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1.
J Community Genet ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32880035

RESUMO

Individuals having a genetic predisposition to cancer and their partners face challenging decisions regarding their wish to have children. This study aimed to determine the effects of an online decision aid to support couples in making an informed decision regarding their reproductive options. A nationwide pretest-posttest study was conducted in the Netherlands among 131 participants between November 2016 and May 2018. Couples were eligible for participation if one partner had a pathogenic variant predisposing for an autosomal dominant hereditary cancer syndrome. Participants completed a questionnaire before use (T0), and at 3 months (T3) after use of the decision aid to assess the primary outcome measure informed decision-making, and the secondary outcome measures decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy. T0-T3 comparisons show an overall positive effect for all outcome measures (all ps < 0.05; knowledge (ES = - 1.05), decisional conflict (ES = 0.99), participants' decision self-efficacy (ES = -0.55), level of deliberation (ES = - 0.50), and realistic expectations (ES = - 0.44). Informed decision-making increased over time and 58.0% of the participants made an informed reproductive decision at T3. The online decision aid seems to be an appropriate tool to complement standard reproductive counseling to support our target group in making an informed reproductive decision. Use of the decision aid may lessen the negative psychological impact of decision-making on couples' daily life and wellbeing.

2.
Clin J Am Soc Nephrol ; 15(9): 1279-1286, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32855195

RESUMO

BACKGROUND AND OBJECTIVES: A genetic cause can be identified for an increasing number of pediatric and adult-onset kidney diseases. Preimplantation genetic testing (formerly known as preimplantation genetic diagnostics) is a reproductive technology that helps prospective parents to prevent passing on (a) disease-causing mutation(s) to their offspring. Here, we provide a clinical overview of 25 years of preimplantation genetic testing for monogenic kidney disease in The Netherlands. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective cohort study of couples counseled on preimplantation genetic testing for monogenic kidney disease in the national preimplantation genetic testing expert center (Maastricht University Medical Center+) from January 1995 to June 2019. Statistical analysis was performed through chi-squared tests. RESULTS: In total, 98 couples were counseled regarding preimplantation genetic testing, of whom 53% opted for preimplantation genetic testing. The most frequent indications for referral were autosomal dominant polycystic kidney disease (38%), Alport syndrome (26%), and autosomal recessive polycystic kidney disease (9%). Of couples with at least one preimplantation genetic testing cycle with oocyte retrieval, 65% experienced one or more live births of an unaffected child. Of couples counseled, 38% declined preimplantation genetic testing for various personal and technical reasons. CONCLUSIONS: Referrals, including for adult-onset disease, have increased steadily over the past decade. Though some couples decline preimplantation genetic testing, in the couples who proceed with at least one preimplantation genetic testing cycle, almost two thirds experienced at least one live birth rate.

3.
Breast Cancer Res Treat ; 181(1): 77-86, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32236826

RESUMO

PURPOSE: We assessed the uptake of fertility preservation (FP), recovery of ovarian function (OFR) after chemotherapy, live birth after breast cancer, and breast cancer outcomes in women with early-stage breast cancer. METHODS: Women aged below 41 years and referred to our center for FP counseling between 2008 and 2015 were included. Data on patient and tumor characteristics, ovarian function, cryopreservation (embryo/oocyte) and transfer, live birth, and disease-free survival were collected. Kaplan-Meier analyses were performed for time-to-event analyses including competing risk analyses, and patients with versus without FP were compared using the logrank test. RESULTS: Of 118 counseled women with a median age of 31 years (range 19-40), 34 (29%) chose FP. Women who chose FP had less often children, more often a male partner and more often favorable tumor characteristics. The 5-year OFR rate was 92% for the total group of counseled patients. In total, 26 women gave birth. The 5-year live birth rate was 27% for the total group of counseled patients. Only three women applied for transfer of their cryopreserved embryo(s), in two combined with preimplantation genetic diagnosis (PGD) because of BRCA1-mutation carrier ship. The 5-year disease-free survival rate was 91% versus 88%, for patients with versus without FP (P = 0.42). CONCLUSIONS: Remarkably, most women achieved OFR, probably related to the young age at diagnosis. Most pregnancies occurred spontaneously, two of three women applied for embryo transfer because of the opportunity to apply for PGD.

4.
Eur J Hum Genet ; 28(7): 956-962, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32203199

RESUMO

Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide repeat expansion on chromosome 19q13.3. While DM1 premutation (36-50 repeats) and protomutation (51-80 repeats) allele carriers are mostly asymptomatic, offspring is at risk of inheriting expanded, symptom-associated, (CTG)n repeats of n > 80. In this study we aimed to evaluate the intergenerational instability of DM1 pre- and protomutation alleles, focussing on the influence of parental gender. One hundred and forty-six parent-child pairs (34 parental premutations, 112 protomutations) were retrospectively selected from the DM1 patient cohort of the Maastricht University Medical Center+. CTG repeat size of parents and children was determined by (triplet-primed) PCR followed by fragment length analysis and Southern blot analysis. Fifty-eight out of eighty-one (71.6%) paternal transmissions led to a (CTG)n repeat of n > 80 in offspring, compared with 15 out of 65 (23.1%) maternal transmissions (p < 0.001). Repeat length instability occurred for paternal (CTG)n repeats of n ≥ 45, while maternal instability did not occur until (CTG)n repeats reached a length of n ≥ 71. Transmission of premutations caused (CTG)n repeats of n > 80 in offspring only when paternally transmitted (two cases), while protomutations caused (CTG)n repeats of n > 80 in offspring in 71 cases, of which 56 (78.9%) were paternally transmitted. In conclusion, our data show that paternally transmitted pre- and protomutations were more unstable than maternally transmitted pre- and protomutations. For genetic counseling, this implies that males with a small DMPK mutation have a higher risk of symptomatic offspring compared with females. Consequently, we suggest addressing sex-dependent factors in genetic counseling of small-sized CTG repeat carriers.

5.
Am J Hum Genet ; 105(6): 1091-1101, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31708118

RESUMO

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.


Assuntos
Síndrome de Down/diagnóstico , Testes Genéticos/métodos , Genoma Humano , Implementação de Plano de Saúde , Diagnóstico Pré-Natal/métodos , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Adolescente , Adulto , Aberrações Cromossômicas , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Gravidez , Primeiro Trimestre da Gravidez , Prognóstico , Síndrome da Trissomia do Cromossomo 13/epidemiologia , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/epidemiologia , Síndrome da Trissomía do Cromossomo 18/genética , Adulto Jovem
6.
RNA ; 25(9): 1130-1149, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31175170

RESUMO

Minor intron splicing plays a central role in human embryonic development and survival. Indeed, biallelic mutations in RNU4ATAC, transcribed into the minor spliceosomal U4atac snRNA, are responsible for three rare autosomal recessive multimalformation disorders named Taybi-Linder (TALS/MOPD1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes, which associate numerous overlapping signs of varying severity. Although RNA-seq experiments have been conducted on a few RFMN patient cells, none have been performed in TALS, and more generally no in-depth transcriptomic analysis of the ∼700 human genes containing a minor (U12-type) intron had been published as yet. We thus sequenced RNA from cells derived from five skin, three amniotic fluid, and one blood biosamples obtained from seven unrelated TALS cases and from age- and sex-matched controls. This allowed us to describe for the first time the mRNA expression and splicing profile of genes containing U12-type introns, in the context of a functional minor spliceosome. Concerning RNU4ATAC-mutated patients, we show that as expected, they display distinct U12-type intron splicing profiles compared to controls, but that rather unexpectedly mRNA expression levels are mostly unchanged. Furthermore, although U12-type intron missplicing concerns most of the expressed U12 genes, the level of U12-type intron retention is surprisingly low in fibroblasts and amniocytes, and much more pronounced in blood cells. Interestingly, we found several occurrences of introns that can be spliced using either U2, U12, or a combination of both types of splice site consensus sequences, with a shift towards splicing using preferentially U2 sites in TALS patients' cells compared to controls.


Assuntos
Nanismo/genética , Retardo do Crescimento Fetal/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Processamento de RNA/genética , Transcriptoma/genética , Adulto , Idoso , Sequência de Bases/genética , Pré-Escolar , Sequência Consenso/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Lactente , Íntrons/genética , Masculino , Pessoa de Meia-Idade , RNA/genética , RNA Mensageiro/genética , RNA Nuclear Pequeno/genética , Spliceossomos/genética , Adulto Jovem
7.
J Genet Couns ; 28(3): 533-542, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30629779

RESUMO

A nationwide pretest-posttest study was conducted in all clinical genetic centres in the Netherlands, to evaluate the effects of an online decision aid to support persons who have a genetic predisposition to cancer and their partners in making an informed decision regarding reproductive options. Main outcomes (decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy) were measured before use (T0), immediately after use (T1), and at 2 weeks (T2) after use of the decision aid. Paired sample t tests were used to compute differences between the first and subsequent measurements. T0-T1 and T0-T2 comparisons indicate a significant reduction in mean decisional conflict scores with stronger effects for participants with high baseline decisional conflict. Furthermore, use of the decision aid resulted in increased knowledge levels and improved realistic expectations. Level of deliberation only increased for participants with lower baseline levels of deliberation. Decision self-efficacy increased for those with low baseline scores, whereas those with high baseline scores showed a reduction at T2. It can be concluded that use of the decision aid resulted in several positive outcomes indicative of informed decision-making. The decision aid is an appropriate and highly appreciated tool to be used in addition to reproductive counseling.


Assuntos
Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Neoplasias/genética , Sistemas On-Line , Participação do Paciente , Reprodução , Adulto , Feminino , Humanos , Masculino , Países Baixos , Parceiros Sexuais
8.
Fam Cancer ; 18(2): 285-291, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30656480

RESUMO

To support persons having a genetic predisposition to cancer and their partners during reproductive decision-making, an online decision aid was developed and evaluated. To maximize the impact of the support tool, this mixed methods study aims at developing the optimal implementation strategy for the decision aid. A questionnaire to assess the critical determinants that may affect this implementation was completed by health professionals involved in oncogenetic counselling (N = 46). Subsequently, semi-structured focus groups (N = 19) and individual telephonic interviews (N = 15) were performed with a subset of health professionals. All health professionals indicated to be willing to refer couples to the decision aid, preferably at the moment of receiving the genetic test result. They agreed that the primary requirement for implementation in daily practice was ease of referring couples and preferably free online accessibility. Referral to the tool was able to be included in the standard report couples receive after consultation, thereby making the use of additional paper-based materials redundant (e.g. flyers). Furthermore, incorporating the link to the decision aid on patient organization websites was suggested. Health professionals agreed that implementation would benefit more from promoting awareness regarding the decision aid rather than the inclusion of the tool in official clinical guidelines. To foster implementation of the decision aid, the distribution of online newsletters and the designation of a contact person charged with continued implementation in each Clinical Genetic Center were suggested. Based on these preferences and recommendations, the implementation of the online decision aid will be nationally executed to optimize impact.


Assuntos
Tomada de Decisões Assistida por Computador , Tomada de Decisões , Aconselhamento Genético/métodos , Pessoal de Saúde/psicologia , Sistemas On-Line , Feminino , Fertilidade , Grupos Focais , Predisposição Genética para Doença , Testes Genéticos , Pessoal de Saúde/estatística & dados numéricos , Implementação de Plano de Saúde , Humanos , Masculino , Síndromes Neoplásicas Hereditárias/genética , Participação do Paciente , Pesquisa Qualitativa , Encaminhamento e Consulta , Serviços de Saúde Reprodutiva/organização & administração
9.
Fam Cancer ; 18(1): 137-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29846879

RESUMO

An online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making was developed. A two-phase usability test was conducted among 12 couples (N = 22; 2 persons participated without their partner) at risk for hereditary cancer and 15 health care providers. Couples and health care providers expressed similar suggestions for improvements, and evaluated the modified decision aid as acceptable, easy to use, and comprehensible. The final decision aid was pilot tested (N = 16) with paired sample t tests comparing main outcomes (decisional conflict, knowledge, realistic expectations regarding the reproductive options and decision self-efficacy) before (T0), immediately (T1) and 2 weeks after (T2) use of the decision aid. Pilot testing indicated decreased decisional conflict scores, increased knowledge, and improved realistic expectations regarding the reproductive options, at T1 and T2. No effect was found for couples' decision self-efficacy. The positive findings during usability testing were thus reflected in the pilot study. The decision aid will be further evaluated in a nationwide pretest-posttest study to facilitate implementation in the onco-genetic counselling setting. Ultimately, it is expected that the decision aid will enable end-users to make an informed decision.


Assuntos
Tomada de Decisões , Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/genética , Reprodução/genética , Adulto , Feminino , Aconselhamento Genético/métodos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Internet , Masculino , Projetos Piloto
10.
Hum Reprod ; 33(7): 1331-1341, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29850888

RESUMO

STUDY QUESTION: Does germline selection (besides random genetic drift) play a role during the transmission of heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations in humans? SUMMARY ANSWER: We conclude that inheritance of mtDNA is mutation-specific and governed by a combination of random genetic drift and negative and/or positive selection. WHAT IS KNOWN ALREADY: mtDNA inherits maternally through a genetic bottleneck, but the underlying mechanisms are largely unknown. Although random genetic drift is recognized as an important mechanism, selection mechanisms are thought to play a role as well. STUDY DESIGN, SIZE, DURATION: We determined the mtDNA mutation loads in 160 available oocytes, zygotes, and blastomeres of five carriers of the m.3243A>G mutation, one carrier of the m.8993T>G mutation, and one carrier of the m.14487T>C mutation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mutation loads were determined in PGD samples using PCR assays and analysed mathematically to test for random sampling effects. In addition, a meta-analysis has been performed on mutation load transmission data in the literature to confirm the results of the PGD samples. MAIN RESULTS AND THE ROLE OF CHANCE: By applying the Kimura distribution, which assumes random mechanisms, we found that mtDNA segregations patterns could be explained by variable bottleneck sizes among all our carriers (moment estimates ranging from 10 to 145). Marked differences in the bottleneck size would determine the probability that a carrier produces offspring with mutations markedly different than her own. We investigated whether bottleneck sizes might also be influenced by non-random mechanisms. We noted a consistent absence of high mutation loads in all our m.3243A>G carriers, indicating non-random events. To test this, we fitted a standard and a truncated Kimura distribution to the m.3243A>G segregation data. A Kimura distribution truncated at 76.5% heteroplasmy has a significantly better fit (P-value = 0.005) than the standard Kimura distribution. For the m.8993T>G mutation, we suspect a skewed mutation load distribution in the offspring. To test this hypothesis, we performed a meta-analysis on published blood mutation levels of offspring-mother (O-M) transmission for the m.3243A>G and m.8993T>G mutations. This analysis revealed some evidence that the O-M ratios for the m.8993T>G mutation are different from zero (P-value <0.001), while for the m.3243A>G mutation there was little evidence that the O-M ratios are non-zero. Lastly, for the m.14487T>G mutation, where the whole range of mutation loads was represented, we found no indications for selective events during its transmission. LARGE SCALE DATA: All data are included in the Results section of this article. LIMITATIONS, REASON FOR CAUTION: The availability of human material for the mutations is scarce, requiring additional samples to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Our data show that non-random mechanisms are involved during mtDNA segregation. We aimed to provide the mechanisms underlying these selection events. One explanation for selection against high m.3243A>G mutation loads could be, as previously reported, a pronounced oxidative phosphorylation (OXPHOS) deficiency at high mutation loads, which prohibits oogenesis (e.g. progression through meiosis). No maximum mutation loads of the m.8993T>G mutation seem to exist, as the OXPHOS deficiency is less severe, even at levels close to 100%. In contrast, high mutation loads seem to be favoured, probably because they lead to an increased mitochondrial membrane potential (MMP), a hallmark on which healthy mitochondria are being selected. This hypothesis could provide a possible explanation for the skewed segregation pattern observed. Our findings are corroborated by the segregation pattern of the m.14487T>C mutation, which does not affect OXPHOS and MMP significantly, and its transmission is therefore predominantly determined by random genetic drift. Our conclusion is that mutation-specific selection mechanisms occur during mtDNA inheritance, which has implications for PGD and mitochondrial replacement therapy. STUDY FUNDING/COMPETING INTEREST(S): This work has been funded by GROW-School of Oncology and Developmental Biology. The authors declare no competing interests.


Assuntos
Blastômeros/metabolismo , DNA Mitocondrial/genética , Mutação em Linhagem Germinativa , Oócitos/metabolismo , Adulto , DNA Mitocondrial/metabolismo , Feminino , Células Germinativas/metabolismo , Humanos , Masculino , Fosforilação Oxidativa
11.
Hum Mol Genet ; 27(20): 3475-3487, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29931299

RESUMO

Proteoglycans are among the most abundant and structurally complex biomacromolecules and play critical roles in connective tissues. They are composed of a core protein onto which glycosaminoglycan (GAG) side chains are attached via a linker region. Biallelic mutations in B3GALT6, encoding one of the linker region glycosyltransferases, are known to cause either spondyloepimetaphyseal dysplasia (SEMD) or a severe pleiotropic form of Ehlers-Danlos syndromes (EDS). This study provides clinical, molecular and biochemical data on 12 patients with biallelic B3GALT6 mutations. Notably, all patients have features of both EDS and SEMD. In addition, some patients have severe and potential life-threatening complications such as aortic dilatation and aneurysm, cervical spine instability and respiratory insufficiency. Whole-exome sequencing, next generation panel sequencing and direct sequencing identified biallelic B3GALT6 mutations in all patients. We show that these mutations reduce the amount of ß3GalT6 protein and lead to a complete loss of galactosyltransferase activity. In turn, this leads to deficient GAG synthesis, and ultrastructural abnormalities in collagen fibril organization. In conclusion, this study redefines the phenotype associated with B3GALT6 mutations on the basis of clinical, molecular and biochemical data in 12 patients, and provides an in-depth assessment of ß3GalT6 activity and GAG synthesis to better understand this rare condition.


Assuntos
Síndrome de Ehlers-Danlos/genética , Galactosiltransferases/genética , Mutação , Fenótipo , Sequenciamento Completo do Exoma , Adulto , Criança , Pré-Escolar , Síndrome de Ehlers-Danlos/enzimologia , Síndrome de Ehlers-Danlos/patologia , Ensaios Enzimáticos , Feminino , Galactosiltransferases/metabolismo , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino
12.
Br J Cancer ; 119: 357-363, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29937543

RESUMO

BACKGROUND: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers. METHODS: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility. RESULTS: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk. CONCLUSION: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.


Assuntos
Neoplasias da Mama/etiologia , Fertilização In Vitro/efeitos adversos , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Indução da Ovulação , Adulto , Idoso , Neoplasias da Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Risco
13.
Am J Med Genet B Neuropsychiatr Genet ; 177(1): 35-39, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29095566

RESUMO

A consistent feature of predictive testing guidelines for Huntington's disease (HD) is the recommendation not to undertake predictive tests on those < 18 years. Exceptions are made but the extent of, and reasons for, deviation from the guidelines are unknown. The UK Huntington's Prediction Consortium has collected data annually on predictive tests undertaken from the 23 UK genetic centers. DNA analysis for HD in the Netherlands is centralized in the Laboratory for Diagnostic Genome Analysis in Leiden. In the UK, 60 tests were performed on minors between 1994 and 2015 representing 0.63% of the total number of tests performed. In the Netherlands, 23 tests were performed on minors between 1997 and 2016. The majority of the tests were performed on those aged 16 and 17 years for both countries (23% and 57% for the UK, and 26% and 57% for the Netherlands). Data on the reasons for testing were identified for 36 UK and 22 Netherlands cases and included: close to the age of 18 years, pregnancy, currently in local authority care and likely to have less support available after 18 years, person never having the capacity to consent and other miscellaneous reasons. This study documents the extent of HD testing of minors in the UK and the Netherlands and suggests that, in general, the recommendation is being followed. We provide some empirical evidence as to reasons why clinicians have departed from the recommendation. We do not advise changing the recommendation but suggest that testing of minors continues to be monitored.


Assuntos
Testes Genéticos/métodos , Testes Genéticos/normas , Doença de Huntington/diagnóstico , Adolescente , Feminino , Testes Genéticos/ética , Humanos , Masculino , Menores de Idade , Países Baixos/epidemiologia , Reino Unido/epidemiologia
14.
J Med Genet ; 54(10): 693-697, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28668821

RESUMO

BACKGROUND: Preimplantation genetic diagnosis (PGD) is a reproductive strategy for mitochondrial DNA (mtDNA) mutation carriers, strongly reducing their risk of affected offspring. Embryos either without the mutation or with mutation load below the phenotypic threshold are transferred to the uterus. Because of incidental heteroplasmy deviations in single blastomere and the relatively limited data available, we so far preferred relying on two blastomeres rather than one. Considering the negative effect of a two-blastomere biopsy protocol compared with a single-blastomere biopsy protocol on live birth delivery rate, we re-evaluated the error rate in our current dataset. METHODS: For the m.3243A>G mutation, sufficient embryos/blastomeres were available for a powerful analysis. The diagnostic error rate, defined as a potential false-negative result, based on a threshold of 15%, was determined in 294 single blastomeres analysed in 73 embryos of 9 female m.3243A>G mutation carriers. RESULTS: Only one out of 294 single blastomeres (0.34%) would have resulted in a false-negative diagnosis. False-positive diagnoses were not detected. CONCLUSION: Our findings support a single-blastomere biopsy PGD protocol for the m.3243A>G mutation as the diagnostic error rate is very low. As in the early preimplantation embryo no mtDNA replication seems to occur and the mtDNA is divided randomly among the daughter cells, we conclude this result to be independent of the specific mutation and therefore applicable to all mtDNA mutations.


Assuntos
Blastômeros , DNA Mitocondrial/genética , Testes Genéticos/métodos , Diagnóstico Pré-Implantação/métodos , Biópsia , Blastocisto , Erros de Diagnóstico , Feminino , Heterozigoto , Humanos , Mutação , Gravidez
15.
Genet Med ; 19(5): 583-592, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28492530

RESUMO

PURPOSE: Whole-exome sequencing (WES) provides the possibility of genome-wide preconception carrier screening (PCS). Here, we propose a filter strategy to rapidly identify the majority of relevant pathogenic mutations. METHODS: Our strategy was developed using WES data from eight consanguineous and five fictive nonconsanguineous couples and was subsequently applied to 20 other fictive nonconsanguineous couples. Presumably pathogenic variants based on frequency and database annotations or generic characteristics and mutation type were selected in genes shared by the couple and in the female's X-chromosome. Unclassified variants were not included. RESULTS: This yielded an average of 29 (19-51) variants in genes shared by the consanguineous couples and 15 (6-30) shared by the nonconsanguineous couples. For X-linked variants, the numbers per female were 3 (1-5) and 1 (0-3), respectively. Remaining variants were verified manually. The majority were able to be quickly discarded, effectively leaving true pathogenic variants. CONCLUSION: We conclude that WES is applicable for PCS, both for consanguineous and nonconsanguineous couples, with the remaining number of variants being manageable in a clinical setting. The addition of gene panels for filtering was not favorable because it resulted in missing pathogenic variants. It is important to develop and continuously curate databases with pathogenic mutations to further increase the sensitivity of WES-based PCS.Genet Med advance online publication 27 October 2016.


Assuntos
Triagem de Portadores Genéticos/métodos , Sequenciamento Completo do Exoma/métodos , Consanguinidade , Feminino , Genes Ligados ao Cromossomo X , Humanos , Masculino , Mutação , Pais
16.
Hum Reprod ; 32(3): 698-703, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28122886

RESUMO

We report on the first PGD performed for the m.14487 T>C mitochondrial DNA (mtDNA) mutation in the MT-ND6 gene, associated with Leigh syndrome. The female carrier gave birth to a healthy baby boy at age 42. This case adds to the successes of PGD for mtDNA mutations.


Assuntos
DNA Mitocondrial/genética , Doença de Leigh/diagnóstico , Mutação , Feminino , Humanos , Recém-Nascido , Doença de Leigh/genética , Masculino , Mitocôndrias/genética , Linhagem , Gravidez , Diagnóstico Pré-Implantação , Resultado do Tratamento
17.
J Med Genet ; 54(2): 73-83, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27450679

RESUMO

BACKGROUND: Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for many familial mtDNA point mutations to very low for sporadic, large-scale single mtDNA deletions. Comprehensive data are lacking for de novo mtDNA point mutations, often leading to misconceptions and incorrect counselling regarding recurrence risk and reproductive options. We aim to study the relevance and recurrence risk of apparently de novo mtDNA point mutations. METHODS: Systematic study of prenatal diagnosis (PND) and recurrence of mtDNA point mutations in families with de novo cases, including new and published data. 'De novo' based on the absence of the mutation in multiple (postmitotic) maternal tissues is preferred, but mutations absent in maternal blood only were also included. RESULTS: In our series of 105 index patients (33 children and 72 adults) with (likely) pathogenic mtDNA point mutations, the de novo frequency was 24.6%, the majority being paediatric. PND was performed in subsequent pregnancies of mothers of four de novo cases. A fifth mother opted for preimplantation genetic diagnosis because of a coexisting Mendelian genetic disorder. The mtDNA mutation was absent in all four prenatal samples and all 11 oocytes/embryos tested. A literature survey revealed 137 de novo cases, but PND was only performed for 9 (including 1 unpublished) mothers. In one, recurrence occurred in two subsequent pregnancies, presumably due to germline mosaicism. CONCLUSIONS: De novo mtDNA point mutations are a common cause of mtDNA disease. Recurrence risk is low. This is relevant for genetic counselling, particularly for reproductive options. PND can be offered for reassurance.


Assuntos
DNA Mitocondrial/genética , Doenças Genéticas Inatas/diagnóstico , Herança Materna/genética , Diagnóstico Pré-Natal , Adulto , Criança , Feminino , Aconselhamento Genético , Humanos , Masculino , Oócitos/metabolismo , Mutação Puntual/genética , Gravidez , Diagnóstico Pré-Implantação
18.
Fam Cancer ; 16(2): 271-277, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27826806

RESUMO

Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands. Uptake for retinoblastoma (Rb) was compared with uptake for Von Hippel-Lindau disease (VHL), Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and hereditary breast ovarian cancer (HBOC). A questionnaire was completed by all nine DNA-diagnostic laboratories assessing the number of independent mutation-positive families identified from the start of diagnostic testing until May 2013, and the number of PNDs performed for these syndromes within these families. Of 187 families with a known Rb-gene mutation, 22 had performed PND (11.8%), this was significantly higher than uptake for FAP (1.6%) and HBOC (<0.2%). For VHL (6.5%) and LFS (4.9%) the difference was not statistically significant. PND for Rb started 3 years after introduction of diagnostic DNA testing and remained stable over the years. For the other cancer syndromes PND started 10-15 years after the introduction and uptake for PND showed an increase after 2009. We conclude that uptake of PND for Rb was significantly higher than for FAP and HBOC, but not different from VHL and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences.


Assuntos
Detecção Precoce de Câncer/estatística & dados numéricos , Genes do Retinoblastoma/genética , Testes Genéticos/estatística & dados numéricos , Síndromes Neoplásicas Hereditárias/diagnóstico , Diagnóstico Pré-Natal/estatística & dados numéricos , Retinoblastoma/diagnóstico , Análise Mutacional de DNA , Detecção Precoce de Câncer/métodos , Feminino , Aconselhamento Genético , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/genética , Países Baixos , Gravidez , Diagnóstico Pré-Natal/métodos , Retinoblastoma/genética , Estudos Retrospectivos , Inquéritos e Questionários
19.
Child Neurol Open ; 3: 2329048X16642948, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28503609

RESUMO

We present a case of an unusual triad in pediatric neurology: a currently 12-year-old boy with cerebral palsy and epilepsy who was later also diagnosed with Duchenne muscular dystrophy. We describe the clinical path that resulted in this exceptional diagnosis. This case report illustrates how different neurological disorders may overshadow each other. In addition, it demonstrates that every child with cerebral palsy and either an atypical clinical course or with inexplicable laboratory values-as well as every infant boy born to a theoretical Duchenne muscular dystrophy carrier-should be subjected to additional investigations.

20.
Ann N Y Acad Sci ; 1350: 29-36, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26312584

RESUMO

Mitochondrial disorders are among the most common inborn errors of metabolism; at least 15% are caused by mitochondrial DNA (mtDNA) mutations, which occur de novo or are maternally inherited. For familial heteroplasmic mtDNA mutations, the mitochondrial bottleneck defines the mtDNA mutation load in offspring, with an often high or unpredictable recurrence risk. Oocyte donation is a safe option to prevent the transmission of mtDNA disease, but the offspring resulting from oocyte donation are genetically related only to the father. Prenatal diagnosis (PND) is technically possible but usually not applicable because of limitations in predicting the phenotype. For de novo mtDNA point mutations, recurrence risks are low and PND can be offered to provide reassurance regarding fetal health. PND is also the best option for female carriers with low-level mutations demonstrating skewing to 0% or 100%. A fairly new option for preventing the transmission of mtDNA diseases is preimplantation genetic diagnosis (PGD), in which embryos with a mutant load below a mutation-specific or general expression threshold of 18% can be transferred. PGD is currently the best reproductive option for familial heteroplasmic mtDNA point mutations. Nuclear genome transfer and genome editing techniques are currently being investigated and might offer additional reproductive options for specific mtDNA disease cases.


Assuntos
DNA Mitocondrial , Erros Inatos do Metabolismo/prevenção & controle , Doenças Mitocondriais/prevenção & controle , Mutação , Diagnóstico Pré-Implantação , Diagnóstico Pré-Natal , Animais , Feminino , Humanos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/embriologia , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/embriologia , Doenças Mitocondriais/genética , Doação de Oócitos , Gravidez
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