndrome (GCPS). Methods and results Sequencing analysis of the GLI3 coding region identified a novel donor splice site variant NC_000007.14(NM_000168.6):c.473+3A>T in the proband and the same pathogenic variant was subsequently identified in other affected family members. Functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) sample revealed that the splice site variant c.473+3A>T disrupts the original donor splice site, thus leading to exon 4 skipping. Based on further in silico analysis, this pathogenic splice site variant consequently results in a truncated protein NP_000159.3:p.(His123Argfs*57), which lacks almost all functionally important domains. Therefore, functional cDNA analysis confirmed that the haploinsufficiency of the GLI3 is the cause of GCPS in the affected family members. Conclusion Despite the evidence provided, pathogenic variants in the GLI3 do not always definitely correlate with syndromic or nonsyndromic clinical phenotypes associated with this gene. For this reason, further transcriptomic and proteomic evaluation could be suggested.

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Mutational screening of GLI3, SHH, preZRS, and ZRS in 102 Chinese children with nonsyndromic polydactyly

Abstract: This is the first report of the assessment of the frequency of GLI3/SHH/preZRS/ZRS in Chinese patients to show any higher possibility of mutations or variants for the 4 genes or sequences in China. Developmental Dynamics 246:392-402, 2017. © 2017 Wiley Periodicals, Inc.

Cited by 17 publications

References 53 publications

Whole‐exome sequencing revealed a nonsense mutation in STKLD1 causing non‐syndromic pre‐axial polydactyly type A affecting only upper limb

Whole‐exome sequencing revealed a nonsense mutation in STKLD1 causing non‐syndromic pre‐axial polydactyly type A affecting only upper limb

De-novovariants inXIRP1associated with polydactyly and polysyndactyly in Holstein cattle

Novel GLI3 variant causes Greig cephalopolysyndactyly syndrome in three generations of a Lithuanian family

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