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1.
Prenat Diagn ; 40(8): 972-983, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333414

RESUMO

OBJECTIVE: The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging. METHODS: In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7). RESULTS: A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases. CONCLUSIONS: These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.

2.
J Genet Couns ; 29(5): 786-799, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31889383

RESUMO

The uptake of predictive DNA testing in families with a hereditary disease is <50%. Current practice often relies on the proband to inform relatives about the possibility of predictive DNA testing, but not all relatives are informed adequately. To enable informed decision-making concerning predictive DNA testing, the approach used to inform at-risk relatives needs to be optimized. This study investigated the preferences of patients, relatives, and the general population from the Netherlands on how to inform relatives at risk of autosomal dominant diseases. Online surveys were sent to people with autosomal dominant neuro-, onco-, or cardiogenetic diseases and their relatives via patient organizations (n = 379), and to members of the general population via a commercial panel (n = 1,000). Attitudes of the patient and population samples generally corresponded. A majority believed that initially only first-degree relatives should be informed, following the principles of a cascade screening approach. Most participants also thought that probands and healthcare professionals (HCPs) should be involved in informing relatives, and a large proportion believed that HCPs should contact relatives directly in cases where patients are unwilling to inform, both for untreatable and treatable conditions. Participants from the patient sample were of the opinion that HCPs should actively offer support. Our findings show that both patients and HCPs should be involved in informing at-risk relatives of autosomal dominant diseases and suggest that relatives' 'right to know' was considered a dominant issue by the majority of participants. Further research is needed on how to increase proactive support in informing of at-risk relatives.

3.
Genome Med ; 11(1): 38, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31203817

RESUMO

BACKGROUND: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. METHODS: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. RESULTS: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). CONCLUSION: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.


Assuntos
Testes Genéticos/métodos , Doenças da Imunodeficiência Primária/genética , Sequenciamento Completo do Exoma/métodos , Adolescente , Adulto , Pré-Escolar , Feminino , Testes Genéticos/normas , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária/diagnóstico , Sensibilidade e Especificidade , Sequenciamento Completo do Exoma/normas
4.
Invest Ophthalmol Vis Sci ; 60(6): 2049-2063, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074760

RESUMO

Purpose: To assess the phenotypic variability and natural course of inherited retinal diseases (IRDs) caused by EYS mutations. Methods: Multiethnic cohort study (N = 30) with biallelic EYS variants from a clinical IRD database (retinitis pigmentosa [RP], N = 27; cone-rod dystrophy [CRD], N = 1; and macular dystrophy, N = 2). In vitro minigene splice assay was performed to determine the effect on EYS pre-mRNA splicing of the c.1299+5_1299+8del variant in macular dystrophy patients. Results: We found 27 different EYS variants in RP patients and 7 were novel. The rate of visual field loss of the V4e isopter area was -0.84 ± 0.44 ln(deg2) per year, and the rate of visual acuity loss was 0.75 Early Treatment Diabetic Retinopathy Study letters per year. Ellipsoid zone width was correlated with area of the hyperautofluorescent ring, with rs = 0.78 and P < 0.001. Rate of decline in ellipsoid zone width was -57 ± 17 µm per year (P < 0.01) (n = 14) or -3.69% ± 0.51% from baseline per year (P < 0.001). An isolated CRD patient carried a homozygous EYS variant (c.9405T>A), previously identified in RP patients. Two siblings with macular dystrophy carried compound heterozygous EYS variants: c.1299+5_1299+8del and c.6050G>T. The former was novel and shown to result in skipping of exon 8, and the latter was a known RP variant. Conclusions: We report on EYS-associated macular dystrophy, extending the spectrum of EYS-associated IRDs. We observed heterogeneity between RP patients in age of onset and disease progression. Identical EYS variants were found in cases with RP, CRD, and macular dystrophy. Screening for EYS variants in CRD and macular dystrophy patients might increase the diagnostic yield in previously unsolved cases.


Assuntos
Proteínas do Olho/genética , Degeneração Macular/genética , Mutação , RNA Mensageiro/genética , Retina/patologia , Retinite Pigmentosa/genética , Acuidade Visual , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Eletrorretinografia , Proteínas do Olho/metabolismo , Feminino , Homozigoto , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retina/metabolismo , Retina/fisiopatologia , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/metabolismo , Tomografia de Coerência Óptica , Adulto Jovem
6.
Br J Cancer ; 118(2): 266-276, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29301143

RESUMO

BACKGROUND: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. METHODS: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. RESULTS: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml-l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. CONCLUSIONS: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.


Assuntos
Calicreínas/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Detecção Precoce de Câncer/métodos , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
7.
Hum Reprod ; 31(11): 2651-2659, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27907901

RESUMO

STUDY QUESTION: Do BRCA1/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Müllerian hormone (AMH) levels? SUMMARY ANSWER: BRCA1/2 mutation carriers do not show a lower serum AMH level in comparison to proven non-carriers, after adjustment for potential confounders. WHAT IS KNOWN ALREADY: It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum AMH levels and BRCA mutation status. Hence, it is yet unclear whether BRCA1/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE, DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 BRCA1/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in AMH levels of 0.40 µg/l (SD ± 0.12 µg/l, two-sided alpha-error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHOD: Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive BRCA1/2 testing because of a familial BRCA1/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum AMH levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum AMH levels. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 BRCA1/2 mutation carriers and 131 proven non-carriers. The median [range] AMH level in carriers was 1.90 µg/l [0.11-19.00] compared to 1.80 µg/l [0.11-10.00] in non-carriers (P = 0.34). Adjusted linear regression analysis revealed no reduction in AMH level in the carriers (relative change = 0.98 (95%CI, 0.77-1.22); P = 0.76). LIMITATIONS, REASONS FOR CAUTION: Participants were relatively young. Power was insufficient to analyze BRCA1 and BRCA2 mutation carriers separately. AMH levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis. WIDER IMPLICATIONS OF THE FINDINGS: Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent AMH measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care. STUDY FUNDING/COMPETING INTERESTS: This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe & Dome, Organon, and Schering Plough, outside the submitted work. Frank J.M. Broekmans is a member of the external advisory board for Merck Serono (The Netherlands), outside the submitted work. TRIAL REGISTRATION NUMBER: NTR no. 4324.


Assuntos
Hormônio Antimülleriano/sangue , Proteína BRCA1/genética , Heterozigoto , Adulto , Estudos Transversais , Feminino , Humanos , Estudos Prospectivos , Saúde da Mulher
8.
Menopause ; 23(8): 903-10, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27326821

RESUMO

OBJECTIVE: It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature. METHODS: Cross-sectional assessment from an ongoing nationwide cohort study among members of BRCA1/2 mutated families. Information was obtained by a standardized questionnaire. Kaplan-Meier curves were constructed, and Cox regression was used to assess the association between BRCA1/2 mutation status and ANM. Adjustments were made for birth cohort, family, smoking, use of hormonal contraceptives, and parity. RESULTS: A total of 1,208 BRCA1/2 mutation carriers and 2,211 proven noncarriers were included. Overall, no association was found between BRCA1/2 mutation status and ANM (adjusted hazard ratio [HR] = 1.06 [95% CI, 0.87-1.30]). We examined if the null finding was due to informative censoring by uptake of risk-reducing salpingo-oophorectomy. Indeed, within the oldest birth cohort, in which the percentage of surgical menopause events was lowest and comparable between carriers and noncarriers, the HR for earlier natural menopause in carriers was 1.45 (95% CI, 1.09-1.94). The second oldest birth cohort, however, demonstrated a decreased HR (0.67 [95% CI, 0.46-0.98]), and thus no trend over birth cohorts was found. CONCLUSIONS: Various types of selection bias hamper the comparison of ANM between BRCA1/2 mutation carriers and noncarriers, genetically tested in the clinic.


Assuntos
Envelhecimento/genética , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Menopausa/genética , Mutação , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Regressão , Adulto Jovem
10.
PLoS Genet ; 12(2): e1005880, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26901136

RESUMO

Approximately 25-30% of colorectal cancer (CRC) cases are expected to result from a genetic predisposition, but in only 5-10% of these cases highly penetrant germline mutations are found. The remaining CRC heritability is still unexplained, and may be caused by a hitherto-undefined set of rare variants with a moderately penetrant risk. Here we aimed to identify novel risk factors for early-onset CRC using whole-exome sequencing, which was performed on a cohort of CRC individuals (n = 55) with a disease onset before 45 years of age. We searched for genes that were recurrently affected by rare variants (minor allele frequency ≤ 0.001) with potentially damaging effects and, subsequently, re-sequenced the candidate genes in a replication cohort of 174 early-onset or familial CRC individuals. Two functionally relevant genes with low frequency variants with potentially damaging effects, PTPN12 and LRP6, were found in at least three individuals. The protein tyrosine phosphatase PTP-PEST, encoded by PTPN12, is a regulator of cell motility and LRP6 is a component of the WNT-FZD-LRP5-LRP6 complex that triggers WNT signaling. All variants in LRP6 were identified in individuals with an extremely early-onset of the disease (≤30 years of age), and two of the three variants showed increased WNT signaling activity in vitro. In conclusion, we present PTPN12 and LRP6 as novel candidates contributing to the heterogeneous susceptibility to CRC.


Assuntos
Neoplasias Colorretais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Idade de Início , Sequência de Aminoácidos , Segregação de Cromossomos/genética , Estudos de Coortes , Neoplasias Colorretais/enzimologia , Reparo de Erro de Pareamento de DNA/genética , Exoma/genética , Genes Neoplásicos , Humanos , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Proteína Tirosina Fosfatase não Receptora Tipo 12/química , Proteína Tirosina Fosfatase não Receptora Tipo 12/genética , Análise de Sequência de DNA , Transdução de Sinais/genética , Proteínas Wnt/metabolismo
11.
J Genet Couns ; 25(3): 504-14, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26531312

RESUMO

According to standard practice following referral to clinical genetics, most high risk breast cancer (BC) patients in many countries receive face-to-face genetic counseling prior to BRCA-mutation testing (DNA-intake). We evaluated a novel format by prospective study: replacing the intake consultation with telephone, written and digital information sent home. Face-to-face counseling then followed BRCA-mutation testing (DNA-direct). One year after BRCA-result disclosure, 108 participants returned long-term follow-up questionnaires, of whom 59 (55 %) had previously chosen DNA-direct (intervention) versus DNA-intake (standard practice i.e., control: 45 %). Questionnaires assessed satisfaction and psychological distress. All participants were satisfied and 85 % of DNA-direct participants would choose this procedure again; 10 % would prefer DNA-intake and 5 % were undecided. In repeated measurements ANOVA, general distress (GHQ-12, p = 0.01) and BC-specific distress (IES-bc, p = 0.03) were lower in DNA-direct than DNA-intake at all time measurements. Heredity-specific distress (IES-her) did not differ significantly between groups. Multivariate regression analyses showed that choice of procedure did not significantly contribute to either general or heredity-specific distress. BC-specific distress (after BC diagnosis) did contribute to both general and heredity-specific distress. This suggests that higher distress scores reflected BC experience, rather than the type of genetic diagnostic procedure. In conclusion, the large majority of BC patients that used DNA-direct reported high satisfaction without increased distress both in the short term, and 1 year after conclusion of genetic testing.


Assuntos
Neoplasias da Mama/psicologia , Testes Genéticos , Satisfação do Paciente , Estresse Psicológico , Adulto , Idoso , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético/psicologia , Humanos , Pessoa de Meia-Idade , Mutação , Inquéritos e Questionários , Adulto Jovem
12.
Sci Rep ; 5: 14060, 2015 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-26358404

RESUMO

Bloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (≤50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P = 0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa , RecQ Helicases/genética , Adulto , Idade de Início , Estudos de Casos e Controles , Conjuntos de Dados como Assunto , Exoma , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Perda de Heterozigosidade , Masculino , Taxa de Mutação , Linhagem , Vigilância da População , Risco
13.
Ned Tijdschr Geneeskd ; 159: A8910, 2015.
Artigo em Holandês | MEDLINE | ID: mdl-26332814

RESUMO

In the majority of breast cancer families, DNA testing does not show BRCA1 or BRCA2 mutations and the genetic cause of breast cancer remains unexplained. Routine testing for the CHEK2*1100delC mutation has recently been introduced in breast cancer families in the Netherlands. The 1100delC mutation in the CHEK2-gene may explain the occurrence of breast cancer in about 5% of non-BRCA1/2 families in the Netherlands. In the general population the CHEK2*1100delC mutation confers a slightly increased breast cancer risk, but in a familial breast cancer setting this risk is between 35-55% for first degree female carriers. Female breast cancer patients with the CHEK2*1100delC mutation are at increased risk of contralateral breast cancer and may have a less favourable prognosis. Female heterozygous CHEK2*1100delC mutation carriers are offered annual mammography and specialist breast surveillance between the ages of 35-60 years. Prospective research in CHEK2-positive families is essential in order to develop more specific treatment and screening strategies.


Assuntos
Quinase do Ponto de Checagem 2/genética , Predisposição Genética para Doença/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Feminino , Testes Genéticos , Genótipo , Humanos , Mamografia , Mutação , Países Baixos , Prognóstico , Fatores de Risco , Deleção de Sequência
14.
Nat Genet ; 47(6): 668-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25938944

RESUMO

The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.


Assuntos
Polipose Adenomatosa do Colo/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Estudos de Casos e Controles , Códon sem Sentido , Análise Mutacional de DNA , Reparo do DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Homozigoto , Humanos , Pessoa de Meia-Idade , Linhagem
15.
Virchows Arch ; 466(1): 117-21, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25342144

RESUMO

Melanocytic BAP1-associated intradermal tumors (MBAITs) are epithelioid spitzoid looking, mostly intradermally located melanocytic tumors that often have tumor-infiltrating lymphocytes and a common nevus component. They occur sporadically but also in the context of an underlying BAP1 germline mutation. Recognition of these lesions is important because they can be a marker for an underlying BAP1-associated cancer syndrome. Most cases reported in the literature thus far were found to have both a BRAF and BAP1 mutation. Here, we report an unusual case of an MBAIT lesion with a combined NRAS and BAP1 mutation. A BAP1 germline mutation was excluded. Our case is the second case reported until now with this combination of mutations in this subset of lesions. In the other reported NRAS-/BAP1-mutated MBAIT case, presence of a BAP1 germline mutation was not tested. Our case confirms that the mutational spectrum in MBAITs is broader than previously thought. Just as in the BRAF-mutated cases, it is likely that a subset might be associated with a BAP1 germline mutation. In case of suspicion of an MBAIT lesion based on histological examination, diagnostic work-up should include assessment of protein expression and/or mutation analysis of at least BRAF, NRAS, and BAP1. Work-up should not be limited to analyzing only BRAF protein expression or mutation, since NRAS-mutated MBAITs might be missed.


Assuntos
GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Mutação/genética , Nevo Intradérmico/genética , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Procedimentos Cirúrgicos Dermatológicos , GTP Fosfo-Hidrolases/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/metabolismo , Nevo Intradérmico/diagnóstico , Nevo Intradérmico/cirurgia , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/cirurgia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo
16.
Ophthalmology ; 121(8): 1620-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24697911

RESUMO

OBJECTIVE: To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (RP) plus noncongenital and progressive hearing loss, ataxia, or both, respectively. METHODS: A whole exome sequencing (WES) analysis was performed in 2 families segregating arRP. A mutational screening was performed in 378 additional unrelated families for the exon-intron boundaries of the ABHD12 gene. To establish a genotype-phenotype correlation, individuals who were homozygous or compound heterozygotes of mutations in ABHD12 underwent exhaustive clinical examinations by ophthalmologists, neurologists, and otologists. MAIN OUTCOME MEASURES: DNA sequence variants, best-corrected visual acuity, visual field assessments, electroretinogram responses, magnetic resonance imaging, and audiography. RESULTS: After a WES analysis, we identified 4 new mutations (p.Arg107Glufs*8, p.Trp159*, p.Arg186Pro, and p.Thr202Ile) in ABHD12 in 2 families (RP-1292 and W08-1833) previously diagnosed with nonsyndromic arRP, which cosegregated with the disease among the family members. Another homozygous mutation (p.His372Gln) was detected in 1 affected individual (RP-1487) from a cohort of 378 unrelated arRP and syndromic RP patients. After exhaustive clinical examinations by neurologists and otologists, the 4 affected members of the RP-1292 had no polyneuropathy or ataxia, and the sensorineural hearing loss and cataract were attributed to age or the normal course of the RP, whereas the affected members of the families W08-1833 and RP-1487 showed clearly symptoms associated with polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract (PHARC) syndrome. CONCLUSIONS: Null mutations in the ABHD12 gene lead to PHARC syndrome, a neurodegenerative disease including polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract. Our study allowed us to report 5 new mutations in ABHD12. This is the first time missense mutations have been described for this gene. Furthermore, these findings are expanding the spectrum of phenotypes associated with ABHD12 mutations ranging from PHARC syndrome to a nonsyndromic form of retinal degeneration.


Assuntos
Ataxia/genética , Catarata/genética , Exoma/genética , Monoacilglicerol Lipases/genética , Mutação de Sentido Incorreto , Polineuropatias/genética , Retinite Pigmentosa/genética , Adulto , Idoso , Ataxia/diagnóstico , Ataxia/fisiopatologia , Audiometria , Catarata/diagnóstico , Catarata/fisiopatologia , Eletrorretinografia , Feminino , Genes Recessivos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Monoacilglicerol Lipases/química , Linhagem , Fenótipo , Polineuropatias/diagnóstico , Polineuropatias/fisiopatologia , Estrutura Secundária de Proteína , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/fisiopatologia , Análise de Sequência de DNA , Acuidade Visual/fisiologia , Campos Visuais/fisiologia
17.
Eur Urol ; 66(3): 489-99, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24484606

RESUMO

BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. OBJECTIVE: To report the first year's screening results for all men at enrollment in the study. DESIGN, SETTING AND PARTICIPANTS: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. RESULTS AND LIMITATIONS: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. CONCLUSIONS: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. PATIENT SUMMARY: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.


Assuntos
Detecção Precoce de Câncer , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/genética , Mutação , Antígeno Prostático Específico/sangue , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Adulto , Idoso , Biópsia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Valor Preditivo dos Testes , Neoplasias da Próstata/sangue
19.
Gastroenterology ; 146(3): 643-646.e8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24333619

RESUMO

Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes. Tumors are characterized by microsatellite instability (MSI). However, a considerable number of MSI-positive tumors have no known molecular mechanism of development. By using Sanger and ion semiconductor sequencing, 25 MSI-positive tumors were screened for somatic mutations and loss of heterozygosity in mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2). In 13 of 25 tumors (8 MLH1-deficient and 5 MSH2-deficient tumors), we identified 2 somatic mutations in these genes. We conclude that 2 acquired events explain the MMR-deficiency in more than 50% of the MMR-deficient tumors without causal germline mutations or promoter methylation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Encefálicas/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa/genética , Proteína 2 Homóloga a MutS/genética , Síndromes Neoplásicas Hereditárias/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/epidemiologia , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Comorbidade , Metilação de DNA/genética , Reparo de Erro de Pareamento de DNA/genética , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Síndromes Neoplásicas Hereditárias/epidemiologia , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Adulto Jovem
20.
Eur J Hum Genet ; 22(5): 617-24, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24084575

RESUMO

Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c.-27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across ≤2.6-≤6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal ≤2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Epigênese Genética , Grupo com Ancestrais do Continente Europeu/genética , Genes Dominantes , Haplótipos , Proteínas Nucleares/genética , Mutação Puntual , Alelos , Estudos de Casos e Controles , Cromossomos Humanos Par 3 , Neoplasias Colorretais Hereditárias sem Polipose/genética , Variações do Número de Cópias de DNA , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Proteína 1 Homóloga a MutL , Linhagem , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Transcrição Genética
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