Basis Of Family History Research Articles

Hypomorphic PKD1 Alleles Impact Disease Variability in Autosomal Dominant Polycystic Kidney Disease.

Key Points Autosomal dominant polycystic kidney disease (ADPKD) manifesting earlier than expected on the basis of family history can identify clinically tolerant PKD1 alleles with reduced expression.Hypomorphic PKD1 alleles can cause mild kidney disease or liver cysts in the absence of clinically manifest kidney involvement.The presented data highlight pleiotropic ADPKD clinical presentations and varying severity of kidney disease from PKD1 allele combinations.

Advances and Applications of Polygenic Scores for Coronary Artery Disease.

Polygenic scores quantify inherited risk by integrating information from many common sites of DNA variation into a single number. Rapid increases in the scale of genetic association studies and new statistical algorithms have enabled development of polygenic scores that meaningfully measure-as early as birth-risk of coronary artery disease. These newer-generation polygenic scores identify up to 8% of the population with triple the normal risk based on genetic variation alone, and these individuals cannot be identified on the basis of family history or clinical risk factors alone. For those identified with increased genetic risk, evidence supports risk reduction with at least two interventions, adherence to a healthy lifestyle and cholesterol-lowering therapies, that can substantially reduce risk. Alongside considerable enthusiasm for the potential of polygenic risk estimation to enable a new era of preventive clinical medicine is recognition of a need for ongoing research into how best to ensure equitable performance across diverse ancestries, how and in whom to assess the scores in clinical practice, as well as randomized trials to confirm clinical utility.

Family History of Prostate and Breast Cancer Integrated with a Polygenic Risk Score Identifies Men at Highest Risk of Dying from Prostate Cancer before Age 75 Years.

Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown. We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer-specific death. We assessed to what extent family history of prostate or breast cancer, combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants, identifies men at risk of prostate cancer and prostate cancer death across the age span. During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer-specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the HR was 6.95 [95% confidence interval (CI), 5.57-8.66] for prostate cancer and 4.84 (95% CI, 2.59-9.03) for prostate cancer death. Men in the two upper PRS quartiles (50%-100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years. Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.

Role of Intercurrent Remedy in Treatment of Warts

AbstractWart is one of the common skin problems for which patient visits homoeopathic physician. Warts are benign proliferation of skin caused by human papilloma virus and generally a self-limiting condition but treatment is needed when they create discomfort and cosmetic or psychological embarrassment. Homoeopathy offers a safe and effective management in such cases. Occasionally, it has been seen that a well-selected individualised homoeopathic medicine sometimes fails to provide desirable result. In such circumstances, an intercurrent remedy is needed to arouse the reaction of patient or clear the obstacles for smooth action of selected remedy. In this context, a case of wart of 22 years old male patient is presented below. After thorough case taking and repertorisation, the selected remedy (Kali carbonicum) failed to provide any significant improvement even after raising the potency from 200C to 1000C. Then, the case was re-analysed and on the basis of family history, an intercurrent remedy ‘Tuberculinum’ was administered followed by former remedy (Kali carbonicum) which brought remarkable improvement and conspicuous changes rapidly. Possible causal attribution of changes was explicitly depicted by Modified Naranjo Criteria.

Abstract P2-10-02: Random periareolar fine-needle aspiration (RPFNA) cell number, prior precancerous breast disease and subsequent uptake of a prevention intervention predict short-term breast cancer risk

Abstract Introduction: In 2000 we published initial observations from a high-risk cohort of 480 women that cytologic evidence of hyperplasia with atypia in benign breast tissue obtained by random periareolar fine-needle aspiration (RPFNA) was associated with a five-fold increased risk of developing DCIS or invasive breast cancer at a median follow-up of 45 months [Fabian, JNCI 2000]. Few women in the initial cohort had any exposure to prevention agents, as NSABP-P1 was not reported until 1998. We began a new high-risk cohort in 2002 as the tissue processing changed from a filter technique to Thin PrepTM. The superior nuclear detail permitted assessment of cytologic atypia in the absence of high cellularity. Women in the second cohort were told that RPFNA atypia was a risk factor for developing breast cancer and in addition to standard prevention options were offered participation in clinical trials, if applicable. The purpose of this subsequent analysis was to determine if the predictive value of RPFNA atypia was maintained with change in tissue processing and availability of prevention options. Methods: A total of 1,135 high-risk women, eligible on the basis of family history, BRCA1/2 mutation status, prior biopsy indicating LCIS or atypical hyperplasia (AH), prior contralateral breast cancer and/or high mammographic breast density, underwent baseline RPFNA and were enrolled in our second cohort between 2002 and 2015. As in the earlier study published in 2000, if women had 2 aspirations without an intervening intervention within 21 months the worse result was utilized as baseline. In addition to cytomorphology, breast tissue was also categorized by cellularity of the aspirate (10-100, 100-1000, 1000-5000, and >5000 cells per cytology slide). The primary aspirator (CJF) and cytopathologist (CMZ) were the same for both cohorts. Women were censored at the time of prophylactic mastectomy, development of other site cancer, or death. Kaplan-Meier hazard plots and Cox-regression analysis were used to analyze time to development of DCIS or invasive breast cancer and effect of joint variables, respectively. Results: At a median follow-up of 86 months, 79 cases of DCIS or invasive breast cancer had been diagnosed. By univariate analysis, RPFNA atypia at entry was not predictive of subsequent breast cancer (p=0.58; log-rank test). However, breast cancer risk was increased by a prior breast biopsy with LCIS or AH (HR 2.6, 95% CI 1.6-2.4, p<0.001) or by high RPFNA cellularity, defined as >5000 epithelial cells per RPFNA cytomorphology slide (HR 2.1, 95% CI 1.3-3.5, p=0.0034). Thirty-six percent of women subsequently chose to undergo a prevention intervention, including a standard drug, enrollment in a prevention clinical trial of 6-12 months duration, or a prophylactic bilateral salpingo-oophorectomy (BSO) prior to age 45. Prevention interventions were more prevalent in women with RPFNA atypia (49% vs 30%, p<0.001). Not only was uptake of a prevention intervention associated with reduced breast cancer risk on univariate analysis (p=0.043), it was retained on multivariate analysis. The final Cox Regression risk model included prior breast biopsy with LCIS or AH (HR 2.4, 95% CI 1.5-3.9; p<0.001), high RPFNA cellularity (HR 2.2, 95% CI 1.3-3.7; p=0.003) and prevention intervention (HR 0.54, 95% CI 0.33-0.89; p=0.015). Conclusions: In a second large cohort of high-risk women for whom RPFNA acquired cells were processed to slides via ThinPrep™, high RPFNA cellularity (>5000 epithelial cells/slide) but not cytologic atypia predicted short-term breast cancer risk. However, women with atypia were significantly more likely than women without atypia to participate in a prevention intervention, which in turn was associated with reduced breast cancer risk Citation Format: Whitney L Hensing, Carol J Fabian, Carola M Zalles, Priyanka Sharma, Amy L Kreutzjans, Kandy R Powers, Lynn Chollet-Hilton, Bruce F Kimler. Random periareolar fine-needle aspiration (RPFNA) cell number, prior precancerous breast disease and subsequent uptake of a prevention intervention predict short-term breast cancer risk [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-02.

Infant Feeding Clusters Are Associated With Respiratory Health and Allergy at School Age in the PARIS Birth Cohort

To identify first year of life feeding cohorts and examine associations between respiratory health and allergy at 8 years of age and infant feeding practices.A total of 3446 infants born in Paris, France, were managed from birth to 8 years of age.Questionnaires were collected at 1,3,6,9, and 12 months of life, focusing on breastfeeding, consumption of infant formula (regular, partially hydrolyzed, extensively hydrolyzed, prebiotics and probiotics, and soy), and solid food introduction. Multidimensional longitudinal cluster analysis was used to place children with similar early feeding practices into 5 cohorts. Standardized questionnaires, physician documentation, lung function, fractional exhaled nitric oxide, and specific immunoglobulin E were collected at 8 years of life. These data were used to identify atopic morbidity correlations between feeding cohorts. Multivariable logistic and linear regression models adjusted for early respiratory and allergic outcomes and parental history of allergy.Participants were grouped into 5 feeding clusters on the basis of early feeding patterns: cluster 1 (45%): mostly regular formula; cluster 2 (27%): exclusively breastfed during the first 3 months; cluster 3: (17%) prebiotic or probiotic formula; cluster 4: (7%) partially hydrolyzed formula, and cluster 5: (4%) extensively hydrolyzed or soy formula. Compared with infants in cluster 1, children fed extensively hydrolyzed or soy formula were more likely to have diagnosis of food allergy (cluster 5). Infants fed partially hydrolyzed formula (cluster 4) had a significant lower lung function (forced expiratory volume in 1 second; forced vital capacity), higher fractional exhaled nitric oxide, and higher risk of allergic sensitization at 8 years of life, compared with that of cluster 1. Compared with infants fed mostly regular formula (cluster 1), infants exclusively breastfed during the first 3 months (cluster 2) had a lower rate of asthma diagnosis.Children breastfeeding at least 3 months in this study had protection against developing asthma and food allergy later in life, compared with other feeding groups. Infants with early partially hydrolyzed formula had higher rates of asthma and atopy at 8 years of age, even while controlling for early respiratory or allergic disease and family history of atopy.This supports previous recommendations regarding breastfeeding and the prevention of atopic conditions. The authors caution pediatricians against recommending hydrolyzed or hypoallergenic formulas universally or on the basis of family history alone and highlight potential future morbidity. This study revealed no benefits in preventing atopic disease with prebiotic or probiotic formulas, although the grouping of multiple different types of these formulas in 1 heterogenous group is a significant study limitation. The mechanisms underlying these results deserve further study.

Screening for cerebrovascular disorder on the basis of family history in asymptomatic children

Background: Cerebrovascular disorders represent a group of uncommon, heterogeneous, and complex conditions in children. We reviewed the screening practice for the detection of cerebrovascular disorder in asymptomatic children referred to our neurovascular service on the basis of a positive family history and parental and/or treating physician concern. Methods: Retrospective case-note review of referrals to our neurovascular service (July 2008–April 2018). Patients were included if the referral was made for screening, on the basis of a positive family history of cerebrovascular disorder. Symptomatic children, those with previous cranial imaging, or children under the care of a clinical geneticist (i.e. due to the child or their relative having HHT or mutations in KRIT1) were not eligible for inclusion. Results: Forty-one children were reviewed, 22 males (Median age 10.7 years, range 0.6–15.6 years). This represented 22% of the total number of referrals over a 10-year period. Twenty-nine children had an MRI/MRA brain. Twenty-eight children were referred due to a family history of intracranial aneurysm and/or subarachnoid haemorrhage, but only two had two first-degree relatives affected. Ten children were referred due to a family history of arteriovenous malformation. Three children were referred due to a family history of stroke. No cerebrovascular disease was detected during the study period (n = 29). Conclusions: Parental and/or physician concern generated a substantial number of referrals but no pathology was detected after screening. Whilst general screening guidance exists for the detection of intracranial aneurysms, consensus guidelines for the screening of children with a positive family history do not, but are required both to guide clinical practice and to assuage parental and/or physician concerns.

Bicuspid Aortic Valve in Infants, Children, and Adolescents: A Review for Primary Care Providers.

1. Talha Niaz, MBBS* 2. Jonathan N. Johnson, MD*,† 3. Frank Cetta, MD*,† 4. Timothy M. Olson, MD*,† 5. Donald J. Hagler, MD*,† 1. *Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, and 2. †Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN * Abbreviations: AHA : : American Heart Association BAV : : bicuspid aortic valve TTE : : transthoracic echocardiography Bicuspid aortic valve is the most common congenital heart defect in children, adolescents, and adults. Primary care providers play an important role in screening, referral, and follow-up of these patients and should be aware of the family screening guidelines, sports participation recommendations, and periodic follow-up requirements for adequate surveillance of the complications that arise from bicuspid aortic valve. After reading this article, readers should be able to: 1. Describe the epidemiology and anatomy of bicuspid aortic valve (BAV). 2. Understand the clinical presentation and diagnosis of BAV in infants, children, and adolescents. 3. Identify the various complications of BAV disease. 4. Discuss the management and follow-up requirements for BAV. 5. Analyze the family screening and sports participation guidelines for patients with BAV. Bicuspid aortic valve (BAV) is the most common congenital heart defect in children, adolescents, and adults. (1) It is a heterogeneous disease that affects both the aortic valve and the aorta. It can lead to many complications, including aortic valve stenosis, regurgitation, or endocarditis. (2)(3) It also can lead to dilation of the aorta, predisposing individuals to a significantly higher risk of aortic aneurysm and dissection. (4) Although most individuals with BAV present with these long-term complications during adulthood, a considerable number of patients may also present during childhood and adolescence with early-onset disease; that may require interventions in up to 12% to 15% of the patients. (5)(6) Therefore, patients with BAV require lifelong follow-up and surveillance. BAV has multiple implications in terms of sports participation and family screening, making it an important subject for primary care providers. This article reviews the anatomy, genetics, presentation, diagnosis, …

P96 Screening for cerebrovascular pathology on the basis of positive family history in the paediatric population

ObjectivesNeurovascular disorders are uncommon, complex conditions in children. We reviewed the screening practice and outcome of children referred to the neurovascular service on the basis of positive family history.DesignRetrospective review of prospectively maintained database.SubjectsChildren referred to the neurovascular service on the basis of family history, for screening at our hospital.MethodsWe retrospectively examined our database between July 2008 and April 2018 for the reasons for referral, family history, investigations performed, and the outcome of the screening process.Results44 children were reviewed (23 male, median age 10). Thirty-one children had an MRI/MRA brain. One child subsequently had uncomplicated digital subtraction angiography. Thirty children were referred due to a family history of subarachnoid haemorrhage, of which 17 had a single first-degree relative, and two had two first-degree relatives. Nine children were referred with a family history of arteriovenous malformation, (2 were associated with hereditary haemorrhagic telangiectasia). Five children were discussed due to a family history of non-specific haemorrhagic stroke. Seven children had a history of headache, (4 were prescribed Pizotifen for migraine). No neurovascular pathology was detected following screening within our cohort.ConclusionsA consensus screening policy does not exist but is required both to guide clinical practice and to assuage parental or patient concerns. We will survey UK paediatric centres to commence this process.

Added Value of Fetal Magnetic Resonance Imaging in Diagnosis of Central Nervous System Congenital Anomalies in Egyptian Population

CNS anomalies are the second most frequent type of congenital anomalies. It is important to diagnose them as early as possible due to poor outcome. The aim of the study is to assess the role of magnetic resonance imaging in evaluation of congenital anomalies of central nervous system. This study included 80 pregnant women with suspected congenital CNS anomalies. All patients had been examined by 2D ultrasound and MRI. The majority of anomalies in the current study were anencephaly, hydrocephalus with aqueductal stenosis and Chiari malformation . Twenty percentage of brain anomalies was associated with meningioceles. A significant difference was detected in both aqueductal stenosis and dandy walker as regards history of consanguinity. The results were compared with post natal clinical assessment and MRI. It is concluded that fetal MRI is becoming an increasingly important tool in diagnosis of brain abnormalities suspected on the basis of family history or fetal sonography (with equivocal data), with continuing improvements in technology for better improvement of postnatal outcome. BPD = Biparietal diameter, CNS = Central nervous system, EFW = Expected fetal body weight, FL = Femur length, FOV = Field of view, MRI = Magnetic resonance imaging, N= Number, SD = Standard deviation, Ssfp= Steady-state free percession, ST= Slice thickness, TE =time of echo, TR=time of repetition, T2WI=T2 weighted image, US=ultrasound.

Pedigree Analysis and Audiological Investigations of Otosclerosis: An Extended Family Based Study.

Background and ObjectivesTo analyse the audiometric profile and the pedigree of a large family with otosclerosis to understand the inheritance pattern and its implication in clinical management of the disease.Subjects and MethodsPedigree analysis was performed on the basis of family history and audiometric tests. Pure tone audiometry, tympanometry, and acoustic reflexes were evaluated for the family members. Audiometric analysis was also carried out for the individuals who have already underwent corrective surgery at the time of study.ResultsOut of 112 family members, 17 were affected individuals, and 11 of them were surgically confirmed. Hearing loss (HL) started unilaterally and progressed to bilateral form. Otosclerosis was presented in early 20’s in the first and second generations but it was delayed to mid-late 30’s in the fourth generation. An affected female was diagnosed with otosclerosis during her pregnancy. Though the disease was familial, a mother of four affected offspring in this family did not develop otosclerosis until she died at the age of 84.ConclusionsThe five-generation family, which was analysed in the present study, exhibited autosomal dominant inheritance of otosclerosis with reduced penetrance. Bilateral HL and pregnancy-aggravated otosclerosis were observed in this family. It was found for the first time that the age of onset of the disease delayed in the successive generations. The current study indicated the importance of detailed pedigree analysis for better clinical management of otosclerosis.

In utero MR imaging in fetuses at high risk of lissencephaly.

Lissencephaly is a rare disorder of cortical developmental, which usually carries increased risk of recurrence in future pregnancies. In this prospective observational study, we wished to test the hypothesis that sulcation patterns can be used to diagnose lissencephaly successfully on in utero MR (iuMR) imaging in the third-trimester but not in the late second-trimester fetus. Pregnant females were recruited into this study if they had an increased risk of fetal lissencephaly based on a fetus or child with lissencephaly in an earlier pregnancy. All females were offered serial iuMR examinations at one centre and are reported whether they had at least two examinations. The overall recurrence rate of lissencephaly was recorded along with the sulcation patterns of non-affected fetuses. 19 females were recruited with 23 pregnancies. In 3/23 (13%) fetuses, lissencephaly was diagnosed on iuMR and not detected on ultrasonography. In two cases, the diagnosis of lissencephaly was made on second-trimester iuMR imaging-with certainty in one and described as "possible" in the other. Confident diagnoses of lissencephaly were made by 28-week gestation in all three cases. Four fetuses, ultimately shown not to have lissencephaly, were judged to have minor sulcation delay on second-trimester imaging but became gestational age appropriate in the third trimester. iuMR imaging can identify fetal lissencephaly between 20 and 24 weeks, but false positives should be expected, particularly in the second trimester, and follow-up imaging later in pregnancy may be required. Advances in knowledge: It is possible to detect fetal lissencephaly between 20- and 24-week gestational age; but, it is considerably easier in the third trimester. As a result, if a fetus has an increased risk of lissencephaly on the basis of family history, it may be necessary to do serial iuMR studies to confirm normality (or abnormality) of the fetal brain.

Increased Identification of Candidates for High-Risk Breast Cancer Screening Through Expanded Genetic Testing

PurposeBreast MRI screening is recommended for women with a >20% lifetime risk for breast cancer on the basis of estimates derived from risk models dependent largely on family history. Alternatively, a >20% lifetime risk can be established through genetic testing of BRCA1 and BRCA2, as well as a growing selection of other genes associated with inherited breast cancer risk. The aim of this study was to quantify the impact of testing for genes other than BRCA1/2 and the extent to which mutation carriers in these genes would have been identified as candidates for enhanced screening on the basis of family history alone. MethodsWomen were tested with a 25-gene hereditary cancer panel including BRCA1/2 and 7 additional genes known to be associated with a >20% lifetime risk for breast cancer (ATM, CHEK2, PALB2, TP53, PTEN, CDH1, and STK11). Women found to carry pathogenic variants (PVs) were evaluated with the Claus model to assess whether they would have been found to be at >20% lifetime risk on the basis of family history. ResultsIn total, 9,751 PVs in the selected breast cancer risk genes were identified in 9,641 women. BRCA1/2 accounted for 59.1% of the PVs, and 38.8% were in ATM, CHEK2, or PALB2. Only 24.7% of all women with PVs found in any gene reached the >20% lifetime risk threshold using the Claus model. ConclusionsExpanding genetic testing beyond BRCA1/2 significantly increases the number of women who are candidates for breast MRI and other risk reduction measures, most of whom would not have been identified through family history assessment.

ACR Appropriateness Criteria Breast Cancer Screening

Mammography is the recommended method for breast cancer screening of women in the general population. However, mammography alone does not perform as well as mammography plus supplemental screening in high-risk women. Therefore, supplemental screening with MRI or ultrasound is recommended in selected high-risk populations. Screening breast MRI is recommended in women at high risk for breast cancer on the basis of family history or genetic predisposition. Ultrasound is an option for those high-risk women who cannot undergo MRI. Recent literature also supports the use of breast MRI in some women of intermediate risk, and ultrasound may be an option for intermediate-risk women with dense breasts. There is insufficient evidence to support the use of other imaging modalities, such as thermography, breast-specific gamma imaging, positron emission mammography, and optical imaging, for breast cancer screening.The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Do the Trajectories of Bipolar Disorder and Schizophrenia Follow a Universal Staging Model?

The purpose of this study is to address the question of whether a universal staging model of severe psychiatric disorders is a viable direction for future research by examining the extant literature. A narrative review was conducted of the relevant historical, conceptual, and empirical literature pertaining to the clinical trajectory of bipolar disorder and schizophrenia and issues relevant to staging. There is substantive evidence that classic recurrent bipolar disorder is separable from schizophrenia on the basis of family history, developmental and clinical course, treatment response, and neurobiological findings. However, because of the intrinsic heterogeneity of diagnostic categories that has been amplified by recent changes in psychiatric taxonomy, key distinctions between the groups have become obfuscated. While mapping risk and illness markers to emerging psychopathology is a logical approach and may be of value for some psychiatric disorders and/or their clinical subtypes, robust evidence supporting identifiable stages per se is still lacking. Presently, even rudimentary stages such as prodromes cannot be meaningfully applied across different disorders and no commonalities can be found for the basis of universal staging. Advances in the prediction of risk, accurate early illness detection, and tailored intervention will require mapping biomarkers and other risk indicators to reliable clinical phases of illness progression. Given the capricious nature of mood and psychotic disorders, this task is likely to yield success only if conducted in narrowly defined subgroups of individuals at high risk for specific illnesses. This approach is diametrically opposite to that being promulgated by proponents of a universal staging model.

Population-Wide Screening for Germline BRCA1 and BRCA2 Mutations: Too Much of a Good Thing?

Germline testing for highly penetrant mutations in cancer susceptibility genes such as BRCA1 and BRCA2 (BRCA1/2) can prevent cancer and save lives. Inherited BRCA1/2 mutations confer a 39% to 85% lifetime risk of female breast cancer and an 11% to 62% lifetime risk of ovarian cancer. Identifying BRCA1/2 mutation carriers thus allows for prophylactic surgeries, which can markedly decrease cancer incidence, morbidity, and mortality. Despite these benefits and increasing public awareness, a low fraction (35% in a recent Israeli study) of women with high-risk histories have undergone BRCA1/2 testing. Moreover, women from families with few female relatives are unlikely to recognize their risk of carrying a BRCA1/2 mutation until they themselves develop cancer. Recently, citing the impact of riskreducing surgeries, King et al published a high-profile appeal for BRCA1/2 mutation screening to be offered to all US women at age 30 years. King is to be commended for stimulating a serious discussion on the potential impact of bringing modern genetic medicine to the general population in a compelling circumstance. However, because testing all women for BRCA1/2 mutations would represent the first population-based screening for a hereditary cancer syndrome, careful consideration of the potential limitations, risks, and benefits of population-wide BRCA1/2 testing is essential. Currently, genetic screening efforts in the general population examine newborns for rare recessive disorders (eg, phenylketonuria, beta thalassemia) or screen prenatally for carriers of populationdependent recessive conditions (eg, Tay-Sachs, cystic fibrosis), seeking to prevent morbidity and mortality from childhood-onset diseases. In the case of autosomal dominantly inherited BRCA1/2 mutations, the goal is to reduce suffering and mortality from associated adult-onset malignancies, particularly in individuals who would not otherwise be aware of their cancer risk. Demonstration studies in the Ashkenazi Jewish population have shown that screening for its three BRCA1/2 founder mutations (with a combined 1-in-40 prevalence among unselected Ashkenazi Jews) is cost-effective and identifies carriers who would not have been suspected on the basis of their family cancer history. Citing a recent study of population-wide screening for the Ashkenazi founder mutations in Israel, King et al claim that the high penetrance of BRCA1/2 mutations is independent of whether patients who carry the mutations are ascertained on the basis of family history. However, all such studies examined Ashkenazi founder mutations only, which constitute more than 90% of mutations in the Ashkenazi population, thereby limiting generalizability to other populations. In the general US population, in which combined prevalence of a diverse array of BRCA1/2 mutations is 10-fold lower, widespread screening would have different performance characteristics than in the Ashkenazim. Whether the assortment of BRCA1/2 mutations found in non-Ashkenazi populations would have the same penetrance in population-based ascertainment as they do in clinicbased patients is unknown.

A Case of Intracranial Hemorrhage in a Neonate with Osteogenesis Imperfecta Type III with a Novel Mutation in COL1A2

Background: Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by fractures with minimal trauma. Despite the detailed information about skeletal abnormalities, data about the involvement of neurovascular structures in osteogenesis imperfecta (OI) is limited. Methods: We report a case of male neonate with OI type III who presented with intracranial hemorrhage. OI type III was diagnosed on the basis of family history and clinical, radiologic and genetic test findings. Results: A novel genetic mutation was found; splicing mutation heterozygous c.1036-2A>C (IVS19) in COL1A2 gene. Conclusion: This case demonstrates that intracranial hemorrhage could be a major complication in patients with OI type III by underlying unknown mechanisms. OI seems to be an entity associated with intracranial hemorrhage. Thus, we suggest a need for awareness of risk of this complication when evaluating a neonate with OI.

The association between Hirschsprung’s disease and multiple endocrine neoplasia type 2a: a systematic review

The co-occurrence of Hirschsprung's disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event. The basis for this association is the presence of a "Janus" mutation in the RET proto-oncogene--a mutation that acts simultaneously as both a gain-in-function and a loss-of-function mutation. To date, four mutations in the exon 10 region of RET that are known to cause MEN2A have been implicated in this association: C620, C618, C611 and C609. We performed a systematic review of the published literature on this association to determine its incidence, the prevalence and phenotype of HSCR associated with the 4 RET mutations mentioned above. A systematic literature-based search for relevant articles was conducted using three online databases. After exclusion of ineligible publications, we recorded data on all patients with a diagnosis of HSCR or MEN2A with a "Janus" RET mutation, as well as those who carried the mutation but were unaffected. Statistical analysis was performed using SPSS. The literature search yielded 885 publications, of which 36 articles, incorporating data on 341 individuals, were eligible for inclusion in the final analysis. Co-occurrence of HSCR and MEN2A was recorded in 84 cases (24.6 %). HSCR occurred alone in 64 carriers of a "Janus" mutation (18.8 %) and MEN2A occurred in isolation in 173 cases (50.7 %). Twenty individuals (5.9 %) were found to carry a "Janus" mutation after screening on the basis of family history but were unaffected by either MEN2A or HSCR. The most common mutation recorded was the C620 mutation [114 cases (48.1 %)]. There was a relatively high incidence of long-segment aganglionosis (29.3 %) and total colonic aganglionosis (17.3 %) in this cohort. This trend was particularly notable in those with C620 mutations, only 33 % of whom had short-segment disease. While the overall incidence of HSCR co-occurring with MEN2A is low, both conditions occur with a relatively high frequency in families with a RET mutation at exon 10. The proportion of cases of long-segment HSCR and total colonic aganglionosis is higher than that in the general population with HSCR in those with C620 and C618 mutations. These findings reinforce the importance of RET mutation testing in HSCR when a family history of either HSCR or MEN2 is present. In families with MEN2A and known exon 10 RET mutations, the threshold for investigation for HSCR in those with gastrointestinal symptoms should be very low. High-quality prospective longitudinal studies of large HSCR populations are required to shed greater light on this rare but important phenomenon.

Genetic Biomarkers in Cardiovascular Disease

Inherited cardiac conditions (ICCs) are a group of largely monogenic disorders affecting the heart, its conducting system and its vasculature. When an ICC is diagnosed in an individual, there are implications for the wider family circle, particularly the first-degree relatives. The understanding of the molecular pathology of ICCs has dramatically improved with advances in molecular genetics, and genetic testing is increasingly available as part of the diagnostic and predictive tools available for the management of these disorders. Genetic tests offer many advantages over traditional cardiovascular tests. They do not require invasive sampling, have high accuracy and can be performed whether or not symptoms of disease are present. The indications for performing a genetic test in ICCs are broadly divided into diagnostic testing and presymptomatic testing or cascade screening. Diagnostic testing is performed in most cases on the proband, the first individual in the family with observed signs and/or symptoms of disease, with a goal of establishing a precise diagnosis. Genetic testing can achieve this without sampling the affected tissue and can serve as a basis for treatment, anticipatory guidance and genetic counseling. Presymptomatic testing or cascade screening is applied to individuals who are yet to present signs or symptoms of disease, but are identified as at risk on the basis of family history. Genetic testing can determine the risk of disease, but it cannot be guaranteed whether or not the disease will become symptomatic. ICCs are a group of highly heterogeneous disorders, both clinically and genetically, and the first indication that an individual is affected with an ICC can be when they present with a sudden cardiac death. In the UK, the National Service Framework for coronary disease sets out,

Multiplex Genetic Testing for Cancer Susceptibility: Out on the High Wire Without a Net?

The integration of germline genetic testing into cancer care has been a gradual process. It has taken years to construct the evidence base to define the optimal management of individuals who carry mutations in cancer susceptibility genes. Although this evidence remains imperfect, it would be less robust if it were not for the role of the American Society of Clinical Oncology and other organizations, which have firmly and consistently endorsed the principle that genetic susceptibility testing should, if at all possible, be offered in the context of clinical trials with appropriate informed consent and follow-up. Substantial investment in research by individual centers and large international collaborations, including PROSE, the Hereditary Breast-Ovarian Cancer Study Group, and the Breast Cancer Family Registry, has generated data to guide clinical interventions, such as preventive salpingooophorectomy in BRCA mutation carriers. It is clear that the genetic architecture of cancer predisposition can be quite complex. Researchers have identified numerous cancer susceptibility syndromes and their causative genes. The risk of cancer at a given site may be elevated by mutations in one of a number of different genes, and a mutation in a particular gene often increases risk for more than one type of cancer. There are high-penetrance genes that result in autosomal-dominant predispositions recognizable by pedigree analysis, and moderate-penetrance genes, in which mutations are associated with lower relative risks (usually 2 to 5) and in which mutations may not cosegregate with implicated cancers in individual families. In the traditional model of clinical cancer genetics, patients are evaluated on the basis of family history or patient-specific factors such as age at diagnosis or disease histology. After appropriate evaluation and consent, testing is performed, usually serially, for the most likely genetic causes. The advantage of this approach is that testing is more specific, because genes that are unlikely to be mutated are not analyzed. Importantly, the process of pretest counseling for each gene allows the patient to participate in the decision of whether to pursue a particular test after considering the clinical and personal utility of the result. However, the standard approach of serial testing is time consuming and expensive. In contrast, next-generation sequencing (NGS) technologies now allow simultaneous analysis of multiple susceptibility genes (multiplex testing) at a cost that is modestly greater than single-gene testing (currently $3,855 to $5,466 at one commercial laboratory). Multiplex testing employs the same technologies as whole-exome and whole-genome sequencing but generates a more limited amount of information about predefined target genes. Multiplex test panels that evaluate highand moderatepenetrance genes are now available and are being marketed as a means of quickly assessing cancer susceptibility, either generically or for a specific disease site (Table 1). The multiplex approach has evident advantages, especially the potential for greater time and cost efficiency. It may be particularly useful in situations where: there is significant genetic heterogeneity; the prevalence of actionable mutations in one of several genes is significant; and it is difficult to predict which gene may be mutated on the basis of phenotype or family history. Examples of such situations include early-onset pheochromocytoma/paraganglioma and Lynch syndrome. However, there are nontechnical challenges that must be met to ensure the most responsible and effective implementation of these new technologies.