F‐syndrome (F‐form of acro‐pectoro‐vertebral dysplasia): Report on a second family

Camera, G; Camera, Andrea; Pozzolo, Silvano; Costa, Margherita; Mantero, R

doi:10.1002/ajmg.1320570322

Cited by 8 publications

(3 citation statements)

References 2 publications

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“…F-syndrome had previously been mapped to this chromosomal region (2q36), but its genetic cause remained unknown (Camera et al, 1995; Thiele et al, 2004). We used whole-exome sequencing to detect mutations in genes located in the linkage interval but were not able to identify any potentially pathogenic changes.…”

Section: Resultsmentioning

confidence: 99%

Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

Lupiáñez

Kraft

Heinrich

et al. 2015

Cell

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1,702

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SUMMARY Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.

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Section: Resultsmentioning

confidence: 99%

Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

Lupiáñez

Kraft

Heinrich

et al. 2015

Cell

1,902

1,702

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“…It was first described in 1969 in eight members of a four generation American family whose surname began with the letter F1 and has only once been reported since, in an Italian father and daughter 2. In the hands, the malformation primarily involves the thumbs and index fingers, which are short, deformed, often partially duplicated, and joined by soft tissue webbing and sometimes a bony bridge.…”

mentioning

confidence: 99%

A novel acropectoral syndrome maps to chromosome 7q36

Dündar

Gordon²,

Özyazgan³

et al. 2001

Journal of Medical Genetics

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F syndrome (acropectorovertebral syndrome) is a dominantly inherited skeletal dysplasia aVecting the hands, feet, sternum, and lumbosacral spine, which has previously been described in only two families. Here we report a six generation Turkish family with a related but distinct dominantly inherited acropectoral syndrome. All 22 aVected subjects have soft tissue syndactyly of all fingers and all toes and 14 also have preaxial polydactyly of the hands and/or feet. In addition, 14 have a prominent upper sternum and/or a blind ending, inverted U shaped sinus in the anterior chest wall. Linkage studies and haplotype analysis carried out in 16 aVected and nine unaVected members of this family showed that the underlying locus maps to a 6.4 cM interval on chromosome 7q36, between EN2 and D7S2423, a region to which a locus for preaxial polydactyly and triphalangeal thumb-polysyndactyly has previously been mapped. Our findings expand the range of phenotypes associated with this locus to include total soft tissue syndactyly and sternal deformity, and suggest that F syndrome may be another manifestation of the same genetic entity. In mice, ectopic expression of the gene Sonic hedgehog (Shh) in limb buds and lateral plate mesoderm during development causes preaxial polydactyly and sternal defects respectively, suggesting that misregulation of SHH may underlie the unusual combination of abnormalities in this family. A recently proposed candidate gene for 7q36 linked preaxial polydactyly is LMBR1, encoding a novel transmembrane receptor which may be an upstream regulator of SHH. (J Med Genet 2001;38:304-309)

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“…Acro-pectoro-vertebral dysplasia (F-syndrome) is a rare skeletal disorder with a dominant inheritance pattern (28,29). Symptoms include carpal and tarsal synostosis, malformations of the first and second fingers with frequent syndactyly, and spina bifida occulta (28)(29)(30). Although the molecular basis remains unknown, Thiele et al (29) mapped the disease to a 6.5 cM region on chromosome 2q36, where the WNT6 gene is located.…”

Section: Wnt6mentioning

confidence: 99%

WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

et al. 2020

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Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.

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F‐syndrome (F‐form of acro‐pectoro‐vertebral dysplasia): Report on a second family

Cited by 8 publications

References 2 publications

Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

A novel acropectoral syndrome maps to chromosome 7q36

WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

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