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1.
Genet Med ; 26(5): 101101, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38362852

RESUMEN

PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies. METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291). RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins. CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.


Asunto(s)
Quinasa de Punto de Control 2 , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alelos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa de Punto de Control 2/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Secuenciación del Exoma/métodos , Mutación de Línea Germinal/genética , Neoplasias/genética , Fenotipo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología
2.
Int J Cancer ; 147(8): 2150-2158, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-32510614

RESUMEN

Universal mismatch repair deficiency (dMMR) testing of colorectal cancer (CRC) is promoted as routine diagnostics to prescreen for Lynch syndrome. We evaluated the yield and experience of age-related molecular investigation for heritable and nonheritable causes of dMMR in CRC below age 70 to identify Lynch Syndrome. In a prospective cohort of 3602 newly diagnosed CRCs below age 70 from 19 hospitals, dMMR, MLH1 promoter hypermethylation, germline MMR gene and somatic MMR gene testing was assessed in daily practice. Yield was evaluated using data from the Dutch Pathology Registry (PALGA) and two regional genetic centers. Experiences of clinicians were evaluated through questionnaires. Participating clinicians were overwhelmingly positive about the clinical workflow. Pathologists routinely applied dMMR-testing in 84% CRCs and determined 10% was dMMR, largely due to somatic MLH1 hypermethylation (66%). Of those, 69% with dMMR CRC below age 70 without hypermethylation were referred for genetic testing, of which 55% was due to Lynch syndrome (hereditary) and 43% to somatic biallelic pathogenic MMR (nonhereditary). The prevalence of Lynch syndrome was 18% in CRC < 40, 1.7% in CRC age 40-64 and 0.7% in CRC age 65-69. Age 65-69 represents most cases with dMMR, in which dMMR due to somatic causes (13%) is 20 times more prevalent than Lynch syndrome. In conclusion, up to age 65 routine diagnostics of (non-)heritable causes of dMMR CRCs effectively identifies Lynch syndrome and reduces Lynch-like diagnoses. Above age 64, the effort to detect one Lynch syndrome patient in dMMR CRC is high and germline testing rarely needed.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN/genética , Adolescente , Adulto , Anciano , Metilación de ADN/genética , Femenino , Pruebas Genéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , Mutación/genética , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Adulto Joven
3.
Gastroenterology ; 155(3): 844-851, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29758216

RESUMEN

BACKGROUND & AIMS: Germline variants in mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in older patients than CRCs with variants in other mismatch repair genes. METHODS: We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3,000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher exact test. RESULTS: None of the PMS2-associated CRCs contained any somatic variants in the catenin-ß1 gene (CTNNB1), which encodes ß-catenin, whereas 14 of 24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half the PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%; P = .44) and MSH2 (71.4%; P = .035) than in those associated with variants in PMS2. CONCLUSIONS: In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Mutación de Línea Germinal , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Adulto , Anciano , Reparación de la Incompatibilidad de ADN , Proteínas de Unión al ADN/genética , Molécula de Adhesión Celular Epitelial/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , beta Catenina/genética
4.
J Med Genet ; 55(10): 669-674, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29330337

RESUMEN

BACKGROUND: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. METHODS: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. RESULTS: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. CONCLUSIONS: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.


Asunto(s)
Antígenos CD/genética , Cadherinas/genética , Quinasas Quinasa Quinasa PAM/genética , Factor 88 de Diferenciación Mieloide/genética , Neoplasias Gástricas/genética , alfa Catenina/genética , Adulto , Anciano , Estudios de Cohortes , Europa (Continente) , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Adulto Joven
5.
PLoS Genet ; 12(2): e1005880, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26901136

RESUMEN

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.


Asunto(s)
Neoplasias Colorrectales/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Edad de Inicio , Secuencia de Aminoácidos , Segregación Cromosómica/genética , Estudios de Cohortes , Neoplasias Colorrectales/enzimología , Reparación de la Incompatibilidad de ADN/genética , Exoma/genética , Genes Relacionados con las Neoplasias , Humanos , Datos de Secuencia Molecular , Mutación Missense/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 12/química , Proteína Tirosina Fosfatasa no Receptora Tipo 12/genética , Análisis de Secuencia de ADN , Transducción de Señal/genética , Proteínas Wnt/metabolismo
6.
Am J Hum Genet ; 97(5): 647-60, 2015 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-26522471

RESUMEN

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.


Asunto(s)
Ligamiento Genético , Pérdida Auditiva Unilateral/genética , Mutación/genética , Factor de Células Madre/genética , Síndrome de Waardenburg/genética , Alelos , Animales , Femenino , Técnica del Anticuerpo Fluorescente , Pérdida Auditiva Unilateral/metabolismo , Pérdida Auditiva Unilateral/patología , Humanos , Masculino , Ratones , Células 3T3 NIH , Linaje , Fenotipo , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome de Waardenburg/metabolismo , Síndrome de Waardenburg/patología
7.
Am J Hum Genet ; 94(2): 303-9, 2014 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-24462372

RESUMEN

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.


Asunto(s)
Factor de Transcripción COUP I/genética , Discapacidad Intelectual/genética , Atrofia Óptica/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Factor de Transcripción COUP I/metabolismo , Niño , Preescolar , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Genotipo , Humanos , Discapacidad Intelectual/patología , Masculino , Datos de Secuencia Molecular , Mutación Missense , Atrofia Óptica/patología , Fenotipo , Adulto Joven , Dedos de Zinc/genética
9.
Genet Med ; 18(4): 405-9, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26110232

RESUMEN

PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. RESULTS: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. CONCLUSIONS: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409.


Asunto(s)
Heterocigoto , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Mutación , Neoplasias/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Riesgo
10.
J Genet Couns ; 25(3): 504-14, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26531312

RESUMEN

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.


Asunto(s)
Neoplasias de la Mama/psicología , Pruebas Genéticas , Satisfacción del Paciente , Estrés Psicológico , Adulto , Anciano , Neoplasias de la Mama/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Asesoramiento Genético/psicología , Humanos , Persona de Mediana Edad , Mutación , Encuestas y Cuestionarios , Adulto Joven
11.
Gastroenterology ; 145(3): 544-7, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23747338

RESUMEN

The spindle assembly checkpoint controls proper chromosome segregation during mitosis and prevents aneuploidy-an important feature of cancer cells. We performed genome-wide and targeted copy number and mutation analyses of germline DNA from 208 patients with familial or early-onset (40 years of age or younger) colorectal cancer; we identified haploinsufficiency or heterozygous mutations in the spindle assembly checkpoint genes BUB1 and BUB3 in 2.9% of them. Besides colorectal cancer, these patients had variegated aneuploidies in multiple tissues and variable dysmorphic features. These results indicate that mutations in BUB1 and BUB3 cause mosaic variegated aneuploidy and increase the risk of colorectal cancer at a young age.


Asunto(s)
Biomarcadores de Tumor/genética , Proteínas de Ciclo Celular/genética , Neoplasias Colorrectales/genética , Mutación de Línea Germinal , Proteínas Serina-Treonina Quinasas/genética , Adulto , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorrectales/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Proteínas de Unión a Poli-ADP-Ribosa , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Riesgo
12.
Am J Med Genet A ; 164A(8): 1947-52, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24737742

RESUMEN

Genomic duplications of varying lengths at Xq26-q27 involving SOX3 have been described in families with X-linked hypopituitarism. Using array-CGH we detected a 1.1 Mb microduplication at Xq27 in a large family with three males suffering from X-linked hypopituitarism. The duplication was mapped from 138.7 to 139.8 Mb, harboring only two annotated genes, SOX3 and ATP11C, and was shown to be a direct tandem copy number gain. Unexpectedly, the microduplication did not fully segregate with the disease in this family suggesting that SOX3 duplications have variable penetrance for X-linked hypopituitarism. In the same family, a female fetus presenting with a neural tube defect was also shown to carry the SOX3 copy number gain. Since we also demonstrated increased SOX3 mRNA levels in amnion cells derived from an unrelated t(X;22)(q27;q11) female fetus with spina bifida, we propose that increased levels of SOX3 could be a risk factor for neural tube defects.


Asunto(s)
Dosificación de Gen , Genes Ligados a X , Hipopituitarismo/genética , Defectos del Tubo Neural/genética , Factores de Transcripción SOXB1/genética , Adolescente , Adulto , Duplicación Cromosómica , Mapeo Cromosómico , Segregación Cromosómica , Cromosomas Humanos X , Hibridación Genómica Comparativa , Femenino , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite/genética , Linaje , ARN Mensajero/genética , Factores de Riesgo , Adulto Joven
13.
Hum Mutat ; 34(12): 1721-6, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24123792

RESUMEN

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene-specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger-based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite-stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost.


Asunto(s)
Exoma , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de Secuencia de ADN , Asesoramiento Genético , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Humanos , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de ADN/normas
14.
Am J Hum Genet ; 87(3): 418-23, 2010 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-20817137

RESUMEN

Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities. We sequenced the exomes of two unrelated CED patients and identified compound heterozygous mutations in WDR35 as the cause of the disease in each of the two patients independently, showing that it is possible to find the causative gene by sequencing the exome of a single sporadic patient. With RT-PCR, we demonstrate that a splice-site mutation in exon 2 of WDR35 alters splicing of RNA on the affected allele, introducing a premature stop codon. WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder.


Asunto(s)
Anomalías Múltiples/genética , Proteínas Reguladoras de la Apoptosis/genética , Displasia Ectodérmica/genética , Exones/genética , Proteínas de la Membrana/genética , Mutación/genética , Análisis de Secuencia de ADN/métodos , Secuencia de Bases , Niño , Análisis Mutacional de ADN , Humanos , Datos de Secuencia Molecular , Sitios de Empalme de ARN/genética , Síndrome
15.
Int J Gynecol Cancer ; 23(8): 1406-10, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23975082

RESUMEN

OBJECTIVES: Epithelial ovarian cancer in women 40 years or younger is rare; diagnosis at this age justifies referral for genetic testing. We evaluated clinical data, family history, and risk of identifying BRCA1/2 mutations in women with early-onset epithelial ovarian cancer. MATERIALS/METHODS: Women 40 years or younger with epithelial ovarian cancer tested for BRCA1/2 mutation at our department of human genetics between 1996 and 2012 were included. The rate of BRCA1/2 mutation was obtained; carriers were compared to noncarriers regarding clinical data. RESULTS: Ten (19%) of 52 women had a BRCA1/2 mutation. This mutation was detected in 67% of women with and in 9% of the women without first-degree relatives with breast and/or ovarian cancer (P < 0.001; Fisher exact test). The median age at diagnosis was lower in the noncarriers compared to the carriers (30 vs 38 years; P = 0.014). Among the BRCA1/2 mutation carriers, 60% had serous tumors, 80% had moderately to poorly differentiated tumors, and 70% had International Federation of Gynecology and Obstetrics stage III/IV compared to 55%, 43%, and 45%, respectively, in the noncarriers. CONCLUSIONS: The risk of finding a BRCA1/2 mutation in women 40 years or younger is comparable to women of all ages with epithelial ovarian cancer. Prior probability of finding a BRCA1/2 mutation in these young women is largely determined by their family history, which can help caregivers in informing ahead of genetic counseling and testing.


Asunto(s)
Adenocarcinoma/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Ováricas/genética , Adenocarcinoma/epidemiología , Adolescente , Adulto , Edad de Inicio , Análisis Mutacional de ADN , Femenino , Humanos , Países Bajos/epidemiología , Neoplasias Ováricas/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven
16.
J Med Genet ; 48(6): 390-5, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21378380

RESUMEN

BACKGROUND: Sensenbrenner syndrome is a heterogeneous ciliopathy that is characterised by skeletal and ectodermal anomalies, accompanied by chronic renal failure, heart defects, liver fibrosis and other features. OBJECTIVE: To identify an additional causative gene in Sensenbrenner syndrome. METHODS: Single nucleotide polymorphism array analysis and standard sequencing techniques were applied to identify the causative gene. The effect of the identified mutation on protein translation was determined by western blot analysis. Antibodies against intraflagellar transport (IFT) proteins were used in ciliated fibroblast cell lines to investigate the molecular consequences of the mutation on ciliary transport. RESULTS: Homozygosity mapping and positional candidate gene sequence analysis were performed in two siblings with Sensenbrenner syndrome of a consanguineous Moroccan family. In both siblings, a homozygous mutation in the initiation codon of C14ORF179 was identified. C14ORF179 encodes IFT43, a subunit of the IFT complex A (IFT-A) machinery of primary cilia. Western blots showed that the mutation disturbs translation of IFT43, inducing the initiation of translation of a shorter protein product from a downstream ATG. The IFT-A protein complex is implicated in retrograde ciliary transport along axonemal microtubules. It was shown that in fibroblasts of one of the siblings affected by Sensenbrenner syndrome, disruption of IFT43 disturbs this transport from the ciliary tip to its base. As anterograde transport in the opposite direction apparently remains functional, the IFT complex B proteins accumulate in the ciliary tip. Interestingly, similar results were obtained using fibroblasts from a patient with Sensenbrenner syndrome with mutations in WDR35/IFT121, encoding another IFT-A subunit. CONCLUSIONS: The results indicate that Sensenbrenner syndrome is caused by disrupted IFT-A-mediated retrograde ciliary transport.


Asunto(s)
Proteínas Portadoras/genética , Cilios/metabolismo , Anomalías Craneofaciales/genética , Displasia Ectodérmica/genética , Flagelos/metabolismo , Transporte de Proteínas/genética , Proteínas Recombinantes/genética , Animales , Secuencia de Bases , Proteínas Portadoras/metabolismo , Niño , Cilios/genética , Anomalías Craneofaciales/etnología , Displasia Ectodérmica/etnología , Fibroblastos/fisiología , Flagelos/genética , Células HEK293 , Humanos , Masculino , Datos de Secuencia Molecular , Marruecos/etnología , Mutación , Países Bajos/epidemiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Proteínas Recombinantes/metabolismo , Hermanos , Síndrome , Transfección
17.
BMC Womens Health ; 12: 12, 2012 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-22569005

RESUMEN

BACKGROUND: Current practice for patients with breast cancer referred for genetic counseling, includes face-to-face consultations with a genetic counselor prior to and following DNA-testing. This is based on guidelines regarding Huntington's disease in anticipation of high psychosocial impact of DNA-testing for mutations in BRCA1/2 genes. The initial consultation covers generic information regarding hereditary breast cancer and the (im)possibilities of DNA-testing, prior to such testing. Patients with breast cancer may see this information as irrelevant or unnecessary because individual genetic advice depends on DNA-test results. Also, verbal information is not always remembered well by patients. A different format for this information prior to DNA-testing is possible: replacing initial face-to-face genetic counseling (DNA-intake procedure) by telephone, written and digital information sent to patients' homes (DNA-direct procedure). METHODS/DESIGN: In this intervention study, 150 patients with breast cancer referred to the department of Clinical Genetics of the Radboud University Nijmegen Medical Centre are given the choice between two procedures, DNA-direct (intervention group) or DNA-intake (usual care, control group). During a triage telephone call, patients are excluded if they have problems with Dutch text, family communication, or of psychological or psychiatric nature. Primary outcome measures are satisfaction and psychological distress. Secondary outcome measures are determinants for the participant's choice of procedure, waiting and processing times, and family characteristics. Data are collected by self-report questionnaires at baseline and following completion of genetic counseling. A minority of participants will receive an invitation for a 30 min semi-structured telephone interview, e.g. confirmed carriers of a BRCA1/2 mutation, and those who report problems with the procedure. DISCUSSION: This study compares current practice of an intake consultation (DNA-intake) to a home informational package of telephone, written and digital information (DNA-direct) prior to DNA-testing in patients with breast cancer. The aim is to determine whether DNA-direct is an acceptable procedure for BRCA1/2 testing, in order to provide customized care to patients with breast cancer, cutting down on the period of uncertainty during this diagnostic process.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , ADN de Neoplasias/análisis , Asesoramiento Genético , Neoplasias de la Mama/psicología , Femenino , Estudios de Seguimiento , Pruebas Genéticas/métodos , Humanos , Países Bajos , Proyectos de Investigación , Encuestas y Cuestionarios
18.
Biochim Biophys Acta ; 1797(2): 197-203, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19836344

RESUMEN

Ninety-five percent of Leber hereditary optic neuropathy (LHON) patients carry a mutation in one out of three mtDNA-encoded ND subunits of complex I. Penetrance is reduced and more male than female carriers are affected. To assess if a consistent biochemical phenotype is associated with LHON expression, complex I- and complex II-dependent adenosine triphosphate synthesis rates (CI-ATP, CII-ATP) were determined in digitonin-permeabilized peripheral blood mononuclear cells (PBMCs) of thirteen healthy controls and for each primary mutation of a minimum of three unrelated patients and of three unrelated carriers with normal vision and were normalized per mitochondrion (citrate synthase activity) or per cell (protein content). We found that in mitochondria, CI-ATP and CII-ATP were impaired irrespective of the primary LHON mutation and clinical expression. An increase in mitochondrial density per cell compensated for the dysfunctional mitochondria in LHON carriers but was insufficient to result in a normal biochemical phenotype in early-onset LHON patients.


Asunto(s)
Complejo II de Transporte de Electrones/genética , Complejo I de Transporte de Electrón/genética , Mitocondrias/metabolismo , Mutación/genética , Atrofia Óptica Hereditaria de Leber/metabolismo , Fosforilación Oxidativa , Adenosina Trifosfato/metabolismo , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Citrato (si)-Sintasa/genética , Citrato (si)-Sintasa/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/metabolismo , Femenino , Humanos , Masculino , Potencial de la Membrana Mitocondrial/fisiología , Persona de Mediana Edad , Atrofia Óptica Hereditaria de Leber/genética , Protones , Adulto Joven
19.
Elife ; 92020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33258446

RESUMEN

Telomere shortening is a presumed tumor suppressor pathway that imposes a proliferative barrier (the Hayflick limit) during tumorigenesis. This model predicts that excessively long somatic telomeres predispose to cancer. Here, we describe cancer-prone families with two unique TINF2 mutations that truncate TIN2, a shelterin subunit that controls telomere length. Patient lymphocyte telomeres were unusually long. We show that the truncated TIN2 proteins do not localize to telomeres, suggesting that the mutations create loss-of-function alleles. Heterozygous knock-in of the mutations or deletion of one copy of TINF2 resulted in excessive telomere elongation in clonal lines, indicating that TINF2 is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the TINF2 truncations predispose to a tumor syndrome. We conclude that TINF2 acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.


Asunto(s)
Genes Supresores de Tumor , Acortamiento del Telómero/genética , Proteínas de Unión a Telómeros/fisiología , Telómero/genética , Línea Celular , Femenino , Células HEK293 , Heterocigoto , Humanos , Mutación con Pérdida de Función , Masculino , Neoplasias/genética , Telómero/patología , Proteínas de Unión a Telómeros/genética , Proteína 1 de Unión a Repeticiones Teloméricas/metabolismo , Proteínas Supresoras de Tumor
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