Positive Gene Test Research Articles

S2096 PALB2 and the Risk for Colorectal Cancer

Introduction: Colorectal cancer (CRC) is the most prevalent cancer in the gastrointestinal system and the third leading cause of cancer-related deaths in the United States. Hereditary factors play an important role in the risk of CRC and it has been estimated that up to 30% of CRC cases are affected by genetic factors. However, mutations in CRC-susceptibility genes explain less than 10% of CRC cases. Germline mutations in deoxyribonucleic acid (DNA)-repair genes have recently been reported more frequently in CRC. PALB2 is one such germline mutation that was recently evidenced as a CRC risk gene. We present a case of a female patient diagnosed with invasive sigmoid adenocarcinoma in the setting of no significant risk factors except for positive gene testing for PALB2. Case Description/Methods: A 32-year-old female with no significant past medical history presented with an episode of painless, large-volume bright red blood per rectum. She endorsed a 2-month history of intermittent rectal bleeding noted on wiping. Complete blood count revealed a microcytic anemia with hemoglobin of 8.4. Iron panel was consistent with anemia of chronic disease. Colonoscopy revealed a large, infiltrating and partially obstructing mass in the recto-sigmoid colon measuring 6 cm with evidence of mucosal bleeding. Biopsy confirmed invasive adenocarcinoma. Computed tomography (CT) of the abdomen showed multiple hypodense hepatic lesions suggestive of metastatic disease (Figure 1). Discussion: Mutations in PALB2 have been associated with an increased risk of familial cancers including breast, pancreatic, and gastric cancers. PALB2 encodes a protein that functions in tumor suppression and is primarily involved in the DNA repair process. PALB2 is altered in 2.8% of colorectal cancer cases. One study proved that PALB2 was an independent prognostic factor in CRC. Further studies on mutations involving PALB2 in CRC can help delineate a patient’s risk for malignancy and provide vital information for gastric cancer prevention. It will also allow for more personalized treatment options to have improved survival outcomes.Figure 1.: Malignant, partially obstructing tumor in the recto-sigmoid colon that was about 19 to 25 cm from the anal verge.

Familial Cardiomyopathy Is Associated With A Significantly Worse Prognosis Than Non-familial Cardiomyopathy.

Introduction Risk stratification of nonischemic dilated cardiomyopathic (NICM) patients is challenging due to the large heterogeneity in disease phenotype, genetic background, and poorly characterized progression of disease. We postulated that patients with familial NICM (F-NICM, operationally defined as a strong family history or genetically proven) carry a significantly worse prognosis than nonfamilial/idiopathic NICM (I-NICM) patients for the composite endpoint of death, left ventricular assist device (LVAD) placement, or orthotopic heart transplantation (OHT). Methods A total of 127 consecutive patients, 52 F-NICM and 85 I-NICM, with implanted cardiac defibrillators (ICDs) or cardiac resynchronization devices (CRT) were studied. F-NICM patients were identified from the cardiovascular genetics clinic. Patients were followed for a mean of 6.1 +/- 5.1 years for cardiovascular outcomes: death, LVAD, or OHT. Results There were no significant differences regarding incidence of diabetes, hypertension, NYHA functional class, use of guideline directed medical therapy (GDMT), use of CRT, ICD shocks, or years of follow-up. Patients with F-NICM were significantly younger as compared to I-NICM group (45.8 +/- 15.8 years vs. 61.2 +/- 17 years, p=0.001). Mean ejection fraction (EF) was not significantly different between F-NICM and I-NICM; 31.2 +/- 14.5% vs. 31.6 +/- 12.2%. Thirty percent (30%) of F-NICM patients underwent LVAD implant or OHT as compared to 10.4% of I-NICM patients (p=0.008). The composite endpoint of LVAD, OHT, or death was significantly different between F-NICM and I-NICM, occurring in 45.8% vs 21.5% of patients respectively (p=0.004). After multivariate analysis, F-NICM was the only independent predictor of the composite endpoint. The Kaplan-Meier survival estimates for the composite endpoint was significantly lower in F-NICM as compared to I-NICM (Figure 1). Conclusion : In patients with NICM, the family history and/or a positive gene test for cardiomyopathy is a powerful predictor of the composite end point of death, LVAD implantation, or OHT. Risk stratification of nonischemic dilated cardiomyopathic (NICM) patients is challenging due to the large heterogeneity in disease phenotype, genetic background, and poorly characterized progression of disease. We postulated that patients with familial NICM (F-NICM, operationally defined as a strong family history or genetically proven) carry a significantly worse prognosis than nonfamilial/idiopathic NICM (I-NICM) patients for the composite endpoint of death, left ventricular assist device (LVAD) placement, or orthotopic heart transplantation (OHT). A total of 127 consecutive patients, 52 F-NICM and 85 I-NICM, with implanted cardiac defibrillators (ICDs) or cardiac resynchronization devices (CRT) were studied. F-NICM patients were identified from the cardiovascular genetics clinic. Patients were followed for a mean of 6.1 +/- 5.1 years for cardiovascular outcomes: death, LVAD, or OHT. There were no significant differences regarding incidence of diabetes, hypertension, NYHA functional class, use of guideline directed medical therapy (GDMT), use of CRT, ICD shocks, or years of follow-up. Patients with F-NICM were significantly younger as compared to I-NICM group (45.8 +/- 15.8 years vs. 61.2 +/- 17 years, p=0.001). Mean ejection fraction (EF) was not significantly different between F-NICM and I-NICM; 31.2 +/- 14.5% vs. 31.6 +/- 12.2%. Thirty percent (30%) of F-NICM patients underwent LVAD implant or OHT as compared to 10.4% of I-NICM patients (p=0.008). The composite endpoint of LVAD, OHT, or death was significantly different between F-NICM and I-NICM, occurring in 45.8% vs 21.5% of patients respectively (p=0.004). After multivariate analysis, F-NICM was the only independent predictor of the composite endpoint. The Kaplan-Meier survival estimates for the composite endpoint was significantly lower in F-NICM as compared to I-NICM (Figure 1). : In patients with NICM, the family history and/or a positive gene test for cardiomyopathy is a powerful predictor of the composite end point of death, LVAD implantation, or OHT.

Patients' perception on the quality of care for multiple endocrine neoplasia disorders in Europe: an online survey from a patient support group.

European Patient Advocacy Groups (ePAGs) within the Endo-ERN identified a lack of knowledge about quality of care (QoC) of patients with multiple endocrine neoplasia (MEN). The aim of this study was to identify inequalities in care and to encourage improvements. The European MEN Alliance (EMENA) developed and conducted a survey, using the European Commissions' EUSurvey platform. Patient groups and healthcare professionals (HCPs) distributed the survey. A total of 288 participants completed the survey (MEN1 n = 203, MEN2 n = 67, MEN3 n = 18) from 18 European countries. The majority of respondents were recruited via patient groups (58%), aged between 41 and 60 years (53%) and were female (67%). All participants reported having been diagnosed on average 5.58 years (95%-CI: 4.45-6.60) after first symptoms occurred. This timeframe was lower in the group with MEN2 (2.97 years, 95%-CI: 1.37-4.57). Most of the participants (67%) received their diagnosis by a positive gene test after presenting with one or more MEN-related tumours. Overall QoC was rated as either "good" (43%) or "excellent" (36%). The results of this unique Europe-wide, patient-driven survey on QoC of patients with MEN show that ratings for overall QoC were lower than ratings for different aspects of care. This may be because of the complex nature of care for genetic syndromes. Furthermore, patients who connect with patient groups may be deemed "expert patients" whose answers are not representative of the overall MEN patient community. We hope that Endo-ERN can support further education and training for HCPs based on these results.

Multicenter study of the clinical features and mutation gene spectrum of Chinese children with Dent disease.

Dent disease is a rare X-linked recessive inherited tubular disease. In this multicenter study, the clinical presentation and genetic background of Chinese children with Dent disease are studied to improve the cognition and diagnostic ability of pediatricians. In this prospective cohort, we described the genotype and phenotype of a national cohort composed of 45 pediatric probands with Dent disease belonging to 45 families from 12 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system. The CLCN5 gene from 32 affected families revealed 28 different mutations. The OCRL gene from 13 affected families revealed 13 different mutations. The incidence of low-molecular-weight proteinuria (LMWP) in both Dent disease type 1 populations and Dent disease type 2 populations was 100.0%; however, the incidence of other manifestations was not high, which was similar to previously reported data. Therefore, LMWP is a key clinical feature that should alert clinicians to the possibility of Dent disease. A high amount of LMWP combined with positive gene test results can be used as the diagnostic criteria for this disease. The diagnostic criteria are helpful in reducing the missed diagnosis of this disease and are beneficial for protecting the renal function of these patients through early diagnosis and early intervention.

Chapter 10 - The psychopharmacology of Huntington disease

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded cytosine-adenine-guanine triplet repeat in the huntingtin gene. The current diagnosis is based on the presence of typical motor signs in combination with a positive gene test. The motor onset of the disease is usually between 30 and 50 years of age, and the disease then progresses over around 20 more years. Nonmotor symptoms and signs such as cognitive decline, metabolic dysfunction, sleep disturbances, as well as psychiatric symptoms are common and can occur many years before motor onset. Psychiatric symptoms include irritability, apathy, depression, anxiety, and OCD. Although there exist no disease-modifying treatment, available pharmacologic drugs often offer significant symptom relief and improve quality of life. Today, there are only two drugs that are approved by the US Food and Drug Association for the treatment of HD. These are the dopamine-depleting drugs tetrabenazine and deutetrabenazine that both target motor symptoms. The current status of best clinical practice for HD is based on expert opinions as well as evidence and/or experience of treating similar symptoms in other conditions. In this chapter, we provide an overview of the complex clinical manifestations of HD and the commonly used psychopharmacologic treatments.

Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection.

Previous studies describing genetics evaluation in spontaneous coronary artery dissection (SCAD) have been retrospective in nature or presented as single case reports. As part of a dedicated clinical program, we evaluated patients in cardiovascular genetics clinic to determine the role of genetically triggered vascular disease and genetic testing in SCAD. Patient data were entered prospectively into the Massachusetts General Hospital SCAD registry database from July 2013 to September 2017. Clinically indicated genetic testing was conducted based on patient imaging, family history, physical examination, and patient preference. Of the 107 patients enrolled in the registry, 73 underwent cardiovascular genetics evaluation at our center (average age, 45.3±9.4 years; 85.3% female), and genetic testing was performed for 44 patients. A family history of aneurysm or dissection was not a prevalent feature in the study population, and only 1 patient had a family history of SCAD. Six patients (8.2%) had identifiable genetically triggered vascular disease: 3 with vascular Ehlers-Danlos syndrome (COL3A1), 1 with Nail-patella syndrome (LMX1B), 1 with autosomal dominant polycystic kidney disease (PKD1), and 1 with Loeys-Dietz syndrome (SMAD3). None of these 6 had radiographic evidence of fibromuscular dysplasia. In this series, 8.2% of the SCAD patients evaluated had a molecularly identifiable disorder associated with vascular disease. The most common diagnosis was vascular Ehlers-Danlos syndrome. Patients with positive gene testing were significantly younger at the time of their first SCAD event. A low threshold for genetic testing should be considered in patients with SCAD.

To Treat or Not to Treat: A Therapeutic Dilemma in a Gene Positive, Phenotypic Negative CPVT Woman Throughout Her Pregnancies

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterised by polymorphic VT, which may cause palpitations, syncope or sudden death, often triggered by exercise or emotion, in the absence of structural heart disease. The mainstay of therapy is high dose beta blockade. Implantable defibrillators are considered, if prior cardiac arrest. There are isolated case reports of patients with CPVT experiencing pregnancy. We describe the treatment challenges in a 23-year-old woman with RyR2 gene mutation, but no prior symptoms, during three consecutive pregnancies. She was diagnosed through cascade testing, following a cousin's arrest. Atenolol was commenced at 24 weeks’ gestations after the positive gene test, given a stress test revealed rare VPCs. She had an elective Caesarean section given a prior spinal fusion. A 2.75 kg growth-restricted baby was born at 39 weeks. The patient self-ceased atenolol, and remained off therapy in her second pregnancy given low birth weight of her first child. At 39 weeks, a repeat Caesarean section delivered a healthy 3.21 kg baby. Her third pregnancy was uncomplicated, also off therapy, and she delivered a 2.93 kg baby at 39 weeks. There were no cardiac symptoms reported. Conclusion: This case demonstrates the clinical dilemma faced in gene positive, phenotypic negative women undergoing pregnancy, where beta blockers are recommended, but patient declines due to baby growth issues.

34 Hour QT analysis in the prediction of genotype positivity in suspected LQTS: a study in both proband and family screening populations

Introduction LQTS is an inheritable condition with a suspected prevalence on 1/2000 and has a risk of sudden cardiac death due to ventricular arrhythmia if untreated. 24 hour QT analysis is a method of averaging QT measurements obtained via holter monitoring over a 24 hour period. The utility of 24 hour QT analysis to predict genotype positivity has not been widely studied. Methods 28 probands with genetic testing results and 107 first degree relatives of genotyped LQTS patients were included in the analysis. Retrospective review of the medical charts of all patients was performed. Parameters analysed included corrected QT (QTc) interval on 12 lead ECG, 24 hour ambulatory ECG, the QTc after 4 minutes of recovery post exercise stress testing (EST), and the Schwartz score based on clinical and ECG criteria. All these parameters were then compared to the results of subsequent genetic testing. Results 28 probands were analysed with 7 returning a positive gene test and 21 returning a negative gene test. Gene positive individuals had significantly greater QTc by resting ECG (p = 0.047), 24 hour ECG (p = 0.005) and after 4 minutes recovery post EST (p = 0.001) (independent t-test). Using standard cut offs (450 ms for males and 460 ms for females) the association between clinically positive resting ECG and positive genotype was not statistically significant (p = 0.17). Schwartz score >3.5 showed no significant difference between gene positive and gene negative groups (p = 0.33). 24 hour QTc (p = 0.029) was significantly associated with positive genotype and QTc at 4 minutes recovery post EST showed a trend toward significance (p = 0.069). Of 107 first degree relatives of LQTS cases there were 50% gene positive cases. There were statistically significant differences between gene positive and gene negative family members in QTc (p 3.5 was 98% specific for genotype positive LQTS but this test had a very low sensitivity of 29%. The most sensitive test was 24 hour QTc with a cut off of 450 ms for males and 460 ms for females with a sensitivity of 69% and specificity of 83%. Conclusions Family screening and prevention of sudden cardiac death is central to the management of LQTS. Current individual clinical testing methods are not sufficiently sensitive to diagnose LQTS alone and must be used in combination to assess the risk of LQTS. 24 hour QT analysis is the most sensitive method of predicting positive genotype in both probands and family members of affected individuals.

Mentalizing in preclinical Huntington’s disease: an fMRI study using cartoon picture stories

Huntington's disease (HD) is an autosomal dominant degenerative brain disorder that is characterized by motor, cognitive and affective symptoms. Previous research has shown that patients with HD, similar to patients with schizophrenia, are impaired in their ability to appreciate the mental states of others. Functional brain imaging studies have shown that patients with schizophrenia underactivate the neural network involved in mentalizing, and that deviant patterns of brain activation are also present in individuals at high risk of developing a psychotic disorder. Accordingly, the present study sought to examine the brain activation in premanifest mutation carriers for HD. Thirty premanifest mutation carriers (13 males) defined by a positive gene test and absence of unequivocal HD symptoms ("pre-HD") performed a cartoon mentalizing task during functional brain imaging. For comparison, a group of 26 healthy controls took part in the study. BOLD responses revealed that pre-HD subjects activated the mentalizing network comprising prefrontal, temporoparietal and parietal brain regions during task performance. A comparison between pre-HD patients and healthy controls revealed no significant activation differences. Premanifest mutation carriers of HD activated the neural network involved in mentalizing similar to healthy control subjects. This suggests that impaired mentalizing emerges with the clinical manifestation of the disease, but is not necessarily part of the pre-manifest stage.

Imaging Phenotype Versus Genotype in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common monogenetic cardiac disease with a prevalence of 0.2%1 that usually is inherited as an autosomal dominant trait with variable penetrance and expression. Clinically, HCM is defined by the presence of left ventricular (LV) hypertrophy (LVH) unexplained by abnormal loading conditions.1 The natural history varies from an asymptomatic course to drug-refractory angina/dyspnea, sudden cardiac death (SCD), and end-stage heart failure. The incidence of HCM-related SCD is approximately 1% to 2% in children and adolescents and 0.5% to 1% in adults.2,3 In this review, we examine the impact of advanced diagnostic imaging technologies on HCM, with particular emphasis on the detection of particular genetic subtypes. In ≈60% of cases, HCM is inherited as an autosomal dominant trait caused by mutations in genes coding for cardiac sarcomere proteins (Figure 1).4–7 Mutations in genes encoding Z-disc proteins and proteins involved in calcium regulation account for <5% of cases. The absence of sarcomeric gene mutations can be explained by limitations of current mutation detection techniques or mutations in as yet unidentified genes, but in some cases, hypertrophy is caused by other diseases that mimic the phenotype of sarcomeric protein disease. Table 1 lists genetic disorders associated with HCM. Figure 1. A schematic illustration of a cardiac sarcomere. View this table: Table 1. Currently Known Genes Implicated in HCM More than 600 different sarcomeric gene mutations are reported in patients with HCM.8–16 The majority are missense mutations, but nonsense, frameshift, and in-frame insertion/deletion mutations also occur. Most mutations are characterized by incomplete penetrance and variable clinical expression likely due to locus heterogeneity and the effect of mutations at different locations within the same gene. Most mutations probably have a dominant negative effect on sarcomere function, but in some cases, haploinsufficiency (ie, only a single functional …

Estimating probability of germline mismatch repair mutations in colorectal cancer patients with microsatellite stable tumors

identified in patients from families that met the Amsterdam Criteria (AC I/II), whereas 3 mutations were found in patients from families that were AC I/II negative. The modified likelihood for a germline mutation (+LRmod )i n an AC I/II patient was 1.56 (95% CI: 0.47 - 5.18) and the modified negative likelihood ratio (-LRmod )f or ap atient not meeting the AC I/II criteria was 0.81 (95% CI: 0.39 1.69). We quantified the meaning of the AC I/II criteria to guide clinical choices about genetic testing in MSS tumors by multiplying the pretest odds by the +LRmod and the -LRmod. The probability of a mutation was modified from a baseline of 11.4% to 16.7% in AC I/II families, compared to 9.4% in AC I/II-negative families. Conclusions Germline MMR testing in high risk patients with MSS colorectal tumors identifies mutations in a small, but meaningful proportion of patients. The diagnostic yield is dependent on the strength of the family history. Modified likelihood ratios can be helpful to quantify the probability of a positive gene test for Lynch Syndrome, and can be applied to pre-test probabilities derived from clinical models.

EXTRAPYRAMIDAL SIGNS ARE A COMMON FEATURE OF SPINOCEREBELLAR ATAXIA TYPE 17

Spinocerebellar ataxia type 17 (SCA17) is a CAG repeat expansion disorder in the TATA-binding protein (TBP) gene.1 Previous studies have shown that SCA17 is a rare cause of ataxia, especially in the East.2,3 SCA17 may show nonataxic manifestations, such as choreic movement, cognitive decline, dystonia, parkinsonism, and pyramidal tract signs. Previously we reported that SCA17 is not rare among our parkinsonian patients (0.9%).4 Thus, we examined the frequency of SCA17 among Korean patients with ataxia or chorea as a main phenotype. ### Methods. Gene samples obtained from the Movement Disorder Gene Bank of Seoul National University Hospital collected until April 2007 were analyzed. All patients were native Koreans. Written informed consent was obtained from all subjects before blood sampling for gene studies, and the genetic study was approved by our Institutional Review Board. Patients with a positive gene test for SCA1, 2, 3, 6, 7, dentatorubropallidoluysian atrophy, or Huntington disease (HD) were excluded. In both groups, acquired causes were excluded. We did not exclude the patients with familial history of ataxia or chorea. Finally, 661 ataxia patients and 98 chorea patients were included (2 patients had both ataxia and chorea). The method of gene analysis used is described in the previous report.4 ### Results. The 2 patients with both ataxia and chorea were found to have …

Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities

The ground-breaking discovery of genotype-phenotype relationships in hereditary medullary thyroid cancer has greatly facilitated early prophylactic thyroidectomy. Its timing depends not solely on a positive gene test but, more importantly, on the type of the REarranged during Transfection (RET) mutation and its underlying mode of RET receptor tyrosine kinase activation. In the past decade, the therapeutic corridor opened by molecular information has been defined down to a remarkable level of detail. Based on mutational risk profiles, preemptive thyroidectomy is recommended at 6 months of age for carriers of highest-risk mutations, before the age of 5 years for carriers of high-risk mutations, and before the age of 5 or 10 years for carriers of least-high-risk mutations. Additional lymph node dissection may not be needed in the absence of increased preoperative basal calcitonin levels. Better comprehension of RET function should enable the design of targeted therapies for RET carriers beyond surgical cure in whom the DNA-based 'window of opportunity' has been missed.

Oncogenes (and tumour suppressors) in endocrine tumours - current diagnostics and future approaches

The rapid discovery of genetic changes associated with neoplasia has been successfully translated to clinical practice for several inherited endocrine tumour syndromes. These gene tests have current applications in diagnosis, presymptomatic detection, prognosis, and tumour subclassification, and are likely to allow for targeted therapies (pharmacogenomics) in the near future. Gene tests are available for the familial syndromes: multiple endocrine neoplasia type 1 (MENIN), type 2 (RET), hyperparathyroidism-jaw tumour syndrome (HRPT2), neurofibromatosis type 1 (NF1), von Hippel Lindau disease (VHL) and the phaeochromocytoma/paraganglioma syndromes caused by mutations in the genes encoding the succinate dehydrogenase subunits B, C and D (SDHB, SDHC, SDHD, respectively). Arguably, targeted gene testing should be offered for all cases of medullary thyroid cancer, all parathyroid cancers and all phaeochromocytomas. A positive gene test establishes a molecular diagnosis and permits screening and early treatment for affected family members. For several of these gene tests, a positive result identifies additional risk for multiorgan disease requiring ongoing clinical surveillance. In addition to the above germline DNA tests, testing somatic (tumour) DNA may be clinically valuable in several scenarios such as for BRAF mutations in papillary thyroid cancers. The future for molecular diagnostics will include high-throughput mutation detection combined with improved genotype-phenotype correlations. The rapid discovery of genetic changes associated with neoplasia has been successfully translated to clinical practice for several inherited endocrine tumour syndromes. These gene tests have current applications in diagnosis, presymptomatic detection, prognosis, and tumour subclassification, and are likely to allow for targeted therapies (pharmacogenomics) in the near future. Gene tests are available for the familial syndromes: multiple endocrine neoplasia type 1 (MENIN), type 2 (RET), hyperparathyroidism-jaw tumour syndrome (HRPT2), neurofibromatosis type 1 (NF1), von Hippel Lindau disease (VHL) and the phaeochromocytoma/paraganglioma syndromes caused by mutations in the genes encoding the succinate dehydrogenase subunits B, C and D (SDHB, SDHC, SDHD, respectively). Arguably, targeted gene testing should be offered for all cases of medullary thyroid cancer, all parathyroid cancers and all phaeochromocytomas. A positive gene test establishes a molecular diagnosis and permits screening and early treatment for affected family members. For several of these gene tests, a positive result identifies additional risk for multiorgan disease requiring ongoing clinical surveillance. In addition to the above germline DNA tests, testing somatic (tumour) DNA may be clinically valuable in several scenarios such as for BRAF mutations in papillary thyroid cancers. The future for molecular diagnostics will include high-throughput mutation detection combined with improved genotype-phenotype correlations.

Oncogenes (and tumour suppressors) in endocrine tumours – current diagnostics and future approaches

The rapid discovery of genetic changes associated with neoplasia has been successfully translated to clinical practice for several inherited endocrine tumour syndromes. These gene tests have current applications in diagnosis, presymptomatic detection, prognosis, and tumour subclassification, and are likely to allow for targeted therapies (pharmacogenomics) in the near future. Gene tests are available for the familial syndromes: multiple endocrine neoplasia type 1 ( MENIN ), type 2 ( RET ), hyperparathyroidism-jaw tumour syndrome ( HRPT2 ), neurofibromatosis type 1 ( NF1 ), von Hippel Lindau disease ( VHL ) and the phaeochromocytoma/paraganglioma syndromes caused by mutations in the genes encoding the succinate dehydrogenase subunits B, C and D ( SDHB , SDHC , SDHD , respectively). Arguably, targeted gene testing should be offered for all cases of medullary thyroid cancer, all parathyroid cancers and all phaeochromocytomas. A positive gene test establishes a molecular diagnosis and permits screening and early treatment for affected family members. For several of these gene tests, a positive result identifies additional risk for multi-organ disease requiring ongoing clinical surveillance. In addition to the above germline DNA tests, testing somatic (tumour) DNA may be clinically valuable in several scenarios such as for BRAF mutations in papillary thyroid cancers. The future for molecular diagnostics will include high-throughput mutation detection combined with improved genotype-phenotype correlations.

Decoding cryptogenic cardioembolism

Decoding cryptogenic cardioembolism

Perceptions of discrimination among persons who have undergone predictive testing for Huntington's disease

Potential discrimination from genetic testing may undermine technological advances for health care. Researching long-term consequences of testing for genetic conditions that may lead to discrimination is a public health priority. The consequences of genetic discrimination generate social, health, and economic burdens for society by diminishing opportunities for at-risk individuals in a range of contexts. The current study objective was to investigate perceptions of genetic stigmatization and discrimination among persons who completed predictive testing for Huntington's disease (HD). Using semi-structured interviews and computerized qualitative analysis, the perceptions of 15 presymptomatic persons with a positive gene test predicting HD were examined with regard to differential treatment following testing. The sample comprised 11 women and 4 men, mostly married (73%), aged between 22 and 62 years, with an average education of 14.6 years (SD +/- 2.57) and residing in urban, rural and suburban settings of eight U.S. States. Participants reported perceptions of consequences following disclosure of genetic test results in three areas: employment, insurance, and social relationships. Although most employed participants (90%) revealed their test results to their employers, nearly all reported they would not disclose this information to future employers. Most (87%) participants disclosed test results to their physician, but a similar majority (83%) did not tell their genetic status to insurers. Most participants (87%) disclosed test results to family and peers; patterns of disclosure varied widely. Discrimination concerns remain high in this sample and point to the need for more information to determine the extent and scope of the problem.

Risk and risk assessment for breast cancer: Molecular and clinical aspects

Chemoprevention, prophylactic surgery and intensified screening programs are options which can be offered the patients with an increased lifetime risk (p(life)) for breast cancer (BC). Estimation of p(life) includes BRCA mutation analysis and risk estimation based on individual risk factors and family history. MENDEL and BRCAPRO are models which can estimate mutation carrier status probability (p(mut)), p(life) and p(mut) can be estimated using Cyrillic3 software which incorporates BRCAPRO and MENDEL. To integrate age, hormonal factors and benign breast biopsies in risk assessment the Tyrer–Cuzick model can be used. These models support the decision pro or contra genetic analysis and improve the number of positive gene testing results. Estimations of p(life) and p(mut), based on a mathematical model, should deal with algorithms and penetrance/frequency data adequate to the population counselled. Being the main modulatory factors, reproductive/hormonal data should be incorporated like the Tyrer–Cuzick model does.

P0082 PP A PROSPECTIVE STUDY TO DIAGNOSE ADULT-TYPE HYPOLACTASIA BY CORRELATING RESULTS OF HYDROGEN BREATH TESTING AND DETERMINATION OF LACTASE-NONE PERSISTENCE GENE.

Introduction: Adult primary lactase deficiency also known as lactase non-persistence is a common autosomal recessive condition that can give rise to symptoms mainly in adolescents and early childhood. Lactose breath hydrogen test (BHT) is used most commonly for the diagnosis of lactose malabsorption. Recent studies have shown that the DNA variant C/C-13910 located upstream from the LCT locus is associated with lactase nonpersistence due to a defect in the expression of the lactasephlorizin hydrolase. We conducted a prospective study to diagnose lactose intolerance by correlating results of genetic testing for the C/T-13910 variant and lactose BHT. Methods: 26 patients (15 females, 10 males, mean age 10.7yr) seen in the Gastroenterology clinic at Children’s Hospital of Michigan for possible lactose intolerance were tested by standard BHT after ingestion of 2 gram/Kg lactose (maximum 25 gm). Same patients were also tested for presence of the C/T-13910 variant using specific restriction enzyme digest assays (Prometheus Laboratories) at the time of blood draw for routine laboratories. Results: (Table 1). Ten patients had a positive hydrogen test, and 16 were negative. C/C-13910 variant was detected in all patients with positive BHT. Three patients had a negative BHT but positive gene test. Those three patient showed arise in breath hydrogen concentration but was <10 PPM over baseline, and none reported any symptoms after lactose ingestion Thirteen patients were negative for both BHT and gene tests. Based on these data, positive predictive value, negative predictive value, sensitivity and specificity of gene test compared to lactose BHT were 77%, 100%, 100% and 81% respectively.Table 1: Results of lactose BHT test and gene testConclusion: Analysis of T/C-13910 variant is a reliable test to diagnose adult-onset hypolactasia with a high certainty for the rule out of genetically based lactose intolerance syndrome. However, further studies are needed in this ongoing study to understand the reliability of genetic testing in low- or non-hydrogen producers. Financial Disclosure (put None if not applicable): None

Comprehensive genetic counseling for families at risk for HNPCC: impact on distress and perceptions.

The aim of the study was to explore distress and health beliefs before and after comprehensive interdisciplinary counseling in families at risk for hereditary non-polyposis colorectal cancer (HNPCC). Results reported here were derived from a consecutive sample of 65 counselees [31 patients with colorectal cancer (CRC) and 34 unaffected at-risk persons] who participated in interdisciplinary counseling provided by human geneticists, surgeons, and psycho-oncologists before genetic testing. Data were collected from self-administered questionnaires before, as well as 4-6 weeks after, counseling. Distress and perceptions specific to HNPCC were assessed at both timepoints using standardized as well as author-derived instruments. Distress declined after counseling, as did worries related to HNPCC. An increase was found in personal belief in control of cancer risk, for instance, in the perceived efficacy of early detection of CRC. We also observed a trend toward greater anticipated ability to cope with a positive gene test after counseling. Changes after counseling were generally more pronounced for persons at risk, as compared to patients with cancer. The decrease in distress was partly attributable to an increase in personal self-confidence. One-third of the sample reported enhanced communication specific to hereditary disease within the family after counseling. A substantial minority, however, said they experienced increased worry and physical symptoms after counseling. Overall, counselees demonstrated less stress and perceived cancer threat as well as enhanced beliefs regarding personal control over cancer, suggesting an overall beneficial impact of comprehensive counseling. Further research is needed to identify those individuals most at risk for increased fear and worry related to HNPCC so that they may be most appropriately counseled.