共查询到20条相似文献,搜索用时 31 毫秒
1.
Lehtonen HJ Kiuru M Ylisaukko-Oja SK Salovaara R Herva R Koivisto PA Vierimaa O Aittomäki K Pukkala E Launonen V Aaltonen LA 《Journal of medical genetics》2006,43(6):523-526
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n=98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n=22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15–29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC. 相似文献
2.
AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome 总被引:4,自引:0,他引:4
Parisi MA Doherty D Eckert ML Shaw DW Ozyurek H Aysun S Giray O Al Swaid A Al Shahwan S Dohayan N Bakhsh E Indridason OS Dobyns WB Bennett CL Chance PF Glass IA 《Journal of medical genetics》2006,43(4):334-339
Background
Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1).Methods
We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis.Results
We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions.Conclusions
Overall, 11% of subjects had AHI1 mutations, while ∼2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype‐phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease. 相似文献3.
Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes 总被引:2,自引:0,他引:2
Tezenas du Montcel S Clot F Vidailhet M Roze E Damier P Jedynak CP Camuzat A Lagueny A Vercueil L Doummar D Guyant-Maréchal L Houeto JL Ponsot G Thobois S Cournelle MA Durr A Durif F Echenne B Hannequin D Tranchant C Brice A;French Dystonia Network 《Journal of medical genetics》2006,43(5):394-400
Background
Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon‐sarcoglycan gene (SGCE) on chromosome 7q21.Methods
We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M‐D), essential myoclonus (E‐M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested.Results
Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M‐D and five E‐M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non‐carriers. None of the patients had severe psychiatric disorders.Conclusion
This large cohort of index patients shows that SGCE mutations are primarily found in patients with M‐D and to a lesser extent E‐M, but are present in only 30% of these patients combined (M‐D and E‐M). 相似文献4.
Casilli F Tournier I Sinilnikova OM Coulet F Soubrier F Houdayer C Hardouin A Berthet P Sobol H Bourdon V Muller D Fricker JP Capoulade-Metay C Chompret A Nogues C Mazoyer S Chappuis P Maillet P Philippe C Lortholary A Gesta P Bézieau S Toulas C Gladieff L Maugard CM Provencher DM Dugast C Delvincourt C Nguyen TD Faivre L Bonadona V Frébourg T Lidereau R Stoppa-Lyonnet D Tosi M 《Journal of medical genetics》2006,43(9):e49
Background
Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer.Objective
To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects.Methods
Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2.Results
We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of ⩽50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum.Conclusion
The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects. 相似文献5.
Prigoda NL Savas S Abdalla SA Piovesan B Rushlow D Vandezande K Zhang E Ozcelik H Gallie BL Letarte M 《Journal of medical genetics》2006,43(9):722-728
Background
Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder present in 1 in 8000 people and associated with arteriovenous malformations. Genetic testing can identify individuals at risk of developing the disease and is a useful diagnostic tool.Objective
To present a strategy for mutation detection in families clinically diagnosed with HHT.Methods
An optimised strategy for detecting mutations that predispose to HHT is presented. The strategy includes quantitative multiplex polymerase chain reaction, sequence analysis, RNA analysis, validation of missense mutations by amino acid conservation analysis for the ENG (endoglin) and ACVRL1 (ALK1) genes, and analysis of an ACVRL1 protein structural model. If no causative ENG or ACVRL1 mutation is found, proband samples are referred for sequence analysis of MADH4 (associated with a combined syndrome of juvenile polyposis and HHT).Results
Data obtained over the past eight years were summarised and 16 novel mutations described. Mutations were identified in 155 of 194 families with a confirmed clinical diagnosis (80% sensitivity). Of 155 mutations identified, 94 were in ENG (61%), 58 in ACVRL1 (37%), and three in MADH4 (2%).Conclusions
For most missense variants of ENG and ACVRL1 reported to date, study of amino acid conservation showed good concordance between prediction of altered protein function and disease occurrence. The 39 families (20%) yet to be resolved may carry ENG, ACVRL1, or MADH4 mutations too complex or difficult to detect, or mutations in genes yet to be identified. 相似文献6.
DL Smit AR Mensenkamp S Badeloe MH Breuning MEH Simon KY Van Spaendonck CM Aalfs JG Post S Shanley IPC Krapels LH Hoefsloot RJA Van Moorselaar TM Starink J‐P Bayley J Frank MAM Van Steensel FH Menko 《Clinical genetics》2011,79(1):49-59
Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon MEH, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IPC, Hoefsloot LH, van Moorselaar RJA, Starink TM, Bayley J‐P, Frank J, van Steensel MAM, Menko FH. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation‐dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole‐gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management. 相似文献
7.
Pithukpakorn M Wei MH Toure O Steinbach PJ Glenn GM Zbar B Linehan WM Toro JR 《Journal of medical genetics》2006,43(9):755-762
Background
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the autosomal dominant heritable syndrome with predisposition to development of renal cell carcinoma and smooth muscle tumours of the skin and uterus.Objective
To measure the fumarate hydratase (FH) enzyme activity in lymphoblastoid cell lines and fibroblast cell lines of individuals with HLRCC and other familial renal cancer syndromes.Methods
FH enzyme activity was determined in the whole cell, cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations.Results
Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with HLRCC had lower FH enzyme activity than cells from normal controls (p<0.05). The enzyme activity in lymphoblastoid cell lines from three individuals with mutations in R190 was not significantly different from individuals with other missense mutations. The cytosolic and mitochondrial FH activity of cell lines from individuals with HLRCC was reduced compared with those from control cell lines (p<0.05). There was no significant difference in enzyme activity between control cell lines (n = 4) and cell lines from affected individuals with other hereditary renal cancer syndromes (n = 22).Conclusions
FH enzyme activity testing provides a useful diagnostic method for confirmation of clinical diagnosis and screening of at‐risk family members. 相似文献8.
Comprehensive genomic and phenotypic characterization of germline FH deletion in hereditary leiomyomatosis and renal cell carcinoma 下载免费PDF全文
Cathy D. Vocke Christopher J. Ricketts Maria J. Merino Ramaprasad Srinivasan Adam R. Metwalli Lindsay A. Middelton James Peterson Youfeng Yang W. Marston Linehan 《Genes, chromosomes & cancer》2017,56(6):484-492
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial cancer syndrome associated with the development of cutaneous and uterine leiomyomas, and an aggressive form of type 2 papillary kidney cancer. HLRCC is characterized by germline mutation of the FH gene. This study evaluated the prevalence and clinical phenotype of FH deletions in HLRCC patients. Patients with phenotypic manifestations consistent with HLRCC who lacked detectable germline FH intragenic mutations were investigated for FH deletion. A series of 28 patients from 13 families were evaluated using a combination of a comparative genomic hybridization (CGH) array and/or CLIA‐approved FH deletion/duplication analyses. Thirteen distinct germline deletions were identified in the 13 UOB families, including 11 complete FH gene deletions and 2 partial FH gene deletions. The size of eight evaluated complete FH deletions varied from ~4.74 Mb to 249 kb, with all deletions resulting in additional gene losses. Two partial FH gene deletions were identified, with one resulting in loss of exon 1 and the upstream region of the FH gene only. Kidney cancer was diagnosed in 9 (32%) of 28 patients and 7 (54%) of 13 families possessing either complete or partial FH deletions. Cutaneous and uterine leiomyomas were observed at similar rates to those in FH point mutation families. Complete or partial FH gene alterations in HLRCC families are associated with all of the canonical HLRCC manifestations, including type 2 papillary kidney cancer and should be screened for in any patient at‐risk for this disorder. 相似文献
9.
Helou J Otto EA Attanasio M Allen SJ Parisi MA Glass I Utsch B Hashmi S Fazzi E Omran H O'Toole JF Sayer JA Hildebrandt F 《Journal of medical genetics》2007,44(10):657-663
Background
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1‐6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/hypoplasia, retinal degeneration and mental retardation. In Senior–Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS.Methods
Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis.Results
Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in‐frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP. 相似文献10.
Gronwald J Huzarski T Byrski B Medrek K Menkiszak J Monteiro AN Sun P Lubinski J Narod SA 《Journal of medical genetics》2006,43(5):424-428
Background
Mutations in the BRCA1 (MIM 113705) gene are found in many families with multiple cases of breast and ovarian cancer, and women with a BRCA1 mutation are at significantly higher risk of developing breast and ovarian cancer than are the general public.Methods
We obtained blood samples and pedigree information from 3568 unselected cases of early‐onset breast cancer and 609 unselected patients with ovarian cancer from hospitals throughout Poland. Genetic testing was performed for three founder BRCA1 mutations. We also calculated the risk of breast and ovarian cancer to age 75 in the first degree relatives of carriers using Kaplan‐Meier methods.Results
The three founder BRCA1 mutations were identified in 273 samples (187 with 5382insC, 22 with 4153delA, and 64 with C61G). A mutation was present in 4.3% of patients with breast cancer and 12.3% of patients with ovarian cancer. The overall risk of breast cancer to age 75 in relatives was 33% and the risk of ovarian cancer was 15%. The risk for breast cancer was 42% higher among first degree relatives of carriers of the C61G missense mutation compared to other mutations (HR = 1.42; p = 0.10) and the risk for ovarian cancer was lower than average (OR = 0.26; p = 0.03). Relatives of women diagnosed with breast cancer had a higher risk of breast cancer than relatives of women diagnosed with ovarian cancer (OR = 1.7; p = 0.03).Conclusions
The risk of breast cancer in female relatives of women with a BRCA1 mutation depends on whether the proband was diagnosed with breast or ovarian cancer. 相似文献11.
Roux AF Faugère V Le Guédard S Pallares-Ruiz N Vielle A Chambert S Marlin S Hamel C Gilbert B Malcolm S Claustres M;French Usher Syndrome Collaboration 《Journal of medical genetics》2006,43(9):763-768
Background
Usher syndrome, a devastating recessive disorder which combines hearing loss with retinitis pigmentosa, is clinically and genetically heterogeneous. Usher syndrome type 1 (USH1) is the most severe form, characterised by profound congenital hearing loss and vestibular dysfunction.Objective
To describe an efficient protocol which has identified the mutated gene in more than 90% of a cohort of patients currently living in France.Results
The five genes currently known to cause USH1 (MYO7A, USH1C, CDH23, PCDH15, and USH1G) were tested for. Disease causing mutations were identified in 31 of the 34 families referred: 17 in MYO7A, 6 in CDH23, 6 in PCDH15, and 2 in USH1C. As mutations in genes other than myosin VIIA form nearly 50% of the total, this shows that a comprehensive approach to sequencing is required. Twenty nine of the 46 identified mutations were novel. In view of the complexity of the genes involved, and to minimise sequencing, a protocol for efficient testing of samples was developed. This includes a preliminary linkage and haplotype analysis to indicate which genes to target. It proved very useful and demonstrated consanguinity in several unsuspected cases. In contrast to CDH23 and PCDH15, where most of the changes are truncating mutations, myosin VIIA has both nonsense and missense mutations. Methods for deciding whether a missense mutation is pathogenic are discussed.Conclusions
Diagnostic testing for USH1 is feasible with a high rate of detection and can be made more efficient by selecting a candidate gene by preliminary linkage and haplotype analysis. 相似文献12.
13.
Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases 总被引:4,自引:0,他引:4
Depienne C Tallaksen C Lephay JY Bricka B Poea-Guyon S Fontaine B Labauge P Brice A Durr A 《Journal of medical genetics》2006,43(3):259-265
Background
SPG4 encodes spastin, a member of the AAA protein family, and is the major gene responsible for autosomal dominant spastic paraplegia. It accounts for 10–40% of families with pure (or eventually complicated) hereditary spastic paraparesis (HSP).Objective
To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories.Methods
146 mostly European probands with progressive spastic paraplegia were studied (103 with pure spastic paraplegia and 43 with additional features). Major neurological causes of paraplegia were excluded. None had a family history of paraplegia. DNA was screened by DHPLC for mutations in the 17 coding exons of the SPG4 gene. Sequence variants were characterised by direct sequencing. A panel of 600 control chromosomes was used to rule out polymorphisms.Results
The overall rate of mutations was 12%; 19 different mutations were identified in 18 patients, 13 of which were novel. In one family, where both parents were examined and found to be normal, the mutation was transmitted by the asymptomatic mother, indicating reduced penetrance. The parents of other patients were not available for analysis but were reported to be normal. There was no evidence for de novo mutations. The mutations found in these apparently isolated patients were mostly of the missense type and tended to be associated with a less severe phenotype than previously described in patients with inherited mutations.Conclusions
: The unexpected presence of SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories. 相似文献14.
Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax
Gunji Y Akiyoshi T Sato T Kurihara M Tominaga S Takahashi K Seyama K 《Journal of medical genetics》2007,44(9):588-593
Rationale
Birt–Hogg–Dubé (BHD) syndrome, a rare inherited autosomal genodermatosis first recognised in 1977, is characterised by fibrofolliculomas of the skin, an increased risk of renal tumours and multiple lung cysts with spontaneous pneumothorax. The BHD gene, a tumour suppressor gene located at chromosome 17p11.2, has recently been shown to be defective. Recent genetic studies revealed that clinical pictures of the disease may be variable and may not always present the full expression of the phenotypes.Objectives
We hypothesised that mutations of the BHD gene are responsible for patients who have multiple lung cysts of which the underlying causes have not yet been elucidated.Methods
We studied eight patients with lung cysts, without skin and renal disease; seven of these patients have a history of spontaneous pneumothorax and five have a family history of pneumothorax. The BHD gene was examined using PCR, denaturing high‐performance liquid chromatography and direct sequencing.Main results
We found that five of the eight patients had a BHD germline mutation. All mutations were unique and four of them were novel, including three different deletions or insertions detected in exons 6, 12 and 13, respectively and one splice acceptor site mutation in intron 5 resulting in an in‐frame deletion of exon 6.Conclusions
We found that germline mutations of the BHD gene are involved in some patients with multiple lung cysts and pneumothorax. Pulmonologists should be aware that BHD syndrome can occur as an isolated phenotype with pulmonary involvement. 相似文献15.
A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history 总被引:1,自引:0,他引:1
Kittles RA Baffoe-Bonnie AB Moses TY Robbins CM Ahaghotu C Huusko P Pettaway C Vijayakumar S Bennett J Hoke G Mason T Weinrich S Trent JM Collins FS Mousses S Bailey-Wilson J Furbert-Harris P Dunston G Powell IJ Carpten JD 《Journal of medical genetics》2006,43(6):507-511
Background
The EphB2 gene was recently implicated as a prostate cancer (PC) tumour suppressor gene, with somatic inactivating mutations occurring in ∼10% of sporadic tumours. We evaluated the contribution of EphB2 to inherited PC susceptibility in African Americans (AA) by screening the gene for germline polymorphisms.Methods
Direct sequencing of the coding region of EphB2 was performed on 72 probands from the African American Hereditary Prostate Cancer Study (AAHPC). A case‐control association analysis was then carried out using the AAHPC probands and an additional 183 cases of sporadic PC compared with 329 healthy AA male controls. In addition, we performed an ancestry adjusted association study where we adjusted for individual ancestry among all subjects, in order to rule out a spurious association due to population stratification.Results
Ten coding sequence variants were identified, including the K1019X (3055A→T) nonsense mutation which was present in 15.3% of the AAHPC probands but only 1.7% of 231 European American (EA) control samples. We observed that the 3055A→T mutation significantly increased risk for prostate cancer over twofold (Fisher''s two sided test, p = 0.003). The T allele was significantly more common among AAHPC probands (15.3%) than among healthy AA male controls (5.2%) (odds ratio 3.31; 95% confidence interval 1.5 to 7.4; p = 0.008). The ancestry adjusted analyses confirmed the association.Conclusions
Our data show that the K1019X mutation in the EphB2 gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA. 相似文献16.
Background
A 3 bp deletion located at the 5′ end of exon 3 of MLH1, resulting in deletion of exon 3 from RNA, was recently identified.Hypothesis
That this mutation disrupts an exon splicing enhancer (ESE) because it occurs in a purine‐rich sequence previously identified as an ESE in other genes, and ESEs are often found in exons with splice signals that deviate from the consensus signals, as does the 3′ splice signal in exon 3 of MLH1.Design
The 3 bp deletion and several other mutations were created by polymerase chain reaction mutagenesis and tested using an in vitro splicing assay. Both mutant and wild type exon 3 sequences were cloned into an exon trapping vector and transiently expressed in Cos‐1 cells.Results
Analysis of the RNA indicates that the 3 bp deletion c.213_215delAGA (gi:28559089, ), a silent mutation c.216T→C, a missense mutation c.214G→C, and a nonsense mutation c.214G→T all cause varying degrees of exon skipping, suggesting the presence of an ESE at the 5′ end of exon 3. These mutations are situated in a GAAGAT sequence 3 bp downstream from the start of exon 3. NM_000249.2Conclusions
The results of the splicing assay suggest that inclusion of exon 3 in the mRNA is ESE dependent. The exon 3 ESE is not recognised by all available motif scoring matrices, highlighting the importance of RNA analysis in the detection of ESE disrupting mutations. 相似文献17.
Dahlqvist J Klar J Hausser I Anton-Lamprecht I Pigg MH Gedde-Dahl T Gånemo A Vahlquist A Dahl N 《Journal of medical genetics》2007,44(10):615-620
Background
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood.Methods
To investigate genotype–phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI.Results
Mutation screening of ichthyin revealed missense or splice‐site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin.Discussion
Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI. 相似文献18.
19.
Nicolas Wyvekens Nadejda Valtcheva Axel Mischo Birgit Helmchen Thomas Hermanns Matthias Choschzick Andreas M. Htker Anita Rauch Beda Mühleisen Dilara Akhoundova Achim Weber Holger Moch Niels J. Rupp 《Genes, chromosomes & cancer》2020,59(11):611-619
The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome‐associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome‐associated RCC exhibited an unusual morphology with accumulation of “colloid‐like” cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next‐generation sequencing analyses of HLRCC syndrome‐associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC‐RCC showed a second, undescribed NM_000143.3; c.947C>T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378+2T>C. In the other HLRCC syndrome‐associated RCC, the FH mutation (NM_000143.3; c.462T>G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC ‐ and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome‐associated RCC, both cases were treated in first line with bevacizumab/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the “second hit” hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach. 相似文献
20.
Kerr B Delrue MA Sigaudy S Perveen R Marche M Burgelin I Stef M Tang B Eden OB O'Sullivan J De Sandre-Giovannoli A Reardon W Brewer C Bennett C Quarell O M'Cann E Donnai D Stewart F Hennekam R Cavé H Verloes A Philip N Lacombe D Levy N Arveiler B Black G 《Journal of medical genetics》2006,43(5):401-405