Prevalence and Complications of Single-Gene and Chromosomal Disorders in Craniosynostosis

Wilkie, Andrew O.M.; Byren, Jo C.; Hurst, Jane A.; Jayamohan, Jayaratnam; Johnson, David; Knight, Samantha J. L.; Lester, Tracy; Richards, Peter G.; Twigg, Stephen R.F.; Wall, Steven A.

doi:10.1542/peds.2009-3491

Cited by 260 publications

(237 citation statements)

References 46 publications

Supporting

Mentioning

222

Contrasting

Unclassified

Order By: Relevance

“…The pathogenicity of the detected alterations was assessed by determining: (1) If the mutation had been previously reported; (2) If not, the variations were assessed using the programs Ensembl and NCBI dbSNP to determine if the alteration has been described as a polymorphism. Allelic frequencies were obtained using NHLBI Exome Sequencing Project (ESP) Exome Variant Server (EVS) and the 1000 genomes, and where necessary in 300 Spanish healthy controls; (3) Amino acid conservation analysis; (4) Prediction of the function and pathogenicity using the bioinformatics package, Alamut 2.4.1 which includes PolyPhen, SIFT, MutationTaster and various splicing predictor tools (Human Splicing Finder (HSF), MaxEntScan, Splice Site Finder (SSF), GeneSplicer, Splice Site Prediction by Neural Network (NNsplice); (5) Functional analysis of splicing variants using minigene assays.…”

Section: Pathogenicity Assessmentmentioning

confidence: 99%

“…The most commonly mutated gene is FGFR2, whereas the p. Pro250Arg mutation in FGFR3 is the most frequent mutation, 2 characteristic of the Muenke syndrome. 3 EFNB1 (Ephrin B1, MIM 300035) encodes for a ligand, ephrin-B1, which binds to EphB receptors and has an important role in cell adhesion and the development and maintenance of the nervous system.…”

Section: Introductionmentioning

confidence: 99%

“…The incidence of mutations in FGFRs were FGFR2 (32%), FGFR3 (25%), TWIST1 (19%) and EFNB1 (7%). 2 This study formed the basis of our work, which aimed to improve the genetic diagnosis of craniosynostosis in the Spanish population, but also resulted in the screening of the entire coding sequence and intron: exon boundaries of these genes and mutation analysis of TCF12 and ERF.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

et al. 2014

View full text Add to dashboard Cite

Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre-Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up.

show abstract

Section: Pathogenicity Assessmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

et al. 2014

View full text Add to dashboard Cite

show abstract

“…50 Others have reported this mutation in 31% of patients with nonsyndromic coronal craniosynostosis. 23 The FGFR2 mutations (S252T and P253R) have also been reported in children with nonsyndromic craniosynostosis.…”

mentioning

confidence: 98%

“…23 The FGFR2 mutations (S252T and P253R) have also been reported in children with nonsyndromic craniosynostosis. 50 Several translational animal models have been developed to study the effect of various FGFR mutations. Deletion of both FGFR1 and FGFR2 are lethal.…”

mentioning

confidence: 99%

Insights into the development of molecular therapies for craniosynostosis

Kosty

Vogel

2015

FOC

View full text Add to dashboard Cite

For the past 2 decades, clinical and basic science researchers have gained significant insights into the molecular and genetic pathways associated with common forms of craniosynostosis. This has led to invaluable information for families and physicians in their attempts to understand the heterogeneity of craniosynostosis. Genetic mutations have been identified in the fibroblast growth factor receptors (FGFRs) as well as in other targets, including TWIST1, BMP, and RUNX2. Greater understanding of these and other pathways has led to the development of innovative approaches for applying medical therapies to the treatment of craniosynostosis, in particular by maintaining suture patency. In this article, the authors discuss the molecular pathophysiological mechanisms underlying various forms of craniosynostosis. They also highlight recent developments in the field of molecular craniosynostosis research with the hope of identifying targets for medical therapies that might augment the results of surgical intervention.

show abstract

Molecular Genetics of Achondroplasia

Narayana

Horton

2013

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Affecting approximately 250 000 individuals worldwide, achondroplasia (Ach) represents a family of skeletal dysplasias. Although inherited as an autosomal dominant trait, it results most often from a new mutation to unaffected parents. Virtually all patients have the same mutation in the gene that codes for the receptor tyrosine kinase, FGFR3. The mutation exaggerates the receptor's inhibitory functions on bone growth resulting in characteristic clinical features. Similar mutations of FGFR3 cause other members of this disease family. Our understanding of how mutant FGFR3 antagonises bone growth remains incomplete, and delineating the relevant molecular details has proved challenging. Nevertheless, new insights into the FGFR3 biology, that is, downstream FGFR3 signals are modulated by the paracrine hormone CNP, FGFR3 is processed to a fragment with potential nuclear function and FGFR3 signal output is influenced by the molecular chaperone Hsp90, have advanced the field and provided a glimpse into future growth stimulating treatments for Ach. Key Concepts: Achondroplasia is the prototype of a ‘family’ of human skeletal dysplasias characterised by dwarfism and characteristic craniofacial manifestations. Achondroplasia results from gain of function mutations of the tyrosine kinase‐mediated receptor, FGFR3, which is an important negative regulator of linear bone growth. Although achondroplasia can be inherited as an autosomal dominant trait, it most often results from de‐novo mutations to nonachondroplastic parents. The new mutations display a paternal age effect. Virtually all patients with achondroplasia have the same FGFR3 mutation. Other mutations of FGFR3 that enhance its function cause similar but more or less severe dwarfing conditions, such as thanatophoric dysplasia and hypochondroplasia. FGFR3 acts through ‘signals’ it transmits to the cellular machinery that regulates the proliferation and other behaviours of cells responsible for bone growth – chondrocytes that occupy the growth plates of growing bones. The predominant signalling output involves tyrosine kinase cascades collectively referred to as the MAPK signalling pathway. FGFR3 receptors bearing the achondroplasia mutation exhibit exaggerated MAPK signalling when investigated in both cell culture and mouse models of achondroplasia. The major goal in developing treatments for achondroplasia has been to safely reduce the output of FGFR3 signals to or towards normal. Strategies have ranged from blocking receptor activation to inhibiting FGFR3 tyrosine kinase activity to shortening the survival of actively signalling receptor to antagonising signals downstream of the receptor. These strategies are based on understanding the relevant molecular events. The most promising strategy at present involves administration of the peptide, CNP, which antagonises MAPK signals initiated by FGFR3.

show abstract

Prevalence and Complications of Single-Gene and Chromosomal Disorders in Craniosynostosis

Cited by 260 publications

References 46 publications

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

Insights into the development of molecular therapies for craniosynostosis

Molecular Genetics of Achondroplasia

Contact Info

Product

Resources

About