Split hand/foot malformation syndrome (SHFM): rare congenital orthopaedic disorder

Patel, Ankur; Sharma, Deepak; Yadav, Jaivinder; Garg, Eva

doi:10.1136/bcr-2014-204731

Cited by 6 publications

(6 citation statements)

References 9 publications

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“…Split hand/foot malformation (SHFM OMIM # 605289) is a genetically congenital heterogeneous syndrome with highly variable and asymmetrical clinical features ranging from mild defects such as hypoplasia of a single phalanx or syndactyly to aplasia of one or more digits (Patel et al, 2014). It is estimated that the prevalence of SHFM is around 1/100,000 births (Miyake et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Whole genome sequencing reveals translocation breakpoints disrupting TP63 gene underlying split hand/foot malformation in a Chinese family

Peng

Yang

et al. 2021

Molec Gen & Gen Med

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Background Split hand/foot malformation (SHFM) is a congenital limb developmental disorder, which impairs the fine activities of hand/foot in the affected individuals seriously. SHFM is commonly inherited as an autosomal dominant disease with incomplete penetrance. Chromosomal aberrations such as copy number variations and translocations have been linked to SHFM. This study aimed to identify the genetic cause for three patients with bilateral hand and foot malformation in a Chinese family. Methods Karyotyping, single‐nucleotide polymorphism (SNP) array, whole exome sequencing, whole genome sequencing, and Sanger sequencing were applied to identify the pathogenic variant. Results Karyotyping revealed that the three patients had balanced reciprocal translocation, 46, XX, t(3;15) (q29;q22). SNP array identified no pathogenic copy number variation in the proband. Trio‐WES (fetus–mother–father) sequencing results revealed no pathogenic variants in the genes related to SHFM. Whole‐genome low‐coverage mate‐pair sequencing (WGL‐MPS), breakpoint PCR, and Sanger sequencing identified the breakpoints disrupting TP63 in the patients, but not in healthy family members. Conclusion This study firstly reports that a translocation breakpoint disrupting TP63 contributes to the SHFM in a Chinese family, which expands our knowledge of genetic risk and counseling underlying SHFM. It provides a basis for genetic counseling and prenatal diagnosis (preimplantation genetic diagnosis) for this family.

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Section: Introductionmentioning

confidence: 99%

Whole genome sequencing reveals translocation breakpoints disrupting TP63 gene underlying split hand/foot malformation in a Chinese family

Peng

Yang

et al. 2021

Molec Gen & Gen Med

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“…Use of artificial tears and emollients may be necessary for ectodermal dysplasia for prevention of evaporative eye loss ( 35 ). Patel et al reported 17-year-old man with EEC syndrome whose diagnosis was confirmed with genetic analysis showing the importance of genetic analysis and late presentation ( 17 ). Sharma et al reported a newborn with lobster foot syndrome showing that any limb can be involved ( 36 ).…”

Section: Discussionmentioning

confidence: 93%

“…The majority of the patients usually have mild limb abnormality and very rarely may be unaffected. The patients of EEC may sometimes have webbing or fusion (syndactyly) of the fingers and/or toes ( 17 ). In some cases, syndactyly may be the only limb defect that is seen.…”

Section: Discussionmentioning

confidence: 99%

“…Few long-term case report has shown their progression to Hodgkin lymphoma ( 30 ). There has been one case report of EEC syndrome associated with congenital heart disease (Ventricular septal defect with aortic regurgitation) ( 17 ). In other case report, Valenzise et al reported the R298Q mutation of p63 gene in autosomal dominant ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

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Ectrodactyly, Ectodermal Dysplasia, Cleft Lip, and Palate (EEC Syndrome) with Tetralogy of Fallot: A Very Rare Combination

et al. 2015

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Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC) syndrome is a rare genetic disorder with an incidence of around 1 in 90,000 in population. It is known with various names including split hand–split foot–ectodermal dysplasia–cleft syndrome or split hand, cleft hand, or lobster claw hand/foot. We report first case of EEC with associated heart disease (Tetralogy of Fallot) who was diagnosed as EEC on the basis of clinical features and EEC was confirmed with genetic analysis.

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“…This result, along with previous data in this manuscript, suggest WDFY2 as a possible susceptibility gene in our patients to be placed in the p63 network of limb development. Firstly, it has been identified as an effector of TP63 gene ([19] and present work) whose mutations have been recurrently reported in association with both isolated and syndromic split-hand/foot malformation [8,68]. Secondly, as revealed by RNA-seq expression data from GTEx (Release V6) [69], WDFY2 expression is skin-specific (highest median expression: 13.56 RPKM in Skin - Sun Exposed) in contrast with the ADGRE4P pseudogene that is characterised by low levels in many tissues, being mainly expressed in the spleen (highest median expression: 5.36 RPKM).…”

Section: Discussionmentioning

confidence: 99%

P63 modulates the expression of theWDFY2gene which is implicated in cancer regulation and limb development

et al. 2019

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TP63 is a member of the TP53 gene family, sharing a common gene structure that produces two groups of mRNAs’ encoding proteins with different N-terminal regions (ΔN and TA isoforms); both transcripts are also subjected to alternative splicing mechanisms at C-terminus, generating a variety of isoforms. p63 is a master regulator of epidermal development and homoeostasis as well as an important player in tumorigenesis and cancer progression with both oncogenic and tumour suppressive roles. A number of studies have aimed at the identification of p63 target genes, allowing the dissection of the molecular pathways orchestrated by the different isoforms. In the present study we investigated in more detail the p63 responsiveness of the WDFY2 (WD repeat and FYVE domain containing 2) gene, encoding for an endosomal protein identified as a binding partner of the PI-3K/AKT signalling pathway. We showed that overexpression of different p63 isoforms was able to induce WDFY2 expression in TP53-null cells. The p63-dependent transcriptional activation was associated with specific response elements (REs) that have been identified by a bioinformatics tool and validated by yeast- and mammal-based assays. Interestingly, to confirm that WDFY2 belongs to the p63 network of cancer regulation, we analysed the impact of WDFY2 alterations, by showing its frequent deletion in different types of tumours and suggesting its expression level as a prognostic biomarker. Lastly, we identified a chromosomal translocation involving the WDFY2 locus in a patient affected by a rare congenital limb anomaly, indicating WDFY2 as a possible susceptibility gene placed downstream p63 in the network of limb development.

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Split hand/foot malformation syndrome (SHFM): rare congenital orthopaedic disorder

Cited by 6 publications

References 9 publications

Whole genome sequencing reveals translocation breakpoints disrupting TP63 gene underlying split hand/foot malformation in a Chinese family

Whole genome sequencing reveals translocation breakpoints disrupting TP63 gene underlying split hand/foot malformation in a Chinese family

Ectrodactyly, Ectodermal Dysplasia, Cleft Lip, and Palate (EEC Syndrome) with Tetralogy of Fallot: A Very Rare Combination

P63 modulates the expression of theWDFY2gene which is implicated in cancer regulation and limb development

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