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Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

Approximately 25 % of individuals undergoing genetic counseling for cancer experiences clinically relevant levels of distress, anxiety and/or depression. However, these general psychological outcomes that are used in many studies do not provide detailed information on the specific psychosocial problems experienced by counselees. The aim of this review was to investigate the specific psychosocial issues encountered by individuals undergoing genetic counseling for cancer, and to identify overarching themes across these issues. A literature search was performed, using four electronic databases (PubMed, PsychInfo, CINAHL and Embase). Papers published between January 2000 and January 2013 were selected using combinations, and related indexing terms of the keywords: ‘genetic counseling’, ‘psychology’ and ‘cancer’. In total, 25 articles met our inclusion criteria. We identified the specific issues addressed by these papers, and used meta-ethnography to identify the following six overarching themes: coping with cancer risk, practical issues, family issues, children-related issues, living with cancer, and emotions. A large overlap in the specific issues and themes was found between these studies, suggesting that research on specific psychosocial problems within genetic counseling has reached a point of saturation. As a next step, efforts should be made to detect and monitor these problems of counselees at an early stage within the genetic counseling process.

Background Screening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia. Objective To develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition to PC. Methods A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥75% agreed or disagreed. Results There was excellent agreement that, to be successful, a screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). It was agreed that the following were candidates for screening: first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz–Jeghers syndrome; and p16, BRCA2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥1 affected FDR. Consensus was not reached for the age to initiate screening or stop surveillance. It was agreed that initial screening should include endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or endoscopic retrograde cholangiopancreatography. There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts. There was disagreement on optimal screening modalities and intervals for follow-up imaging. When surgery is recommended it should be performed at a high-volume centre. There was great disagreement as to which screening abnormalities were of sufficient concern to for surgery to be recommended. Conclusions Screening is recommended for high-risk individuals, but more evidence is needed, particularly for how to manage patients with detected lesions. Screening and subsequent management should take place at high-volume centres with multidisciplinary teams, preferably within research protocols.

Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3′ end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. We obtained clinical data for 194 carriers of a 3′ end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM–MSH2 deletion. 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65–85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM–MSH2 deletion (69% [95% CI 47–91], p=0·8609) or mutations in MSH2 (77% [64–90], p=0·5892) or MLH1 (79% [68–90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38–62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0–27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM–MSH2 deletion (55% [20–90], p<0·0001) or of a mutation in MSH2 (51% [33–69], p=0·0006) or MSH6 (34% [20–48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15–51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers. Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute.

Background An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives. Methods We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples. Results The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families. Conclusions We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.

This study examined: (1) levels of cancer-specific distress more than one year after genetic counselling for hereditary nonpolyposis colorectal cancer (HNPCC); (2) associations between sociodemographic, clinical and psychosocial factors and levels of distress; (3) the impact of genetic counselling on family relationships, and (4) social consequences of genetic counselling. In this cross-sectional study, individuals who had received genetic counselling for HNPCC during 1986-1998 completed a self-report questionnaire by mail. 116 individuals (81% response rate) completed the questionnaire, on average 4 years after the last counselling session. Of all respondents, 6% had clinically significant levels of cancer-specific distress (Impact of Event Scale, IES). Having had contact with a professional psychosocial worker for cancer risk in the past 10 years was significantly associated with higher levels of current cancer specific distress. Only a minority of the counselees reported any adverse effects of genetic counselling on: communication about genetic counselling with their children (9%), family relationships (5%), obtaining life insurance (8%), choice or change of jobs (2%), and obtaining a mortgage (2%). On average, four years after genetic counselling for HNPCC, only a small minority of counselled individuals reports clinically significant levels of distress, or significant family or social problems.

Hereditary diffuse gastric cancer (HDGC) is a relatively rare disorder, with a mutated CDH1 gene as the only known cause. Carriers of a germline mutation in CDH1 have a lifetime risk of >80% of developing diffuse gastric cancer. As periodic gastric surveillance is of limited value in detecting early stages of HDGC, prophylactic gastrectomy is advised for this patient group. Little is known about other types of familial gastric cancer. The Dutch working group on hereditary gastric cancer has formulated guidelines for various aspects of medical management for families and individuals at high risk of developing gastric cancer, including criteria for referral, classification, diagnostics, and periodic gastric surveillance. These guidelines are not limited to HDGC and are therefore partially complementary to the guidelines on hereditary diffuse gastric cancer of the international gastric cancer linkage consortium (IGCLC 2010). In order to optimize the care and increase the knowledge on hereditary gastric cancer it is important to centralize medical care for these patients. National and international collaboration is warranted to improve the quality of research by increasing the size of study cohorts.

BackgroundMutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors. This study investigated the occurrence of homozygosity for the CHEK2*1100delC allele among familial breast cancer cases and the associated breast cancer risk.Methods and resultsHomozygosity for the CHEK2*1100delC allele was identified in 8/2554 Dutch independent familial non-BRCA1/2 breast cancer cases. The genotype relative risk for breast cancer of homozygous and heterozygous familial breast cancer cases was 101.34 (95% CI 4.47 to 121 000) and 4.04 (95% CI 0.88 to 21.0), respectively. Female homozygotes appeared to have a greater than twofold increased breast cancer risk compared to familial CHEK2*1100delC heterozygotes (p=0.044). These results and the occurrence of multiple primary tumours in 7/10 homozygotes indicate a high cancer risk in homozygous women from non-BRCA1/2 families.ConclusionsIntensive breast surveillance is therefore justified in these homozygous women. It is concluded that diagnostic testing for biallelic mutations in CHEK2 is indicated in non-BRCA1/2 breast cancer families, especially in populations with a relatively high prevalence of deleterious mutations in CHEK2.

Purpose: The success of any surveillance program depends not solely on its technological aspects but also on the commitment of participants to adhere to follow-up investigations, which is influenced by the psychological impact of surveillance. This study investigates the psychological impact of participating in a pancreatic cancer surveillance program. Methods: High-risk individuals participating in an endoscopic ultrasonography-magnetic resonance imaging-based pancreatic cancer surveillance program received a questionnaire assessing experiences with endoscopic ultrasonography and magnetic resonance imaging, reasons to participate, psychological distress, and benefits and barriers of surveillance. High-risk individuals were individuals with a strong family history of pancreatic cancer or carriers of pancreatic cancer-prone gene mutations. Results: Sixty-nine participants (85%) completed the questionnaire. Surveillance was reported as “very to extremely uncomfortable” by 15% for magnetic resonance imaging and 14% for endoscopic ultrasonography. Most reported reason to participate was that pancreatic cancer might be detected in a curable stage. Abnormalities were detected in 27 respondents, resulting in surgical resection in one individual and a shorter follow-up interval in five individuals. Surveillance outcomes did not influence cancer worries. Overall, 29% was “often” or “almost always” concerned about developing cancer. Six respondents (9%) had clinical levels of depression and/or anxiety. According to 88% of respondents, advantages of surveillance outweighed disadvantages. Conclusions: Although endoscopic ultrasonography is more invasive than magnetic resonance imaging, endoscopic ultrasonography was not perceived as more burdensome. Despite one third of respondents worrying frequently about cancer, this was not related to the surveillance outcomes. Anxiety and depression levels were comparable with the general population norms. Advantages of participation outweighed disadvantages according to the majority of respondents. From a psychological point of view, pancreatic cancer surveillance in high-risk individuals is feasible and justified.

Obesity is an established risk factor for postmenopausal breast cancer in the general population. However, it is still unclear whether this association also exists in BRCA1/2 mutation carriers. We investigated the association between self-reported anthropometric measures and breast cancer risk in a nationwide retrospective cohort study, including 719 BRCA1/2 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. All time-varying Cox proportional hazards analyses were stratified by menopausal status. For premenopausal breast cancer, no statistically significant associations were observed for any of the anthropometric measures. The association between body mass index (BMI) at age 18 and premenopausal breast cancer risk suggested a trend of decreasing risk with increasing BMI (HR₂₂.₅₀₋₂₄.₉₉ vs. ₁₈.₅₀₋₂₂.₄₉ = 0.83, 95% CI = 0.47-1.44 and HR≥₂₅.₀₀ vs. ₁₈.₅₀₋₂₂.₄₉ = 0.41, 95% CI = 0.13-1.27). For postmenopausal breast cancer, being 1.67 m and taller increased the risk 1.7-fold (HR = 1.67, 95% CI = 1.01-2.74) when compared to a height <1.67 m. Compared with a current body weight <72 kg, a current body weight of ≥72 kg increased the risk of postmenopausal breast cancer 2.1-fold (95% CI = 1.23-3.59). A current BMI of ≥25.0 kg/m², an adult weight gain of 5 kg or more, and a relative adult weight gain of 20% or more were all non-significantly associated with a 50-60% increased risk of postmenopausal breast cancer [HR = 1.46 (0.86-2.51), HR = 1.56 (95% CI = 0.85-2.87), and HR = 1.60 (95% CI = 0.97-2.63), respectively], when compared with having a healthy or stable weight. No associations for body weight or BMI at age 18 were observed. In conclusion, menopausal status seemed to modify the association between body weight and breast cancer risk among BRCA1/2 carriers. We observed no clear association between body weight and premenopausal breast cancer, while overweight and weight gain increased postmenopausal breast cancer risk. Carriers may reduce their risk of postmenopausal breast cancer by maintaining a healthy body weight throughout life.