RAS-MAPK pathway disorders: important causes of congenital heart disease, feeding difficulties, developmental delay and short stature

Wright, Emma M.M. Burkitt; Kerr, Bronwyn

doi:10.1136/adc.2009.160069

Cited by 30 publications

(19 citation statements)

References 30 publications

(47 reference statements)

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“…Several individuals in that series also had features of ectodermal dysplasia, whilst 3/11 had pulmonary stenosis, and other cardiac lesions were also described [6]. Normal birthweight and relative macrocephaly are features which appear to be present in the majority of patients both with 17q21.31 deletion [6] and RAS pathway disorders [5]. Variable degrees of developmental delay have been noted in patients with 17q21.31 deletion, and this spectrum is still liable to expansion.…”

Section: Introductionmentioning

confidence: 92%

“…CFC syndrome was first described in 1986 [4], and shows considerable overlap with other neuro-cardio-facio-cutaneous syndromes, particularly Noonan and Costello syndromes. The reason for these observed overlaps is that the protein products of all genes known to be mutated in these conditions interact within the RAS-MAPK pathway [5]. A previously published series of 17q21.31 microdeletion patients included several with features reminiscent of Noonan syndrome, including one in whom this diagnosis was thought sufficiently likely for Noonan syndrome genes to be tested [6].…”

Section: Introductionmentioning

confidence: 99%

“…Variable degrees of developmental delay have been noted in patients with 17q21.31 deletion, and this spectrum is still liable to expansion. Similarly, patients with CFC syndrome may have variable degrees of intellectual disability [5].…”

Section: Introductionmentioning

confidence: 99%

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Cutaneous features in 17q21.31 deletion syndrome

Wright

Johnson

Clayton‐Smith

2011

Clinical Dysmorphology

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Microdeletion of 17q21.31 causes a recurrent recognisable dysmorphic syndrome. Four further patients with 17q21.31 microdeletions are reported here where previously the diagnosis of cardiofacio-cutaneous (CFC) syndrome was suggested. These patients have significant similarities of facial gestalt to previously reported 17q21.31 microdeletion patients, but a striking feature that has not been emphasised previously is the large number of naevi and other pigmentary skin abnormalities that may be present. These features, together with a coarse facial appearance, relative macrocephaly and significant learning disabilities, had led to the previous diagnostic suggestion of CFC syndrome in each of these four cases.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Cutaneous features in 17q21.31 deletion syndrome

Wright

Johnson

Clayton‐Smith

2011

Clinical Dysmorphology

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“…The second aberrant cluster on chromosome 14 due to an inversion disrupts the MAP3K9 gene, which is an interesting candidate gene for the cardiac phenotype observed in the patient. 32 Without mate pair sequencing, this crucial information would not have been revealed. The enhancement in resolution of mate pair sequencing and hence the ability of directly pinpointing disease genes has great diagnostic value.…”

Section: Discussionmentioning

confidence: 99%

Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations

et al. 2013

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Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.

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“…However, in CFCS, intellectual disability is usually more severe than in LS and is associated with short stature and relative macrocephaly. CFCS has also a higher likelihood of structural central nervous system anomalies such as ventriculomegaly/hydrocephalus or epilepsy, more pronounced skin pathology such as absent eyebrows and keratosis pilaris which are characteristic of CFCS and long-lasting gastrointestinal complications including failure to thrive and dysphagia [Wright and Kerr, 2010]. No PTPN11 mutations have been found in individuals with CFCS [Aoki et al, 2008].…”

Section: Differential Diagnosismentioning

confidence: 99%

LEOPARD Syndrome: Clinical Features and Gene Mutations

Martínez‐Quintana

Rodríguez‐González

2012

Mol Syndromol

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The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations.

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RAS-MAPK pathway disorders: important causes of congenital heart disease, feeding difficulties, developmental delay and short stature

Cited by 30 publications

References 30 publications

Cutaneous features in 17q21.31 deletion syndrome

Cutaneous features in 17q21.31 deletion syndrome

Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations

LEOPARD Syndrome: Clinical Features and Gene Mutations

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