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Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

ABSTRACT: We describe an 18-month-old male (BAB7221)with split-hand malformation. Custom high-density array and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother (BAB7219), the fetus (BAB7218) and her later born son (BAB7221). This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother (BAB8247).

ORGANISM(S): Homo sapiens

PROVIDER: GSE75190 | GEO | 2015/11/20

SECONDARY ACCESSION(S): PRJNA302747

REPOSITORIES: GEO

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Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Project description:We describe an 18-month-old male (BAB7221)with split-hand malformation. Custom high-density array and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother (BAB7219), the fetus (BAB7218) and her later born son (BAB7221). This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother (BAB8247). High density custom aCGH detecting all 6 individuals in the family

2015-11-20 | E-GEOD-75190 | biostudies-arrayexpress

Ectrodactyly/split hand feet malformation.

Project description:Split-hand/split-foot malformation is a rare limb malformation with median clefts of the hands and feet and aplasia/hypoplasia of the phalanges, metacarpals and metatarsals. When present as an isolated anomaly, it is usually inherited as an autosomal dominant form. We report a case of autosomal recessive inheritance and discuss the antenatal diagnosis, genetic counseling and treatment for the malformation.

| S-EPMC2922631 | biostudies-other

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [scRNA-seq]

Project description:Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigated the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice resulted in restructuring of the chromatin architecture. This led to an ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern. Artificial repositioning of the AER-specific enhancers of Fgf8 was sufficient to induce misexpression of Lbx1 and Btrc. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression and dosage in the developing limb. Our results reveal new insights into the molecular mechanism underlying SHFM3 and provide novel conceptual framework for how genomic rearrangements can cause gene misexpression and disease.

2023-02-22 | GSE223456 | GEO

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [RNA-seq]

2023-02-22 | GSE223455 | GEO

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [4C-seq]

2023-02-22 | GSE223454 | GEO

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [Capture Hi-C, Virtual4C]

2023-02-22 | GSE223450 | GEO

Nonsyndromic Split-Hand/Foot Malformation: Recent Classification.

Project description:Split-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan.

| S-EPMC6997797 | biostudies-literature

Genetic analysis of a congenital split?hand/split?foot malformation 4 pedigree.

Project description:In the present study whole-exome sequencing using the Complete Genomics platform was employed to scan a proband from a split?hand/split?foot malformation (SHFM) 4 family. The missense mutation c.728G>A (p.Arg243Gln) in the TP63 gene was revealed to be associated with SHFM. Sanger sequencing confirmed the sequences of the proband and his father. The father was diagnosed with SHFM and harbored a CGG?to?CAG mutation in exon 5, which produced a R243Q substitution in the zinc binding site and dimerization site of TP63. The R243Q mutation was predicted to be pathogenic by PolyPhen?2. The proband, who was diagnosed with four digit SHFM, exhibited a more severe phenotype. X?ray analysis returned the following results: Absence of third phalange bilaterally and third metacarpus of the left hand; absence of the second toes bilaterally and partial third toes; and partial fusion of the second, third and metatarsal bones of the right side with deformity of the second metatarsal of the right side. Osteochondroma was present in the fourth proximal radial metacarpal of the left hand and the basal and proximal parts of the second metatarsal of the right side. The proband's father had five digits in both feet. These results indicate that the R243Q mutation produces a novel phenotype named SHFM4. The present study revealed that the R243Q mutation in the TP63 gene produced a novel phenotype named SHFM4, thereby demonstrating the mutational overlap between ectrodactyly?ectodermal dysplasia?cleft syndrome and SHFM4.

| S-EPMC5983954 | biostudies-literature

PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in Split Hand/Foot Malformation

Project description:Split Hand/Foot Malformation (SHFM) is a rare limb abnormality with clefting of the fingers and/or toes. For many patients, the genetic etiology is unknown. Through whole exome and targeted sequencing, we detected three novel variants in a transcription factor, PRDM1 that arose de novo in families with SHFM or segregated with the phenotype. PRDM1 has been shown to be required for limb development; however, its role is not well understood, and it is unclear how the PRDM1 variants affect protein function. Using transient and stable overexpression rescue experiments in zebrafish, we show that the variants have reduced function compared to wildtype PRDM1 likely due to disruption of the proline/serine-rich and DNA-binding zinc finger domains. Through expression assays, RNA-seq, and CUT&RUN in isolated pectoral fin cells, we demonstrate that Prdm1a directly binds to and regulates genes required for limb induction, outgrowth, and anterior/posterior patterning, such as fgfr1a, dlx5a, dlx6a, and smo. Together, these results improve our understanding of the role of PRDM1 in the limb gene regulatory network and help predict the pathogenicity of PRDM1 variants in humans

2023-04-13 | GSE217486 | GEO

Reconstruction of a Monodactylous Hand with Microsurgical Free Foot-to-Hand Transfer in Split-Hand/Split-Foot Malformation with Tibial Aplasia.

Project description:Split-hand/split-foot malformation with long bone deficiency (SHLFD syndrome) is a rare congenital disorder, which may be sporadic or autosomal dominant with incomplete penetrance. When complete tibial aplasia is seen, the mainstay of treatment is amputation and lower limb prosthesis. This rare constellation of congenital differences presents an opportunity for microsurgical free tissue transfer using the principle of "spare parts" to improve the functionality of the hand. We present a rare case of split-hand/split-foot malformation with a monodactylous right hand and complete tibial aplasia, treated with microsurgical free foot-to-hand transfer at the time of lower limb amputation, reconstructing key pinch. At the latest 8 months follow-up, the patient had no pain, active key pinch, and ambulated independently with prostheses. He was able to use his right hand independently for a number of daily activities, such as stacking blocks, drinking from a cup, and playing with toys.

| S-EPMC7159962 | biostudies-literature

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