Novel gene mutation in von Hippel-Lindau disease – a report of two cases

Abstract Background Von Hippel-Lindau (VHL) syndrome is a familial autosomal dominant hereditary neoplastic disease caused by mutations in the VHL gene. Approximately 503 kinds of VHL gene mutations have been reported. Different types of mutations manifest various clinical phenotypes, from benign to malignant tumours or coexisting cysts. Thus, a gene mutation test is essential in the diagnosis of VHL syndrome. Case presentation We reported two cases in which a novel mutation site in the c530-536delGACTGGA region in exon 3 of the VHL gene resulted in the development of VHL syndrome. According to the ACMG guidelines, this variation is pathogenic and consistent with autosomal dominant inheritance. This variation has not been reported anywhere in the databases or literature. Conclusion This report will add a new mutation site to VHL gene databases. The newly added gene mutation and its associated clinical phenotypes will help improve the accuracy of VHL diagnosis and benefit the community of VHL gene mutation carriers.

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Clinical phenotypes of a large Chinese multigenerational kindred with autosomal dominant familial ALS due to Ile149Thr SOD1 gene mutation

Amyotrophic Lateral Sclerosis ◽

10.1080/17482960600732412 ◽

2006 ◽

Vol 7 (3) ◽

pp. 142-149 ◽

Cited By ~ 6

Author(s):

Gardian C. Y. Fong ◽

Ken H. H. Kwok ◽

Y. Q. Song ◽

T. S. Cheng ◽

Philip W. L. Ho ◽

...

Keyword(s):

Gene Mutation ◽

Autosomal Dominant ◽

Sod1 Gene ◽

Clinical Phenotypes ◽

Familial Als

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A Unique Case of Renal Carcinoma with Xp11.2 Translocations/TFE3 Gene Fusions in a 3-Year-old Child, with Coexistent von Hippel-Lindau Gene Mutation

Pediatric and Developmental Pathology ◽

10.1007/s10024-004-1018-8 ◽

2004 ◽

Vol 7 (4) ◽

pp. 403-406 ◽

Cited By ~ 15

Author(s):

Mana M. Parast ◽

Grant Eudy ◽

Kenneth W. Gow ◽

Mahul Amin ◽

Bahig Shehata

Keyword(s):

Gene Mutation ◽

Renal Carcinoma ◽

Pediatric Population ◽

Single Point ◽

Single Point Mutation ◽

Transcription Factor Gene ◽

Unique Case ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease

Renal cell carcinomas (RCCs) are rare in the pediatric population; when they occur, a significant percentage are associated with specific cytogenetic abnormalities and germline mutations. These include mutations in the von Hippel-Lindau (VHL) gene and translocations involving the TFE3 transcription factor gene on Xp11.2. Here we report a case of a 3-year-old child with a large renal mass. Histologic examination of the tumor showed a predominantly nested growth pattern with some papillary foci. Cytogenetic analysis revealed a karyotype of t(X;1)(p11.2; p34.3), consistent with a TFE3-associated RCC. Interestingly, sequencing of the patient's VHL gene revealed a single point mutation, previously seen in a subgroup of patients with von Hippel-Lindau disease. This is the first reported case, to our knowledge, of t(X;1)-associated RCC in a patient with concurrent VHL gene mutation.

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A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation.

Acta Biochimica Polonica ◽

10.18388/abp.2014_1839 ◽

2014 ◽

Vol 61 (4) ◽

Cited By ~ 9

Author(s):

Dagmara Kabzińska ◽

Katarzyna Kotruchow ◽

Joanna Cegielska ◽

Irena Hausmanowa-Petrusewicz ◽

Andrzej Kochański

Keyword(s):

Genetic Counseling ◽

Gene Mutation ◽

Autosomal Dominant ◽

Clinical Course ◽

Axonal Neuropathy ◽

Gene Mutations ◽

Special Importance ◽

Recessive Trait ◽

Dominant Form ◽

Charcot Marie Tooth

Charcot-Marie-Tooth (CMT) disease caused by mutations in the GDAP1 gene has been shown to be inherited via traits that may be either autosomal recessive (in the majority of cases) [CMT4A] or autosomal dominant [CMT2K]. CMT4A disease is characterized by an early onset, and a severe clinical course often leading to a loss of ambulation, whereas CMT2K is characterized by a mild clinical course of benign axonal neuropathy beginning even in the 6th decade of life. Clinical data from a GDAP1 mutated patient suggests that the presence of a particular mutation is associated with a certain trait of inheritance. The association of a particular GDAP1 gene mutation and a dominant or recessive trait of inheritance is of special importance for genetic counseling and the prenatal diagnostics as regards severe forms of CMT. In the present study we report on two CMT families in which a newly identified Glu222Lys mutation within the GDAP1 gene segregates both in autosomal dominant and recessive traits. Our study shows that at least some GDAP1 gene mutations may segregate with the CMT phenotype as both dominant and recessive traits. Thus, genetic counseling for CMT4A/CMT2K families requires more extensive data on GDAP1 phenotype-genotype correlations.

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DLX3 Mutation in a New Family and Its Phenotypic Variations

Journal of Dental Research ◽

10.1177/154405910808700402 ◽

2008 ◽

Vol 87 (4) ◽

pp. 354-357 ◽

Cited By ~ 22

Author(s):

S.-K. Lee ◽

Z.H. Lee ◽

S.-J. Lee ◽

B.-D. Ahn ◽

Y.-J. Kim ◽

...

Keyword(s):

Gene Mutation ◽

Autosomal Dominant ◽

Mutational Analysis ◽

Enamel Hypoplasia ◽

Enamel Defects ◽

Clinical Phenotypes ◽

New Family ◽

Dominant Disease ◽

Curly Hair ◽

Phenotypic Variations

Tricho-dento-osseous syndrome (TDO) is an autosomal-dominant disease characterized by curly hair at birth, enamel hypoplasia, taurodontism, and a thick cortical bone. A common DLX3 gene mutation (c.571_574delGGGG) has been identified in multiple families with variable clinical phenotypes. Recently, another DLX3 gene mutation (c.561_562delCT) was reported to cause amelogenesis imperfecta with taurodontism (AIHHT). We identified a Korean family with overlapping phenotypes of TDO and AIHHT. We performed mutational analysis to discover its genetic etiology. The identified mutation was c.561_562delCT mutation in the DLX3 gene. The enamel was hypomature and hypoplastic. The characteristic taurodontic features were not identified. Increased bone density or thickness could not be revealed by cephalometric, hand-wrist, and panoramic radiographs. Affected individuals reported that their nails were brittle, and they had curly hair at birth. This study clearly showed that the c.561_562delCT mutation had not only enamel defects, but also other clinical phenotypes resembling those of TDO syndrome.

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Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Scientific Reports ◽

10.1038/s41598-020-74744-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Haiqiong Wang ◽

Yongbo Guo ◽

Zhenkun Dong ◽

Tao Li ◽

Xinsheng Xie ◽

...

Keyword(s):

Survival Rate ◽

Myelodysplastic Syndrome ◽

Gene Mutation ◽

Poor Prognosis ◽

Gene Mutations ◽

Chromosome 8 ◽

Common Mutation ◽

Mutation Load ◽

Mutation Site ◽

Increased Risk

Abstract To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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Identification of a VHL gene mutation in a Chinese family with Von Hippel‑Lindau syndrome

Molecular Medicine Reports ◽

10.3892/mmr.2018.8974 ◽

2018 ◽

Author(s):

Zhengwen He ◽

Lu Xia ◽

Zhiyong Deng ◽

Aojie Lian ◽

Zhengmao Hu ◽

...

Keyword(s):

Gene Mutation ◽

Chinese Family ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Von Hippel Lindau Syndrome

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Identification of a VHL gene mutation in atypical Von Hippel-Lindau syndrome: genotype–phenotype correlation and gene therapy perspective

Cancer Cell International ◽

10.1186/s12935-021-02386-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dali Tong ◽

Yao Zhang ◽

Jun Jiang ◽

Gang Bi

Keyword(s):

Gene Therapy ◽

Gene Mutation ◽

Suppressor Gene ◽

Pancreatic Cysts ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Genetic Examination ◽

Examination Methods ◽

Vhl Disease ◽

Von Hippel Lindau Syndrome

Abstract Background Classical von Hippel Lindau (VHL) disease/syndrome includes CNS hemangioblastoma, renal or pancreatic cysts, pheochromocytoma, renal carcinoma and exodermic cystadenoma. The syndrome is caused by mutation of VHL tumor suppressor gene. The most prevalent mutations are present in VHL syndrome. To date, > 500 mutations of gene related to the progression of VHL syndrome have been reported. VHL gene mutation presented in single lung or pancreatic tumor has been reported occasionally, but there is no report of both. Methods In this paper, we used CT scan, pathological and genetic examination methods to diagnose a rare atypical VHL syndrome. Results We reported a rare case of atypical VHL syndrome with authenticated VHL mutation at p.Arg167Gln, that was associated with not only bilateral pheochromocytoma but also lung carcinoid and neuroendocrine tumor of pancreas. Based on literature reviews, the patient was recommended to be further subjected to octreotide-based radionuclide therapy. Conclusions Combined with gene detection and clinical diagnosis, we found the inherent relationship between VHL genotype and phenotype, and constructed the standard diagnosis and treatment process of disease with rare VHL mutation from the perspective of gene therapy.

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Von Hippel-Lindau gene mutation status is associated with a dichotomous response in primary and metastatic tumors in patients receiving bevacizumab and erlotinib for metastatic renal cell carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.15522 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 15522-15522

Author(s):

D. Tsavachidou ◽

N. M. Tannir ◽

C. G. Wood ◽

P. Corn ◽

K. Do ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Gene Mutation ◽

Metastatic Disease ◽

Primary Tumor ◽

Renal Cell ◽

Response To Therapy ◽

Gene Inactivation ◽

Vhl Gene ◽

Von Hippel Lindau

15522 Background: A single arm phase II study is underway evaluating the safety and clinical benefit of presurgical bevacizumab and erlotinib in the management of patients with untreated conventional renal cell carcinoma (RCC). It is not known how the presence or absence of von Hippel Lindau (VHL) mutations affect the response to therapy in the primary or metastatic site, and whether VHL mutational status is predictive for either. Methods: Patients enrolled had conventional RCC, measurable metastatic disease, a primary tumor in place, no prior systemic therapy, a PS of 0 or 1 and no brain metastases. A total of 35 patients were enrolled as of January 8, 2007. Patients were treated with bevacizumab for 4 cycles and erlotinib for 8 weeks, and underwent cytoreductive nephrectomy at week 10 (4 weeks after the last dose of bevacizumab). A VHL gene mutation and methylation analysis was completed on nephrectomy specimens from the first 18 evaluable patients. Patients were grouped according to the presence or absence of functional VHL gene inactivation (mutation and/or methylation). Two-sample T-test and Fisher’s exact test were performed. Results: Ten patients (55%) demonstrated either VHL mutation or methylation ( table 1 ). Patients with no VHL gene inactivation demonstrated more robust primary tumor shrinkage, but did not demonstrate partial responses (PRs). Table 1 . Conclusions: These findings, although preliminary, suggest a dichotomous response in the primary and metastatic disease sites according to VHL functional status. Ongoing evaluation of new treatment strategies using antivascular/targeted agents in RCC may benefit from molecular stratification. [Table: see text] No significant financial relationships to disclose.

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