Clinical Genetics Centres Research Articles

Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.

Clinician perspectives on policy approaches to genetic risk disclosure in families

Genomic sequencing has emerged as a powerful tool with significant implications for patients and their relatives, however, empirical evidence suggests that effective dissemination of risk information within families remains a challenge. Policy responses to address this issue vary across countries, with Belgium notably lacking specific regulations governing nondisclosure of genetic risk. In this study, we conducted semi-structured interviews with clinicians from Belgian clinical genetics centers to gain insight into their perspectives on policy approaches to the disclosure of genetic risk within families. Using real-world examples of legislation and court rulings from France, Australia, and the UK, we explored clinician viewpoints on the roles and responsibilities of both patients and clinicians in the family communication process. Clinicians expressed confusion regarding what was legally permissible regarding contacting at-risk relatives. While there was a consensus among participants that patients have a responsibility to inform their at-risk relatives, participants were hesitant to support the legal enforcement of this duty. Clinicians mostly recognized some responsibility to at-risk relatives, but the extent of this responsibility was a subject of division. Our findings highlight the need for a comprehensive policy that clarifies the roles and responsibilities of clinicians and patients to inform at-risk relatives. Furthermore, the study underscores the practical challenges clinicians face in supporting patients through the complex process of family communication, suggesting a need for additional resources and the exploration of alternative approaches to communication.

Fetal skeletal dysplasia cohort of a single tertiary referral center in Istanbul, Turkey.

We report on 314 fetal cases from 297 unrelated families with skeletal dysplasia evaluated in the postmortem period from 2000 to 2017 at a single clinical genetics center in İstanbul, Turkey. The definite diagnostic yield was 40% during the prenatal period, while it reached 74.5% when combined with postmortem clinical and radiological evaluation. Molecular analyses were performed in 25.5% (n: 76) of families, and 21 novel variants were identified. Classification according to International Skeletal Dysplasia Society-2019 revision revealed limb hypoplasia-reduction defects group (39) as the leading one, 24.5%, then followed by FGFR3 chondrodysplasias, osteogenesis imperfecta, and decreased mineralization and polydactyly-syndactyly-triphalangism groups 13.6, 11.1, and 8.9%, respectively. The inheritance pattern was autosomal recessive in 54% and autosomal dominant in 42.6% of index cases. The overall consanguinity rate of the cohort was 33%. The high prevalence of ultrarare diseases along with two or more unrelated autosomal recessive entities running in the same family was noteworthy. This study highlights the pivotal role of postmortem evaluation by an experienced clinical geneticist to achieve a high diagnostic yield in fetal skeletal dysplasia cohorts. The cohort is not only a representation of the spectrum of skeletal dysplasias in a population with a high consanguinity rate but also provides an ideal research group to work on to identify the unknowns of early fetal life.

Rapid exome sequencing in critically ill children impacts acute and long-term management of patients and their families: A retrospective regional evaluation

IntroductionGenetic disorders are a significant cause of paediatric morbidity and mortality. Rapid exome sequencing was introduced by the National Health Service (NHS) in England on 1st October 2019 for acutely unwell children with a likely monogenic disorder, or to inform current pregnancy management where there was a previously affected child or fetus. We present results of a 12-month patient cohort from one large clinical genetics centre in England. MethodsPatients were identified through local genetics laboratory records. We included all cases which underwent rapid exome sequencing between 1st October 2020 and 30th September 2021. DNA was extracted, quality checked and exported to the Exeter Genomic laboratory where library preparation, exome sequencing of all known human genes, gene-agnostic bioinformatic analysis, variant interpretation, MDT discussions and reporting were performed. ResultsNinety-five probands were included. Trio analysis was performed in 90% (85), duo in 8% (8), singleton in 2% (2). The median turnaround time for preliminary reports was 11 days. The overall diagnostic yield was 40% (38 patients); 36% (34 patients) made solely on exome with a further 4% on concomitant exome and microarray analysis. Highest diagnostic rates were seen in patients with neuro-regression, skeletal dysplasia, neuromuscular and neurometabolic conditions.Where the diagnosis was made solely through exome sequencing, management was altered for the proband or family in 97% (33/34). For the proband, this was most commonly that the diagnosis was able to inform current management and prognosis (20 patients, 59%), as well as direct specialist referrals (10 patients, 29%). For families, the exome sequencing results provided accurate recurrence risk counselling in 88% (30/34) with cascade testing offered if indicated in some families. ConclusionsIn the majority of cases, the genetic diagnoses influenced acute and long-term management for critically ill children and their families. Paediatric and neonatal clinicians in the NHS now have direct access to exome sequencing for their patients. The rapid turnaround time was particularly helpful to alter the management in acute clinical settings and is a powerful tool for diagnosing monogenic conditions. This study is an example of a highly successful integration of a national rapid exome sequencing service with diagnostic rates comparable to previously reported literature.

Investigation and Management of Apparently Sporadic Central Nervous System Haemangioblastoma for Evidence of Von Hippel-Lindau Disease.

Haemangioblastomas are rare, highly vascularised tumours that typically occur in the cerebellum, brain stem and spinal cord. Up to a third of individuals with a haemangioblastoma will have von Hippel–Lindau (VHL) disease. Individuals with haemangioblastoma and underlying VHL disease present, on average, at a younger age and frequently have a personal or family history of VHL disease-related tumours (e.g., retinal or central nervous system (CNS) haemangioblastomas, renal cell carcinoma, phaeochromocytoma). However, a subset present an apparently sporadic haemangioblastoma without other features of VHL disease. To detect such individuals, it has been recommended that genetic testing and clinical/radiological assessment for VHL disease should be offered to patients with a haemangioblastoma. To assess “real-world” clinical practice, we undertook a national survey of clinical genetics centres. All participating centres responded that they would offer genetic testing and a comprehensive assessment (ophthalmological examination and CNS and abdominal imaging) to a patient presenting with a CNS haemangioblastoma. However, for individuals who tested negative, there was variability in practice with regard to the need for continued follow-up. We then reviewed the results of follow-up surveillance in 91 such individuals seen at four centres. The risk of developing a potential VHL-related tumour (haemangioblastoma or RCC) was estimated at 10.8% at 10 years follow-up. The risks of developing a recurrent haemangioblastoma were higher in those who presented <40 years of age. In the light of these and previous findings, we propose an age-stratified protocol for surveillance of VHL-related tumours in individuals with apparently isolated haemangioblastoma.

How will new genetic technologies, such as gene editing, change reproductive decision-making? Views of high-risk couples

Couples at increased risk of having offspring with a specific genetic disorder who want to avoid having an affected child have several reproductive options including prenatal diagnosis (PND) and preimplantation genetic testing (PGT). In the future, non-invasive prenatal diagnosis (NIPD), germline gene editing (GGE) and somatic gene editing (SGE) might become available. This study explores if, and how, availability of new genetic technologies, including NIPD, GGE, SGE, would change reproductive decision-making of high-risk couples. In 2018, semi-structured interviews were conducted with 25 genetically at-risk couples. Couples previously had received genetic counselling for PND and PGT, and in most cases opted for (one of) these techniques, at one Dutch Clinical Genetics Center between 2013 and 2017. Considerations participants mentioned regarding the hypothetical use of NIPD, GGE and SGE, seem similar to considerations regarding PND and PGT and are reflected in underlying concepts. These include safety and burden for mother and child, and moral considerations. Couples generally favoured NIPD over PND as this would be safe and enables earlier diagnosis. Increased opportunities of having a ‘healthy’ embryo and less embryo disposal were considerations in favour of GGE. Some regarded GGE as unsafe and feared slippery slope scenarios. Couples were least favourable towards SGE compared to choosing for a genetic reproductive technology, because of the perceived burden for the affected offspring. With the possibly growing number of technological options, understanding high risk couples’ perspectives can assist in navigating the reproductive decision-making process. Counsellors should be prepared to counsel on more and complex reproductive options.

Telemedicine strategy of the European Reference Network ITHACA for the diagnosis and management of patients with rare developmental disorders

BackgroundThe European Reference Networks, ERNs, are virtual networks for healthcare providers across Europe to collaborate and share expertise on complex or rare diseases and conditions. As part of the ERNs, the Clinical Patient Management System, CPMS, a secure digital platform, was developed to allow and facilitate web-based, clinical consultations between submitting clinicians and relevant international experts. The European Reference Network on Intellectual Disability, TeleHealth and Congenital Anomalies, ERN ITHACA, was formed to harness the clinical and diagnostic expertise in the sector of rare, multiple anomaly and/or intellectual disability syndromes, chromosome disorders and undiagnosed syndromic disorders. We present the first year results of CPMS use by ERN ITHACA as an example of a telemedicine strategy for the diagnosis and management of patients with rare developmental disorders.ResultsERN ITHACA ranked third in telemedicine activity amongst 24 European networks after 12 months of using the CPMS. Information about 28 very rare cases from 13 different centres across 7 countries was shared on the platform, with diagnostic or other management queries. Early interaction with patient support groups identified data protection as of primary importance in adopting digital platforms for patient diagnosis and care. The first launch of the CPMS was built to accommodate the needs of all ERNs. The ERN ITHACA telemedicine process highlighted a need to customise the CPMS with network-specific requirements. The results of this effort should enhance the CPMS utility for telemedicine services and ERN-specific care outcomes.ConclusionsWe present the results of a long and fruitful process of interaction between the ERN ITHACA network lead team and EU officials, software developers and members of 38 EU clinical genetics centres to organise and coordinate direct e-healthcare through a secure, digital platform. The variability of the queries in just the first 28 cases submitted to the ERN ITHACA CPMS is a fair representation of the complexity and rarity of the patients referred, but also proof of the sophisticated and variable service that could be provided through a structured telemedicine approach for patients and families with rare developmental disorders. Web-based approaches are likely to result in increased accessibility to clinical genomic services.

Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study

BackgroundBRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. ObjectiveTo estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. Design, setting, and participantsThis was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively). Outcome measurements and statistical analysisStandardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. Results and limitationsSixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99–6.61) and absolute PCa risk of 27% (95% CI 17–41%) and 60% (95% CI 43–78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43–3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68–7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99–2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07–5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14–0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20–8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24–7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44–10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. ConclusionsThe results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. Patient summaryIn this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.

The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect.

PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.

A validated PROM in genetic counselling: the psychometric properties of the Dutch version of the Genetic Counselling Outcome Scale.

Patient empowerment has been identified as a key outcome goal in genetic counselling, and a patient reported outcome measure (PROM) has been developed to measure empowerment in genetic services: the Genetic Counselling Outcome Scale (GCOS). Here we validate the GCOS for a large and diverse Dutch study sample of 2194 patients referred to two clinical genetic centres for counselling about a wide range of conditions (heart disease, neurological disorders, cancer, congenital syndromes, intellectual disability and prenatal pathology). Our results suggest that the GCOS consists of a hierarchical 6-factor structure, with a main scale for empowerment and six subscales: uncertainty about heredity, hope, negative emotions, knowledge about the condition, knowledge about genetic services and uncertainty about the treatment. Six of the original 24 GCOS items were removed due to low factor loadings and small inter-item correlations. Internal consistency and test-retest reliability of the main scale and most subscales were satisfactory. Convergent validity was confirmed by moderate positive and moderate/strong negative associations between the GCOS main scale and other validated outcome measures. Responsiveness was comparable to that of other validated outcome measures. We saw significant improvement in the GCOS main scale and all the subscales after the first genetic counselling session. This study contributes to the international validation process of the GCOS, with the ultimate goal of using this instrument as a PROM, with empowerment as an outcome measure, to evaluate and improve the quality of genetic counselling in various clinical genetics settings.

Towards establishing consistency in triage in a tertiary specialty.

Clinical Genetics services provide a diagnostic, counselling and genetic testing service for children and adults affected by, or at risk of, a genetic condition, most of which are rare, and/or genetically heterogeneous. Appropriate triage of referrals is crucial to ensure that the most urgent referrals are seen as quickly as possible, without negatively impacting the waiting times of less urgent cases. We aimed to examine triage practice in six Clinical Genetic centres across the United Kingdom and Ireland. Thirteen simulated referrals were drafted based on common referrals to Clinical Genetics. Copies of each referral were forwarded to each centre, where 10 nominated clinicians were asked to triage each referral. Triaged referrals were returned to the coordinating author for analysis. An electronic questionnaire was contemporaneously completed by clinical leads in each unit to gather local demographic details and local operating procedures relevant to triage. Widespread inconsistencies were noted both within and between units, with respect to the acceptance of referrals to the services, prioritisation and designated clinic type. Referral rates, staffing levels and waiting lists varied widely between units. Inconsistencies observed between units are likely influenced by a number of factors, including staffing levels, referral rates and average family size. Inconsistency within units likely reflects the complex nature of many Clinical Genetic referrals, and triage guidelines should help improve decision-making in this setting.

Online decision support for persons having a genetic predisposition to cancer and their partners during reproductive decision-making.

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.

Elevated Proangiogenic Markers are Associated with Vascular Complications within Ghanaian Sickle Cell Disease Patients.

Sickle cell disease (SCD) is an inherited blood disorder that can result in vasculopathy and end organ damage. Angiogenesis has been implicated as a key contributing factor to vascular mediated tissue injury in SCD. The relative plasma levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF) greatly influence angiogenesis. Dysregulation of these growth factors, leading to a pro-angiogenic state in SCD patients, has been documented in the developed world but there is very little data in Africa. There is the need, therefore, for studies in Ghanaian SCD patients. The aim of this study was to assess plasma levels of Ang-1, Ang-2, and VEGF in homozygous (HbSS) SCD patients with or without complications and healthy controls (HbAA) in Ghana. The study was a case-control study involving 544 participants: 396 HbSS SCD patients and 148 HbAA healthy controls. The study was conducted at the Center for Clinical Genetics (Sickle Cell Clinic) and Accra Area Blood Centre for National Blood transfusion at the Korle-Bu Teaching Hospital, Accra, Ghana. The plasma levels of Ang-1, Ang-2, and VEGF of study participants were measured with a double sandwich enzyme-linked immunosorbent assay (ELISA) technique. Complete blood count (CBC) was measured with an autoanalyser. The mean plasma Ang-1, Ang-2, and VEGF were significantly higher in HbSS SCD patients with or without complications than healthy controls (p < 0.001). The Ang-2/Ang-1 ratio was significantly lower in the controls than the HbSS patients (p < 0.001). The Ang-2/Ang-1 ratio was higher in the HbSS patients with leg ulcers as compared with patients with other complications and healthy controls (p < 0.001). There were higher leucocyte counts in HbSS patients than healthy controls. Overall, there was elevated plasma levels of Ang-1, Ang-2, and VEGF in SCD patients. The higher Ang-2/Ang-1 plasma levels in patients with leg ulcers suggests a possible ongoing angiogenesis and response to inflammatory stimuli. The study provides a first report on plasma levels of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factors in homozygous sickle cell disease patients in Ghana.

Editorial introductions

Editorial introductions

Recontacting or not recontacting? A survey of current practices in clinical genetics centres in Europe.

Advances in genomic medicine are improving diagnosis and treatment of some health conditions, and the question of whether former patients should be recontacted is therefore timely. The issue of recontacting is becoming more important with increased integration of genomics in 'mainstream' medicine. Empirical evidence is needed to advance the discussion over whether and how recontacting should be implemented. We administered a web-based survey to genetic services in European countries to collect information about existing infrastructures and practices relevant to recontacting patients. The majority of the centres stated they had recontacted patients to update them about new significant information; however, there were no standardised practices or systems in place. There was also a multiplicity of understandings of the term 'recontacting', which respondents conflated with routine follow-up programmes, or even with post-test counselling. Participants thought that recontacting systems should be implemented to provide the best service to the patients and families. Nevertheless, many barriers to implementation were mentioned. These included: lack of resources and infrastructure, concerns about potential negative psychological consequences of recontacting, unclear operational definitions of recontacting, policies that prevent healthcare professionals from recontacting, and difficulties in locating patients after their last contact. These barriers are also intensified by the highly variable development (and establishment) of the specialties of medical genetics and genetic counselling across different European countries. Future recommendations about recontacting need to consider these barriers. It is also important to reach an 'operational definition' that can be useful in different countries.

Pedigreejs: a web-based graphical pedigree editor.

MotivationThe collection, management and visualization of clinical pedigree (family history) data is a core activity in clinical genetics centres. However, clinical pedigree datasets can be difficult to manage, as they are time consuming to capture, and can be difficult to build, manipulate and visualize graphically. Several standalone graphical pedigree editors and drawing applications exist but there are no freely available lightweight graphical pedigree editors that can be easily configured and incorporated into web applications.ResultsWe developed ‘pedigreejs’, an interactive graphical pedigree editor written in JavaScript, which uses standard pedigree nomenclature. Pedigreejs provides an easily configurable, extensible and lightweight pedigree editor. It makes use of an open-source Javascript library to define a hierarchical layout and to produce images in scalable vector graphics (SVG) format that can be viewed and edited in web browsers.Availability and implementationThe software is freely available under GPL licence (https://ccge-boadicea.github.io/pedigreejs/).Supplementary information Supplementary data are available at Bioinformatics online.

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients.

Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.

The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers.

Germline mutations in succinate dehydrogenase B (SDHB) predispose to hereditary paraganglioma (PGL) syndrome type 4. The risk of developing PGL or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra-adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.

Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers.

CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.

DECURION: A new model for predicting breast and ovarian cancer risks based on family history using French population incidences and Institut Curie’s database.

1534Background: Nowadays, assessing the cancer risk of patients with severe history of cancer is a routine task for the clinical genetic centers. Due to the complex genetic and environmental factor...