Congenital anomalies and genetic disorders in neonates and infants: a single-center observational cohort study.

Neonates with genetic disorders or congenital anomalies (CA) contribute considerably to morbidity and mortality in neonatal intensive care units (NICUs). The objective of this study is to study the prevalence of genetic disorders in an academic level IV NICU. We retrospective collected and analyzed both clinical and genetic data of all 1444 infants admitted to the NICU of the Radboudumc (October 2013 to October 2015). Data were collected until infants reached at least 2 years of age. A total of 13% (194/1444) of the patients were genetically tested, and 32% (461/1444) had a CA. A total of 37% (72/194) had a laboratory-confirmed genetic diagnosis. In 53%, the diagnosis was made post-neonatally (median age = 209 days) using assays including exome sequencing. Exactly 63% (291/461) of the patients with CA, however, never received genetic testing, despite being clinically similar those who did.Conclusions: Genetic disorders were suspected in 13% of the cohort, but only confirmed in 5%. Most received their genetic diagnosis in the post-neonatal period. Extrapolation of the diagnostic yield suggests that up to 6% of our cohort may have remained genetically undiagnosed. Our data show the need to improve genetic care in the NICU for more inclusive, earlier, and faster genetic diagnosis to enable tailored management. What is Known: • Genetic disorders are suspected in many neonates but only genetically confirmed in a minority. • The presence of a genetic disorder can be easily missed and will often lead to a diagnostic odyssey requiring extensive evaluations, both clinically and genetically. What is New: • Different aspects of the clinical features and uptake of genetic test in a NICU cohort. • The need to improve genetic care in the NICU for more inclusive, earlier, and faster genetic diagnosis to enable tailored management.

[European Reference Networks for rare diseases]. / Europese referentienetwerken voor zeldzame ziekten.

Approximately one million patients in the Netherlands and 27-36 million patients in Europe have one of the 5,000-8,000 known rare diseases. These patients often do not receive the care they need or with a substantial delay from diagnosis to treatment. As of March 2017, 24 European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross-border healthcare, where in principle the knowledge travels and not the patient. It is expected that through the ERNs, European patients with a rare disease get more often and more quickly access to expert care and that it will accelerate guideline development and research. In each of the 24 ERNs, one or more Dutch expertise centres for rare diseases participate, and 5 ERNs are coordinated by centres from the Netherlands.

Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

Improving recognition and referral of patients with an increased familial risk of colorectal cancer: results from a randomized controlled trial.

AIM: Only 12-49% of colorectal cancer (CRC) patients and their first-degree relatives with an increased familial CRC risk are referred for cancer prevention measures (surveillance colonoscopies or genetic counselling). The study was performed to evaluate the effectiveness and feasibility of a novel strategy to improve the uptake of genetic counselling for high risk individuals and surveillance colonoscopy for moderate risk groups. METHOD: Eighteen hospitals participated in a clustered randomized controlled trial. Patients in nine hospitals received usual care (group A). Nine other hospitals received the novel strategy (group B) including access to a website for patients and clinicians, patient-targeted brochures and clinician-targeted education and pocket referral cards. Data before and after dissemination of the strategy were collected from questionnaires and medical records. RESULTS: Data were complete for 358 (44%) of 820 CRC patients and 50 (36%) of 137 clinicians before dissemination of the strategy and 392/862 patients (45%) and 47/137 clinicians (34%) after. Referral for cancer prevention measures was assessed at a median of 8 (2-12) months after CRC diagnosis in groups A and B before the dissemination of the strategy and in group A after. In group B referral was assessed at a median of 9 (4-11) months after the dissemination of the strategy. Uptake of genetic counselling by high risk patients was equal in groups A and B, being 33% before and 15% after (P = 0.003). Uptake of surveillance colonoscopy by moderate risk relatives did not change significantly (group A, 36% before vs 41% after; group B, 33% before vs 19% after). In group B 94/140 patients (67%) and 25/72 clinicians (35%) visited the website and 34/140 (24%) patients read the brochure. Patients valued clinicians' information as most useful, followed by the patient brochure. Clinicians preferred pocket cards and education. CONCLUSION: Our strategy did not improve referral for cancer prevention measures. Although the newly offered strategy elements were appreciated, patients preferred clinicians' advice regarding referral for cancer prevention measures. It may be useful to aim future interventions at healthcare professionals rather than patients to improve the prevention of familial cancer.

Patient experiences with gene panels based on exome sequencing in clinical diagnostics: high acceptance and low distress.

The Radboud University Medical Center was among the first to implement two-step exome sequencing in clinical genetic diagnostics. This study is the first to evaluate patient experiences with gene panels based on exome sequencing, using quantified psychological variables: acceptance, psychological distress, expectations of heredity and unsolicited findings. Between August 2011 and July 2012, 177 patients diagnosed with early-onset colorectal/kidney cancer, deafness, blindness or movement disorder consented to diagnostic exome sequencing offered by clinical geneticists. Baseline questionnaires were sent to 141 adults, returned by 111 with median age of 49 [22-79] years and positive family history in 81%. Follow-up included 91 responders at median 4 [2-22] weeks after results from known gene panels per diagnosis group; exome-wide analysis is ongoing. Confirmed or possibly pathogenic mutations were found in 31% with one unsolicited finding (oncogenetic panel). Most patients (92%) were satisfied. There were no significant changes in heredity-specific distress (18% at baseline, 17% at follow-up) and expectations of heredity. Fewer patients expected unsolicited findings at follow-up (29% vs 18%, p = 0.01). Satisfaction and distress were equal in those with vs without mutations. In conclusion, most adults accepted and were satisfied with gene panels based on diagnostic exome sequencing, few reporting distress.

Easy-to-use online referral test detects most patients with a high familial risk of colorectal cancer.

AIM: Currently only 12-30% of individuals with a high risk of Lynch syndrome, the most common hereditary colorectal cancer (CRC) syndrome, are referred for genetic counselling. We assessed the sensitivity, usability and user experiences of a new online referral test aimed at improving referral of high-risk individuals for genetic counselling. METHOD: Sensitivity was assessed by entering pedigree data from high-risk individuals (i.e. Lynch syndrome mutation carriers) into the referral test to determine whether genetic counselling was recommended. For usability, we assessed nonmedical staff members' ability to determine referral, according to guidelines, in seven fictive clinical cases using the referral test after minimal training. Real-life users answered questions about their experience with the referral test. RESULT: Sensitivity of the referral test was 91% for mutation carriers with CRC (n = 164) and 73% for all affected and nonaffected mutation carriers (n = 420). Nonmedical staff members (n = 20) determined referral according to guidelines in 84% of cases using the referral test. Ten per cent (256/2470) of real-life users provided feedback about experiences; of those, 71% reported that the referral test increased reassurance, certainty about their familial risk and/or certainty about referral. CONCLUSION: The referral test has a high sensitivity in detecting individuals with a high risk of Lynch syndrome and is suitable for use in clinical practice. Widespread use of the referral test should improve cancer prevention in high-risk patients and their relatives.

Familial colorectal cancer risk assessment needs improvement for more effective cancer prevention in relatives.

AIM: Twelve to thirty % of colorectal cancer (CRC) patients and relatives with an increased familial risk of CRC are referred for preventive measures. New guidelines recommend genetic counselling for high-risk families and surveillance colonoscopy for moderate-risk families. Assessment of familial risk of CRC and referral rates for these preventive measures were determined 1 year after the introduction of new guidelines. METHOD: Assessment of familial risk of CRC and referral for preventive measures were measured in clinical practice among 358 patients with CRC in 18 hospitals using medical records and questionnaires. Additionally, a knowledge survey was performed among 312 clinicians. RESULTS: Sixty-seven % of patients with an increased familial risk (n = 65/97) were referred for preventive measures, as were 23% (61/261) of low-risk patients. The uptake of genetic counselling in high-risk families was 33% (12/36). The uptake of surveillance colonoscopy in moderate-risk families was 34% (21/61). In the knowledge survey clinicians correctly determined familial risk in 55% and preventive measures in 65% of cases. CONCLUSION: Currently 67% of individuals with an increased familial risk of CRC were referred for preventive measures. Only one-third were referred in accordance with guidelines.

Adding familial risk assessment to faecal occult blood test can increase the effectiveness of population-based colorectal cancer screening.

BACKGROUND: The Dutch Health Council recently recommended the introduction of a colorectal cancer (CRC) screening programme by faecal occult blood testing (FOBT) for individuals aged 55-75 at population risk of CRC. Individuals at an increased familial CRC risk (≥ 2 times population risk) should be identified at a younger age, so they and their relatives can receive earlier, more intensive surveillance instead of FOBT. AIMS: To determine the percentage of participants with a positive FOBT in a CRC screening programme with an increased familial CRC risk. METHODS: In a population-based study, 10,569 individuals aged 50-75 received an FOBT. Individuals with a positive FOBT were invited for colonoscopy and familial risk assessment. Participants with an average familial CRC risk were compared to those with an increased risk. Increased familial CRC risk was defined as a cumulative lifetime risk of CRC of at least 10%. RESULTS: Of 6001 participants, 430 had a positive FOBT, of whom 324 (63% males; mean age 63 years) completed colonoscopy and familial risk assessment. CRC (n=22) and/or advanced adenomas (n=122) were found in 133 participants. Familial CRC risk was increased in 6% of participants with a positive FOBT. No significant differences were found between participants with an average versus an increased familial CRC risk. CONCLUSION: Six percent of participants with a positive FOBT had an increased familial CRC risk. Identifying at-risk participants enables them and their relatives to undergo regular colonoscopies. Adding familial risk assessment to FOBT screening may thus prevent a substantial number of CRCs.

Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.

BACKGROUND: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far. METHODS AND RESULTS: By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein. CONCLUSIONS: The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.