Genetic diagnosis of sporadic neurofibromatosis type 1 with café-au-lait spots as the only presentation in a child
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Abstract:
Objective To make a genetic diagnosis of sporadic neurofibromatosis type 1 with cafe-au-lait spots as the only presentation in a child.Methods Blood samples were collected from an 8-year-old child patient,his parents,and 100 healthy human controls.The mutation of NF1 gene was detected by PCR and direct sequencing.Results No mutation was detected in the NF1 gene of the parents or the healthy controls.There was a de novo nonsense mutation c.3520C ＞ T (p.Q1174X) in the NF1 gene of the patient,which leaded to a premature termination codon.Conclusions The child with cafe-au-lait spots as the only manifestation is diagnosed with sporadic neurofibromatosis type 1 by genetic testing.The mutation c.3520C ＞ T (p.Q1174X) may be an underlying cause of neurofibromatosis type 1.Keywords:
Nonsense mutation
Presentation (obstetrics)
To explore the genetic etiology for 11 sporadic patients with neurofibromatosis type 1.Chip targeting capture and high-throughput sequencing were employed to detect potential mutations of NF1 and NF2 genes among the 11 patients. The data was filtered through multiple mutational databases and in-house whole exome sequence database. Sanger sequencing was used for analysis of family members of the patients.Eleven pathogenic variants were found among the 11 patients, which included two splicing mutations, one missense mutation, two nonsense mutations, and six frame-shifting mutations. None of the mutations was recorded by the public database or the in-house database generated from 1775 samples through whole exome sequencing. None of the unaffected parents carried the same mutation. Seven mutations were associated with neurofibromatosis type 1 previously, while the remaining four were discovered for the first time. Prenatal diagnosis of two high-risk pregnancies suggested that neither fetus has inherited the NF1 mutation from their affected parents.Identification of causative mutations in patients with sporadic-type neurofibromatosis type 1 has provided a basis for genetic counseling. The four novel mutations have enriched the spectrum of NF1 gene mutations.
Sanger sequencing
Exome
Nonsense mutation
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Neurofibromatosis type 1 is a common neurocutaneous disorder, mostly caused by mutations in the NF1 gene. To identify the molecular genetic etiology of neurofibromatosis type 1 in two familiar and three sporadic cases of Han Chinese, DNA was isolated from the peripheral blood of eight patients in two NF1 pedigrees, three sporadic cases, and 100 unrelated healthy controls. Mutation screening for coding and exon-intron boundary sequences of NF1 gene was performed. Three novel missense mutations, c.601T>A in exon 4, c.871G>T in exon 6, and c.1448A>G in exon 10, were identified. These mutations provided new data for the spectrum of NF1 mutations causing neurofibromatosis type 1.
Pedigree chart
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Neurofibromatosis type 1 of von Recklinghausen is a common autosomal dominant disorder, characterized by peripheral neurofibromas, café-au-lait spots and Lisch nodules of the iris. The high mutation rate at the neurofibromatosis type 1 locus results in a wide range of molecular abnormalities. We have screened seven different exons of the neurofibromatosis type 1 gene, including those codifying for the GAP-related domain, using the RNA-Single Strand Conformation Polymorphism (RNA-SSCP) method in a series of 59 neurofibromatosis type 1 patients. We have also analyzed four intragenic repeats and one RFLP to detect hemizygosity and evaluate informativeness in at-risk families. One deletion and a new intronic normal variant have been detected. Thus the majority of Neurofibromatosis type 1 chromosomes have not been characterized, confirming difficulty in providing proper genetic counselling in neurofibromatosis type 1 families, even following extensive DNA analysis.
Single-strand conformation polymorphism
Neurofibromatosis type 2
Neurofibromatosis type I
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Objective
To detect NF1 gene mutations in a patient with neurofibromatosis type 1 (NF1) .
Methods
Polymerase chain reaction (PCR) and DNA sequencing were performed to detect mutations of the NF1 gene in a patient with NF1, his parents and 100 unrelated healthy controls.
Results
A novel frameshift mutation (c.3822delC) was identified in the patient, but not found in his parents or the unrelated healthy controls.
Conclusion
The novel frameshift mutation (c.3822delC) found in the patient is not a rare single nucleotide polymorphism (SNP) , and may be a causative mutation for NF1 by affecting the function of the NF1 gene.
Key words:
Neurofibromatosis 1; Genes, neurofibromatosis 1; Mutation
SNP
Neurofibromin 1
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Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with equal sex incidence that is characterized by neurofibromas, café-au-lait macules, axillary freckling, optic pathway tumor, distinctive osseous lesion, and iris Lisch nodules. Inactivating variants in the NF1 gene have been identified to be correlated with NF1. This tumor suppressor gene is located at 17q11.2.Ten affected NF1 probands and their available relatives from 10 unrelated Chinese families with neurofibromatosis type 1 were clinically studied. All of these probands mainly complained of osseous lesions. PCR was used to analyze and sequence the variants. We collected both laboratory and radiological information.We detected five novel pathogenic variants including two de novo variants in these 10 families: one missense variant, p.Cys709Arg(c.2125T>C), in exon 18 and four frameshift variants: p.Leu1459Profs*2(c.4436dupT) in exon 34; p.Lys99Argfs*4(c.296delA) in exon 4; p.Leu762Cysfs*2(c.2283delA) in exon 19; and p.Leu1522Ilefs*53(c.4562_4563dupAT) in exon 34.Novel pathogenic variants in the NF1 gene in these families correlated with the phenotype and genotype and explained the clinical manifestations of these patients. The results help us to understand the genetic basis of patients with neurofibromatosis type 1 in China. Our study expands the pathogenic variant spectrum of the NF1 gene and may be helpful in genetic counseling and prenatal genetic diagnosis.
Neurofibromin 1
Proband
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To report on two children manifesting multiple cafe-au-lait spots suspected as neurofibromatosis type 1, and perform NF1 gene mutation analysis.Blood samples were collected from the 2 children, their unaffected parents and 100 normal controls. The entire coding region of the NF1 gene was amplified by PCR and subjected to direct sequencing.In patient 1, a novel frameshift mutation c.1948delT (p.Leu650TyrfsX38) was identified in exon 12 of the NF1 gene. And in patient 2, a previously reported nonsense mutation c.541C>T (p.Gln181X) was revealed in exon 4b. The same mutations were not detected in their unaffected parents or 100 normal controls.The two patients were diagnosed with neurofibromatosis type 1 by molecular genetic testing. The pathogenic mutations were c.1948delT and c.541C>T, respectively.
Nonsense mutation
Mutation Testing
Nonsense
Coding region
Genetic Analysis
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Penetrance
Pseudogene
Neurofibromatosis type 2
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The purpose of the study was to determine the sites and types of mutations associated with type I neurofibromatosis (NF1) in the NF1 gene in a family with NF1 patients.The blood samples obtained from this family (four patients and one normal healthy individual) were analyzed by performing polymerase chain reaction (PCR) and DNA sequencing for mutation screening.We found synonymous mutations in exons 7, 38, 50, and 56 of the NF1 gene. This implied that the third codon had a new SNP that did not lead to a change in the amino acid coding. The exon 19 mutation was CAG homozygous, while it was C/TAG heterozygous in normal individuals. The stop codon led to nonsense-codon-mediated decay of the mRNA (NMD), thus resulting in only one copy of the NF1 gene that encodes the normal protein in individuals.The synonymous mutations in the NF1 gene occur in exons 7, 38, 50, and 56. The CAG homozygous mutations may occur in exon 19, and the C/TAG heterozygous mutations may occur in the others. This mutation may be responsible for NF1 in patients in this family and may warrant extensive research on the NF1 gene.
Nonsense mutation
Silent mutation
Coding region
Synonymous substitution
Stop codon
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Neurofibromatosis type 1 (NF1) is the common autosomal dominant disorder of humans appearing in childhood. Features defining the disease are multiple cafe-au-lait spots, multiple neurofibromas and Lisch nodules, but other features such as short stature, intellectual handicap, central-nervous tumors and other malignant diseases are also found. The gene NF1 was mapped to 17q11.2 and has been found to contain the mutations in NF1 patients. The mutation rate in the NF1 gene is one of the highest known for human genes with approximately 50% of all NF1 patients presenting as sporadic cases. Molecular analysis and genetic counseling is limited to the identification of the specific mutation in each patient or family or to the use of DNA polymorphisms and linkage analysis. We analysed 46 families with neurofibromatosis type 1. NF1 was diagnosed clinically according to the NIH criteria. A positive family history was found in 47.8% (22 of 46) and 52.2% (24 of 46) of affected patients were considered to be the result of a new mutation. DNA was obtained from peripheral blood of patients and related individuals. We used PCR-RFLP and VNTR analysis for linkage and LOH analysis in the affected families and individuals. Twenty-four families in Croatia population with the de novo mutation were studied using four intragenic markers. For VNTR analysis PCR products were separated on polyacrylamide gels or were analysed by submerged gel electrophoresis. LOH on the affected individual revealed a gross NF1 gene deletion in 3 (13.6%) families ; in 2 (67%) of them, the deletion was maternally and in one (33%) paternally derived.
Genetic linkage
Genetic Analysis
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Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an incidence of between 1: 3000 and 1: 4000. Common clinical signs include more than six café-au-lait spots, multiple cutaneous neurofibromas and iris Lisch nodules. Rarer are skeletal anomalies, learning disabilities and an increased risk of malignancy. The NF1 gene contains at least 60 exons with intron sizes ranging from 60 bp to more than 40 kb. Despite using different techniques including PTT, SSCP, heteroduplex analyses and direct sequencing, only a relatively small number of mutations have been reported world-wide. Using the more sensitive technique of temperature gradient gel electrophoresis (TGGE), we analysed a part of the NF1-GAP-region, namely exon 25, in DNA samples from 131 unrelated patients. We have identified a novel mutation L1425P in exon 25 of the NF1 gene in a 12-year-old boy (clinically diagnosed with NF1 at the age of 7). In contrast to those cases diagnosed with having both GAP-region mutations and malignant tumours, neither the proband nor four clinically affected family members with this mutation showed any evidence of malignancies. © 1999 Wiley-Liss, Inc.
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Heteroduplex
Single-strand conformation polymorphism
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