Background:Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These ‘RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.Methods:We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.Results:We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4–18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.Conclusions:These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.
Background:Mutations and deletions of the homeobox transcription factor gene SHOX are known to cause short stature. The authors have analysed SHOX enhancer regions in a large cohort of short stature patients to study the importance of regulatory regions in developmentally relevant genes like SHOX.Methods:The authors tested for the presence of copy number variations in the pseudoautosomal region of the sex chromosomes in 735 individuals with idiopathic short stature and compared the results to 58 cases with Leri–Weill syndrome and 100 normal height controls, using fluorescence in situ hybridisation (FISH), single nucleotide polymorphism (SNP), microsatellites, and multiplex ligand dependent probe amplification (MLPA) analysis.Results:A total of 31/735 (4.2%) microdeletions were identified in the pseudoautosomal region in patients with idiopathic short stature; eight of these microdeletions (8/31; 26%) involved only enhancer sequences residing a considerable distance away from the gene. In 58 Leri–Weill syndrome patients, a total of 29 microdeletions were identified; almost half of these (13/29; 45%) involve enhancer sequences and leave the SHOX gene intact. These deletions were absent in 100 control persons.Conclusion:The authors conclude that enhancer deletions in the SHOX gene region are a relatively frequent cause of growth failure in patients with idiopathic short stature and Leri–Weill syndrome. The data highlights the growing recognition that regulatory sequences are of crucial importance in the genome when diagnosing and understanding the aetiology of disease.
The WT1 gene, located on chromosome 11p13, is mutated in a low number of Wilms tumors (WTs). Germ-line mutations in the WT1 gene are found in patients with bilateral WT and͞or associated genital tract malformations (GU). We have identified 19 hemizygous WT1 gene mutations͞deletions in 64 patient samples. The histology of the tumors with mutations was stromal-predominant in 13, triphasic in 3, blastemal-predominant in 1, and unknown in 2 cases. Thirteen of 21 patients with stromal-predominant tumors had WT1 mutations and 10 of these were present in the germ line. Of the patients with germ-line alterations, six had GU and a unilateral tumor, two had a bilateral tumor and normal GU tracts, and two had a unilateral tumor and normal GU. Three mutations were tumor-specific and were found in patients with unilateral tumors without GU. These data demonstrate a correlation of WT1 mutations with stromalpredominant histology, suggesting that a germ-line mutation in WT1 predisposes to the development of tumors with this histology. Twelve mutations are nonsense mutations resulting in truncations at different positions in the WT1 protein and only two are missense mutations. Of the stromal-predominant tumors, 67% showed loss of heterozygosity, and in one tumor a different somatic mutation in addition to the germline mutation was identified. These data show that in a large proportion of a histopathologically distinct subset of WTs the classical two-hit inactivation model, with loss of a functional WT1 protein, is the underlying cause of tumor development.The WT1 gene was isolated by positional cloning from chromosome 11p13 (1, 2) and encodes a transcription factor of the zinc finger (ZF) family. Loss of heterozygosity (LOH) studies showed that tumors frequently have lost markers from chromosome 11p. Subsequently, it was found that this loss is often limited to the region 11p15, where a second locus, WT2, involved in the development of Wilms tumor (WT) has been assumed to exist. Further LOH studies revealed loss of chromosome 16q in about 20% of WTs, suggesting that a third locus is located at this site. Susceptibility for the rare form of familial WT in several generations does not show linkage to either of these regions; therefore, another WT locus must exist in these cases (3-5). The WT1 gene encodes four transcripts produced by alternative splicing (6, 7) and encodes a protein with a predicted size of 45-49 kDa. DNA binding to a GC-rich motif identical to the early growth response-binding site was demonstrated for the WT1 protein lacking splice II in the ZF (WT͞ϪKTS), whereas the WT1 protein containing these amino acids (WT͞ϩKTS) does not bind to this sequence (8). Recently it was shown that WT1͞ϩKTS can also bind to a similar GC-rich DNA motif (9). More recent studies have established that the proline-glutamine rich amino terminus has transcriptional regulatory properties. It was shown that WT1 containing splice I (WT͞ϩ17aa) is a repressor, whereas WT1͞Ϫ17aa can be either a repressor or activator depending on the ar...
ObjectivesTill date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures.DesignProspective analysis.Patients19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype–phenotype analyses.SettingAll analyses were performed in a large German laboratory specialised in genetic diagnostics.Results15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation.ConclusionsOn the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype–phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.
The term "spondyloperipheral dysplasia" (SPD) has been applied to the unusual combination of platyspondyly and brachydactyly as observed in a small number of individuals. The reported cases show wide clinical variability and the nosologic status and spectrum of this condition are still ill defined. Zabel et al. [1996: Am J Med Genet 63(1):123-128] reported an individual with short stature and SPD who was heterozygous for a frameshift mutation in the C-propeptide domain of COL2A1. To explain the additional finding of brachydactyly that is not an usual feature of the type II collagenopathies, it was postulated that the nature of the mutation induced precocious calcification and premature fusion of metacarpal and phalangeal growth plates. The C-propeptide of collagen II had previously been found to promote calcification ("chondrocalcin"). We have ascertained two further individuals with clinical and radiological findings of a type II collagenopathy in infancy who developed brachydactyly type E like changes of fingers and toes in childhood. In both individuals, heterozygosity for novel, distinct mutations in the C-propeptide coding region of COL2A1 were found. Although all three mutations (the one previously reported and the two novel ones) predict premature termination, their location close to the 3'-end of the mRNA probably protects them from nonsense-mediated decay and allows for synthesis of mutant procollagen chains. However, loss of crucial cysteine residues or other sequences essential for trimerization prevents these chains from associating and participating in procollagen helix formation, and thus leads to accumulation in the ER-consistent with EM findings. The mechanism leading to precocious fusion of phalangeal epiphyses remains to be explored. The consistency of clinical, radiographic, and molecular findings in these three unrelated individuals confirms SPD as a distinct nosologic entity. The diagnosis of SPD is suggested by the appearance of brachydactyly in a child who has clinical and radiographic features of a collagen II disorder.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.