Family History Data Research Articles

Prevalence and risk factors of thyroid-associated ophthalmopathy among Indians

Background: Thyroid-associated ophthalmopathy (TAO) is a part of an autoimmune process that can affect the orbital and periorbital tissue, the thyroid gland, and, rarely, the pretibial skin or digits. The aim of the present study was to determine the prevalence of TAO among Indian patients with thyroid dysfunction and the risk factors associated with TAO. Methods: A cross-sectional study of thyroid eye disease was conducted on patients with thyroid dysfunction visiting the outpatient department of a tertiary care centre. Demographic data, past medical history, family history, and life-style data were collected from all patients. An ophthalmologist interviewed the patients and noted the presence of symptoms and signs relevant to thyroid eye disease. Results: Out of a total of 100 patients, who were eligible for analysis, 80 were diagnosed with mild to moderate TAO and 20 were diagnosed with severe TAO. There were more male patients in patients with a severe course (50%) compared to those with a mild to moderate course (42.5%). More patients with a severe course were smokers compared to those with a mild to moderate course (chi-square test, p=0.021). More patients with a severe course had a higher clinical activity score (p=0.007). Conclusions: We have confirmed that smoking is the strongest risk factor for development of a severe course of TAO in Indian patients. Thus, it is important for patients with Graves' disease to refrain from smoking.

Clinical and allelic heterogeneity in a pediatric cohort of 11 patients carrying MFN2 mutation

IntroductionThe Mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein, is known to be the first cause of autosomal dominant Charcot–Marie–Tooth disease type 2 (CMT2) with early onset. This gene is involved in typical CMT2A and in more atypical phenotypes as optic atrophy or spastic paraplegia. CMT2 refers to inherited axonal polyneuropathy, which associates progressive peripheral motor and sensory neuropathy, a family history consistent mainly with autosomal dominant inheritance, and normal nerve conduction velocities. SubjectsBetween 1999 and 2012, the genetic diagnosis of MFN2 mutation was made in 11 children who were treated in our department for different neurological symptoms. All data including family and personal history data, results of standardized clinical and electrophysiology testing, brain magnetic resonance imaging (MRI), neuro-ophthalmic evaluation, muscle biopsy histopathology and molecular diagnosis were retrospectively analyzed. ResultsFive different mutations were found in 6 unrelated families. Three of them have previously been described; the two remaining are new mutations: one of them related a new phenotype.Clinical signs appeared before the age of 6years in more than half of the patients (54%). The motor deficit was predominant in 8 patients (72%). Two children presented an acute onset of disease that stabilized afterwards; the other children showed a more progressive deterioration that was managed symptomatically. ConclusionThis large pediatric study describes a great interfamilial and intrafamilial phenotypic variability. We recommend screening this gene in pediatric patient with chronic neurologic symptoms such as motor deficit or optic atrophy but also in acute neurologic deficiencies such as subacute polyradiculoneuritis.

The IGNITE network: a model for genomic medicine implementation and research.

BackgroundPatients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility.MethodsTo address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches.ResultsThis paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years.ConclusionsThe IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.

Universal Screening for Familial Hypercholesterolemia in Children

BackgroundIndividuals with familial hypercholesterolemia (FH) who are untreated have up to 100-fold elevated risk for cardiovascular complications compared with those who are unaffected. Data for identification of FH with a universal screening for hypercholesterolemia in children are lacking. ObjectivesThis study sought genetic identification of FH from a cohort of children with elevated serum total cholesterol (TC) concentration, detected in a national universal screening for hypercholesterolemia. MethodsSlovenian children born between 1989 and 2009 (n = 272) with TC >6 mmol/l (231.7 mg/dl) or >5 mmol/l (193.1 mg/dl) plus a family history positive for premature cardiovascular complications, identified in a national universal screening for hypercholesterolemia at 5 years of age were genotyped for variants in LDLR, PCSK9, APOB, and APOE. ResultsOf the referred children, 57.0% carried disease-causing variants for FH: 38.6% in LDLR, 18.4% in APOB, and none in PCSK9. Nine novel disease-causing variants were identified, 8 in LDLR, and 1 in APOB. Of the remaining participants, 43.6% carried the APOE E4 isoform. Estimated detection rate of FH in the universal screening program from 2009 to 2013 was 53.6% (95% confidence interval [CI]: 34.5% to 72.8%), peaking in 2013 with an upper estimated detection rate of 96.3%. Variants in LDLR, APOB, or the APOE E4 isoform occurred in 48.6%, 60.0%, and 76.5%, respectively, of patients with a family history negative for cardiovascular complications. ConclusionsMost participants who were referred from a national database of universal screening results for hypercholesterolemia had genetically confirmed FH. Data for family history may not suffice for reliable identification of patients through selective and cascade screening.

Patients with familial abdominal aortic aneurysms are at increased risk for endoleak and secondary intervention following elective endovascular aneurysm repair

A recent investigation has documented an increased risk of aneurysm-related complications after endovascular aneurysm repair (EVAR) of familial abdominal aortic aneurysms (fAAAs). We hypothesized that fAAA patients are not at increased risk for complications following open AAA repair or EVAR when compared with sporadic abdominal aortic aneurysm (spAAA) patients. To this end, we performed a single institution retrospective review. Epidemiologic data were collected through the electronic medical record. Family history data were obtained from a questionnaire administered at the initial vascular surgery consultation. Major adverse events were defined as myocardial infarction, respiratory failure, renal failure, bowel ischemia, limb ischemia, multisystem organ failure, intracranial hemorrhage, paraplegia, hemorrhage, or death. Endoleaks were classified in accordance with the standardized reporting practices of the Society for Vascular Surgery. AAA-related complications were defined as the need for a secondary intervention due to endoleak, limb ischemia, or postimplantation rupture. A total of 392 patients with complete clinical data underwent elective AAA repair from 2004 to 2014. Of these 392 patients, 89 (23%) were classified as fAAA patients and 303 (77%) were classified as spAAA patients. With the exception of increased rates of chronic obstructive pulmonary disease (P= .0009) and pack-years smoked (P= .03) in spAAA patients, demographics did not differ. Sixty-two percent (n= 55) of fAAA patients and 68% (n= 205) of spAAA patients underwent EVAR (P= .30). fAAA patients did not incur any significant difference in major adverse events following open AAA repair (fAAA, 9% vs spAAA, 11%; P= .75). Additionally, fAAA patients did not incur any significant difference in major adverse events following EVAR (fAAA, 4% vs spAAA, 5%; P= .70). Patients with fAAA did have a significantly increased rate of endoleak (fAAA, 24% vs spAAA, 12%; P= .03) and secondary intervention following EVAR (fAAA, 21% vs spAAA, 12%; P= .04). The current study shows that patients with fAAA do not have increased perioperative morbidity following open or endovascular AAA repair. However, patients with fAAA do have an increased risk of endoleak and secondary intervention following EVAR. These findings suggest that EVAR and open AAA repair are both safe and effective for fAAA patients. The increased rate of endoleak and secondary intervention in patients with fAAA suggests that this subpopulation may benefit from closer post-EVAR surveillance or open surgical repair in good risk patients.

Abstract 3449: Risk for death from prostate cancer predicted from complete family history of lethal prostate cancer

Abstract Background: Familial relative risks (RR) for death from prostate cancer (lethal prostate cancer or LPC) are rare. Most risk estimations are for diagnosis of prostate cancer (PC); and typically focus on close relatives, rather than on complete family history. This study provides RRs for LPC based on specific family history data of LPC obtained from a statewide Cancer Registry linked to genealogy data. The risk estimates presented avoid common recall, recruitment, and ascertainment biases, and provide more individualized risk estimates. Methods: We used a population-based resource to estimate RRs for LPC based on a full constellation of family history of LPC. We include complete family history, taking into account degree of relationship (first to third-degree), age at diagnosis, paternal or maternal family history, number of affected individuals, and age at diagnosis of youngest relative. Estimations of RR for LPC based on specific family history are informative for patients and clinicians for appropriate screening decisions. The Utah Population Data Base (UPDB), a computerized population genealogical resource linked to a statewide SEER cancer registry, and statewide death certificates was analyzed. Over 1 million individuals were analyzed. All males with specific constellations of LPC were identified in the UPDB (probands) and the observed number of LPC cases among these probands was compared to the expected number using internal cohort-specific rates to obtain RR estimates. Results: Over 3,921 LPC cases were identified. Risk for LPC was significantly elevated with each additional LPC first-degree relative (FDR), ranging from RR = 2.26 (95% CI: 2.09, 2.44) for >0 FDRs to RR = 3.93 (1.69, 7.73) for >2 FDRs affected. Even in the absence of FDR family history, significantly increased risk for LPC was observed in the presence of >0 second degree relatives (SDR) affected (RR = 1.53: 1.41, 1.66). In the absence of affected FDRs and SDRs, there was significantly increased risk for LPC for >1 third degree relative (TDR) affected (RR = 1.22: 1.15, 1.29). Results indicated higher risks for maternal vs paternal history, e.g. RR = 1.50 (1.27, 1.76) for affected paternal uncle versus RR = 1.83 (1.59, 2.09) for affected maternal uncle. Discussion: RRs for LPC have more clinical significance than RRs for PC. This study provides unbiased, population-based estimates of LPC risk based on a man's specific family history LPC constellation. Many individuals at 2-3 times increased risk for dying from PC were identified based on family history. This study provides a means for containing healthcare costs and conserving resource utilization through informed use of familial LPC risks. Using informative LPC family history in the planning of screening, treatment, and monitoring opens additional avenues for implementation of more sound translational medicine practices, decreasing morbidity and mortality, and improving the quality of life in patients. Citation Format: Frederick S. Albright, Neeraj Agarwal, William T. Lowrance, Robert A. Stephenson, Lisa A. Cannon-Albright. Risk for death from prostate cancer predicted from complete family history of lethal prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3449. doi:10.1158/1538-7445.AM2015-3449

Long-term impact of divorce on women's earnings across multiple divorce windows: A life course perspective

Abstract We investigate divorce as a turning point for women's earnings trajectories and whether those patterns have changed over recent decades. We use a unique data set that links retrospective family history data from the Survey of Income and Program Participation to longitudinal earnings records from the Social Security Administration. Using a panel fixed-effects model, we retrospectively compare women experiencing a marital dissolution across three divorce windows within a 25-year period (1970–1994) to continuously married women, from 3 years before to 10 years following separation. We find that women who divorced experienced long-lasting earnings increases, particularly among those who did not remarry. The increases in earnings levels are comparatively similar for those divorced at different times; however, percentage increases are significantly smaller for women experiencing divorce in more recent (1990–1994) relative to earlier (1970–1974) years. We also document lasting employment gains and higher earnings among employed women arising from divorce. In combination, the results extend our understanding of divorce as a salient turning point in women's work lives and call attention to possible changes in this process over recent decades.

BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study.

Male breast cancer (MBC) is a rare disease that represents <1% of all breast cancers (BCs). We analyze the results of a multicenter study performed in Spanish familial MBC including family history of hereditary breast and ovarian cancer syndrome (HBOCS) and clinicopathological features. We also study the relationship between BRCA1/BRCA2 mutational status in male relatives affected with cancer (MAC) and, family history and tumor types. The study included 312 men index cases with family history of HBOCS and 61 MAC BRCA1/2 mutation-carriers. Family history, histological grade (HG), clinicopathological and immunohistochemistry data were collected. BRCA1/2 mutation analyses were performed by direct sequencing or screening methods and the large rearrangements by multiplex ligation dependent probe amplification. We found 49 mutation-carriers (15.7%), 95.9% with BRCA2 mutations. BRCA2 mutation-carriers were associated with families with at least one MBC and one BC in female (type II; p = 0.05). Strong association were found between the presence of pathogenic mutations in MBCs and the advanced HG (p = 0.003). c.658_659delTG, c.2808_2811delACAA, c.6275_6276delTT and c.9026_9030delATCAT were the most prevalent mutations. In 61 MAC we found 20 mutations in BRCA1 and 41 in BRCA2. For MAC we show that mutational status was differentially associated with family history (p = 0.018) and tumor type, being BRCA2 mutations linked with BC and prostatic cancer (p = 0.018). MBC caused by BRCA1/2 mutations define two types of MBCs. The most frequent caused by BRCA2 mutation linked to type II families and the rarest one attributed to BRCA1 mutation. Tumor associated with MAC suggest that only BRCA2 mutations have to do with a specific type of cancer (BC and prostatic cancer); but the linkage to tumors is questionable for BRCA1 mutations .

Next-generation sequencing as an informing phenotype: A TP53 example.

1554 Background: Li-Fraumeni (LFS) and Li Fraumeni like (LFL) syndromes are characterised by early onset cancers such as breast cancer, leukaemia, sarcoma, brain tumours and adrenocortical carcinoma, and are defined traditionally by clinical criteria such as Chompret and Eeles. Genetic testing for TP53 germline mutation is typically undertaken in families that satisfy these clinical criteria. Next generation sequencing and gene panel testing has resulted in more frequent TP53 testing to include families that don’t meet classic testing criteria. We investigated testing criteria and result outcome in a cohort of Irish probands undergoing TP53full sequencing. Methods: All TP53 test requests processed thought the national genetic testing laboratory between 2012 and 2014 were retrospectively reviewed. Family history data including diagnoses and age at diagnosis was ascertained through hospital charts or electronic pedigrees from two adult cancer genetic services in Ireland. Additional data including reason for...

A novel Cx50 (GJA8) p.H277Y mutation associated with autosomal dominant congenital cataract identified with targeted next-generation sequencing.

To unravel the molecular genetic background responsible for autosomal dominant congenital pulverulent nuclear cataracts in a four-generation Chinese family. Family history data were collected, ophthalmological examinations were performed, and genomic DNA was extracted from peripheral blood of the family members. The candidate genes were captured and sequenced by targeted next-generation sequencing, and the results were confirmed by Sanger sequencing. The structure modelling of the protein was displayed based on Swiss-Model Server, and its possible changes in the secondary structure were predicted using Antheprot 2000 software. The chemical dissimilarity and possible functional impact of an amino acid substitution were performed with Grantham score, PolyPhen-2, and SIFT predictions. Protein distributions were assessed by confocal microscopy. A novel heterozygous c.829C > T transition that led to the substitution of a highly conserved histidine by tyrosine at codon 277 (p.H277Y) in the coding region of connexin50 (Cx50, GJA8) was identified. Bioinformatics analysis showed that the mutation likely altered the secondary structure of the protein by replacing the helix of the COOH-terminal portion with a turn. The mutation was predicted to be moderately conservative by Grantham score and to be deleterious by both PolyPhen-2 and SIFT with consistent results. In addition, when expressed in COS1 cells, the mutation led to protein accumulation and caused changes in Cx 50 protein localization pattern. This is a novel missense mutation [c.829C > T, (p.H277Y)] identified in exon 2 of Cx50. Our findings expand the spectrum of Cx50 mutations that are associated with autosomal dominant congenital pulverulent nuclear cataract.

Data Mining via the Electronic Medical Record to Identify Inherited Colorectal Cancer in an HMO Patient Population

Background/Aims: A family history of colorectal cancer (CRC) and/or endometrial cancer, especially under age 50, is suggestive of Lynch syndrome, the most common form of inherited colorectal cancer. Limited family history (FH) data are currently collected on our members by nongenetics providers and recorded in the FH tab of our electronic medical record (EMR). We used these data as a potential “screening tool” for inherited CRC.

Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec.

Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies. Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk. The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases. Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.

Relationship of age of onset and family history in Parkinson disease.

The aim of this study was to determine whether age of onset of Parkinson disease (PD) is associated with differences in PD risk and PD age of onset in parents and siblings. Clinical and detailed family history data were available for 1,114 PD probands. Proband age of onset was not associated with differences in PD prevalence or PD age of onset in parents. Proband age of PD onset <50, compared with ≥ 50 years, was associated with significantly greater risk of PD in siblings (hazard ratio: 2.4; P=0.002; 95% confidence interval: 1.4, 4.1), and proband age of onset was significantly correlated with sibling age of onset (Somer's D=0.20; P=0.018). Proband age of PD onset is not associated with differences in parental PD risk. Siblings of PD patients with onset before age 50 are at increased risk of PD and are more likely to have early-onset disease.

Birth Prevalence of Overt Congenital Anomalies in Kano Metropolis: Overt Congenital Anomalies in the Kano

Congenital anomalies are abnormalities of prenatal origin, and their prevalence varies worldwide. The objective of this study was to determine the prevalence and spectrum of overt congenital anomalies in live born neonates in selected hospitals in the Kano metropolis of North western Nigeria, as well as the associated maternal, paternal and neonatal risk factors. A descriptive study design was employed. All live born neonates in three major hospitals in Kano metropolis were prospectively studied from April 2013 to December 2013. Detailed family history and clinical data were recorded in a structured questionnaire for each child. A total of 1456 live born neonates were recruited into the study, of which 41 (28.15 per 1000 live births) had overt congenital malformations with 5 (12.20%) having multiple system involvement and 36 (87.80%) having a single system affectation. The most common system involved in neonates with isolated single system malformations were the central nervous system (10 cases) and the genitourinary system (10 cases). The consanguinity rate in the study was 17.83%. Birth weight of the neonates had a significant but negative association with the likelihood of being born with a congenital malformation (OR = 0.374; (95% CI 0.196 - 0.711) P = 0.003). Given the high frequency of potentially preventable central nervous system malformations in this study, emphasis on the primary prevention of congenital malformations by encouraging periconceptional use of folic acid containing multivitamin supplements is recommended.

Risk for death from prostate cancer predicted from complete family history of lethal prostate cancer (LPC).

175 Background: There are few published reports of relative risk (RR) for LPC based on family history of prostate cancer (PC) lethality. This study provides LPC RR using complete LPC family history data obtained from a statewide Cancer Registry linked to a genealogy database. Methods: The Utah Population Data Base (UPDB), which includes a statewide SEER cancer registry, includes 1,192,768 individuals with at least 12 of their 14 immediate ancestors. All males (probands) with specific LPC constellations were identified in the UPDB, and the observed number of LPC cases among these probands was compared to the expected number of LPC cases using internal cohort-specific rates from Utah death certificates including all deceased males with no 1st, 2nd, or 3rd degree relatives with LPC. LPC Family history was estimated for 1st degree to 3rd degree relatives for: number of LPC relatives affected, paternal versus maternal family history, and age at first PC diagnosis. Results: 3,921 individuals in UPDB were diagnosed with histologically confirmed PC, and had a Utah death certificate indicating PC as a cause of death and were designated LPC. The RR for LPC was significantly elevated with each additional first-degree relative (FDR) with LPC; even in the absence of FDR family history of LPC, significantly increased risk for LPC was observed in the presence of at least 1 LPC affected second degree relative (SDR). In the absence of positive FDR and SDR family history for LPC, there was still increased risk for LPC for males with 2 or more third degree relatives with LPC. Early age PC diagnosis in the LPC relative did not appear to affect LPC RR. Higher risks of LPC were associated with the maternal compared to the paternal lineages. Conclusions: Examination of lethal prostate cancer family history (in FDRs through TDRs) may be useful in identifying the cohort of men with prostate cancer most at risk for death from prostate cancer. Focused screening and treatment of this cohort holds potential to decrease the rates of undertreatment of lethal disease while avoiding over diagnosis and overtreatment in inconsequential disease.

Prevalence of Depression and Anxiety Disorders in Peri-Natal Sudanese Women and Associated Risks Factors

The purpose of this study was to estimate a point prevalence of depression and anxiety disorders among Sudanese peri-natal women attending ant-natal and postnatal clinics in the capital city of Sudan. Simultaneously, to examine the associated risks factors. Participants were 945 peri-natal women in two main women antenatal and post natal clinics in the Capital City of Sudan screened consecutively. They were divided into two groups. The first group was of, Four Hundreds eighty (480) women in their third trimester, and the second group consisted of Four Hundreds Sixty Five (465) women in the first 10 week of postnatal period. All participants were screened, using Beck Depression Inventory (BDI), Hospital Anxiety and Depression scale (HADS), and Personal information Questionnaire (PIQ) for collecting socio-demographic, personal, medical, social and family history data. Routine urine and blood results were recorded. Results: 59% of prenatal and 46% of postnatal women suffered from high levels of distress in the form of mixed anxiety and depressive symptoms. However, only 20.9% of peri-natal women suffered of moderate to severe depression. Over 90% of the depressed women were not formally diagnosed or received psychiatric help. Poor marital relationship, physical co-morbidity, positive family history and past psychiatric history of depression were the main significant risk factors associated with perinatal depression and anxiety. Conclusion: Contrary to the commonly held views that perinatal women are mainly plighted with depression as the main mental illness, this study confirms initial findings that, anxiety disorder is far more prevalent and more distressing to this vulnerable group. Moreover, psychiatric morbidities in both prenatal and postnatal periods attract high prevalence rates in low income countries. Maternal health policies in low income countries must incorporate routine screening for mental health status, basic support and interventions for mental illnesses in perinatal women. Depression and emotional disorders in perinatal women should be seen as important public health priority.

Prediction of treatment outcomes in psychiatry—where do we stand ?

Psychiatric treatment relies on a solid armamentarium of pharmacologic and nonpharmacologic treatment modalities that perform reasonably well for many patients but leave others in a state of chronic disability or troubled by problematic side effects. Treatment planning in psychiatry remains an art that depends on considerable trial and error. Thus, there is an urgent need for better tools that will provide a means for matching individual patients with the most effective treatments while minimizing the risk of adverse events. This review will consider the current state of the science in predicting treatment outcomes in psychiatry. Genetic and other biomarkers will be considered alongside clinical diagnostic, and family history data. Problems inherent in prediction medicine will also be discussed, along with recent developments that support the hope that psychiatry can do a better job in quickly identifying the best treatments for each patient.

Mutation Analysis in Chinese Families with Autosomal Dominant Hereditary Cataracts

Purpose: To identify the molecular basis and clinical phenotype in three Chinese families with hereditary cataracts.Methods: Detailed family history and clinical data were recorded. The phenotypes were documented using slit-lamp photography. Candidate genes sequencing was performed to screen out the disease causing mutation. Bioinformatics analysis was performed to predict the function of mutant genes.Results: The phenotypes of the families were identified as nuclear cataract in Family 1, pulverulent cataract in Family 2, and nuclear cataract in Family 3. Direct sequencing revealed transversions of C > T at c.218 (p. S73F) in GJA8 in Family 1, A > C at c.125 (p. E42A) in GJA3 in Family 2, and C > T at c.268 (p. L90F) in GJA3 in Family 3. These mutations co-segregated with all affected individuals in the family and were not found in unaffected family members nor in the 100 unrelated controls. Bioinformatics analysis indicated that S73F in GJA8, E42A and L90F in GJA3 are highly conserved. S73F in GJA8, E42A and L90F in GJA3 could possibly be damaging predicted by PolyPhen-2, with score of 0.858, 1.000, 1.000, respectively.Conclusions: This study identified three mutations in three Chinese families with hereditary cataracts. Of the three mutations, two were novel (c.125 A > C in GJA3 and c.268 C > T in GJA3), one was previously reported (c.218 C > T in GJA8).

Abstract 12: Germline BRCA mutations in an unselected cohort of patients with pancreatic adenocarcinoma

Abstract This is the first prospective study to determine the frequency of BRCA1 and BRCA2 germline mutations in an unselected series of patients with pancreatic adenocarcinoma. Patients with histologically or clinically confirmed pancreatic adenocarcinoma were approached at a single cancer centre to enroll in the IRB-approved Ontario Pancreas Cancer Study. Patients provided informed consent and cancer family history data was obtained. Blood was collected and analyzed by Sanger sequencing and MLPA for germline variants in BRCA1 and BRCA2. All predicted deleterious germline variants were confirmed by a clinical laboratory on an independent blood sample. Pathogenic germline mutations were identified in 12/234 (5%) of unselected incident pancreatic adenocarcinomas. BRCA1 mutations accounted for 1.2% (3/234) and BRCA2 accounted for 3.8% (9/234) cases. For the cohort, average age of pancreatic adenocarcinoma diagnosis was 65 years (27-91) and 46% were female. Previous primary cancer was reported in 24% of cases and 12% were of Ashkenazi Jewish descent. A family history of breast and/or ovarian cancer was reported in 25% of cases; however, of these with a family history, 1/3 did not meet NCCN guidelines to warrant germline BRCA analysis. Pancreatic cancer in another relative was reported in 12% of cases. A personal history of a previous primary cancer diagnosis and a family history of breast and/or ovarian cancer were significantly associated with germline BRCA mutations. Previous studies of BRCA mutations in pancreatic adenocarcinoma have been limited to retrospective case series and incomplete germline analysis. Our study shows that germline BRCA mutations account for a significant proportion of pancreatic adenocarcinoma, regardless of family history of breast and ovarian cancer. Increased identification of patients with germline BRCA mutations and pancreatic adenocarcinoma may allow for tailored chemotherapy through the use of platinum agents or PARP inhibitors. Citation Format: Spring Holter, Ayelet Borgida, Anna Dodd, Steven Narod, Mohammad Akbari, Malcolm Moore, Steven Gallinger. Germline BRCA mutations in an unselected cohort of patients with pancreatic adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 12. doi:10.1158/1538-7445.CANSUSC14-12

Abstract 11215: Exercise Influences Penetrance and Outcomes in Family Members of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients Carrying a Pathogenic Desmosomal Mutation

Background: Endurance exercise is associated with adverse arrhythmic outcomes and development of heart failure in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated desmosomal mutation carriers. However studies comparing exercise participation in family members with desmosomal mutations are lacking. Methods: Structured exercise interviews were performed focusing on duration, intensity and timing among ten families with 37 patients (9 probands, 28 family members) carrying a pathogenic plakophilin ( PKP2 ) mutation. Exercise was classified based on 36 th Bethesda Conference into endurance/dynamic sports and static sports. Baseline characteristics, non-invasive and invasive clinical data, family history data and occurrence of ventricular tachycardia/appropriate defibrillator intervention (VT/VF) were collected. Results: Exercise duration (hours/year) at last follow up was highest among probands. Family members meeting 2010 Task Force Criteria [TFC] had significantly higher exercise duration (Figure 1-A), were more likely to be endurance athletes (77% vs. 33%, p=0.03), and had significantly higher participation in sports with high dynamic component (Median 416[IQR:123-864] vs. 214[IQR:48-408] hours/year; p=0.046) than family members not meeting TFC. Family members who were endurance athletes had worse arrhythmic course (Figure 1-B), were more likely to meet a major or minor 2010 TFC for depolarization/repolarization abnormalities (p=0.05), 2010 TFC for structural abnormalities (p=0.024) and had significantly lower right ventricular ejection fraction (48% vs. 57%; p=0.007). Conclusion: Mutation carrier family members of probands who are endurance athletes have increased penetrance, worse arrhythmic outcomes and greater structural changes compared with family members who are not endurance athletes and should be advised to restrict participation in exercise, especially with a high dynamic component.