Medical Genetic Testing Research Articles

A case report of acute myocardial infarction with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by epistaxis, gastrointestinal bleeding, iron deficiency anemia, and arteriovenous malformations (AVMs) affecting the lungs, liver, and brain. Owing to its rarity and diagnostic challenges, early identification is often elusive. Underdiagnosis and prolonged diagnostic delays are prevalent. Here, we present the case of a 63-year-old male who presented with chest pain and was diagnosed with an ST-elevation myocardial infarction (STEMI). Subsequently, he underwent placement of a drug-eluting stent in the right coronary artery (RCA). However, recurrent postoperative epistaxis resulted in severe anemia, prompting further investigation leading to the diagnosis of hereditary hemorrhagic telangiectasia through comprehensive medical history and genetic testing. Future studies are warranted to evaluate reperfusion strategies in HHT patients presenting with myocardial infarction.

Punctal Atresia As a Clinical Indicator of Systemic Genetic Anomalies

ABSTRACT Background Punctal atresia or agenesis (PA) is a rare congenital anomaly characterized by the absence or closure of the tear duct puncta, potentially linked to systemic genetic anomalies. The necessity of a genetic workup based solely on the presence of PA remains uncertain. This study investigates a cohort of PA patients, examining the prevalence and types of associated syndromes. Methods A retrospective medical records review of all patients diagnosed with PA at the Children’s Hospital of Philadelphia between 2009–2023 was conducted, analyzing medical histories and genetic testing results. Primary outcomes included the prevalence of systemic syndromes, while secondary outcomes focused on the variety of associated syndromes. Results Forty-four patients were included, of which 31 were male (70%) with a mean ± SD age 3.3 ± 3.3 years. Overall, 87 puncta in the study cohort were affected, and 26 cases (59%) were bilateral. Systemic abnormalities or genetic syndromes were identified in 19 patients (43%), with the most common being Ectodermal Dysplasia and Down syndrome. Additional rare syndromes were demonstrated. No significant association was found between systemic abnormalities and gender, bilaterality, or the number of puncta involved. Conclusions A high incidence of systemic syndromes (43%) was observed in the study cohort. In individuals with PA who also exhibit extraocular disease, systemic evaluation and genetic workup should be considered. Syndromic diagnoses identified in our cohort also include: Branchio-oto-renal syndrome, 22q11.2 deletion syndrome, 1q21.1 microdeletion syndrome, NF1, monosomy 4q and trisomy 6q, which represent novel associations. The lack of correlation between PA’s phenotypic severity and systemic abnormalities highlights the need to obtain a comprehensive medical history and consider a systemic workup in PA patients.

Якість життя: бюджетний баласт чи державотворча необхідність

The aim of the study is to determine the risks, challenges and threats caused by the genetic liability, environmental conditions and living environment, to establish the importance of their impact on the quality of life in Ukraine, to develop a methodological approach to their assessment and to develop a set of measures within the context of the spatial regeneration of the national socio-economic system under conditions of the military aggression of the Russian Federation and in the postwar period. The research is based on information from open sources, expert opinions, data of the State Statistics Service of Ukraine and the data base of the World Health Organization, on results presented in medical, demographic and economic monographic studies and the materials included in sample surveys. Systemic approach and analysis methods, sociological, genetic population, statistical, comparative analysis, generalizations and expert evaluations were utilized. It has been recognized that factors such as genetic burden and environmental conditions and the environment of life have increased the impact on the quality of life of the population of Ukraine, the effect of which has determined the requirements for societal, demographic, organizational-economic, medical-social and socio-political response to threatening events. Awareness of demographic determinism, general laws and modern economic trends in the formation of the quality of life in the country in the conditions of military aggression of the Russian Federation allowed: a) to form a complex of medical and genetic, social, public and state mechanisms and measures to ensure it; b) specify the negative factors of the spatial evolution of the socio-economic system, which determined the need to take into account the medical and genetic reserves and opportunities and develop measures to eliminate the destructive influence of environmental conditions and living environment in the course of solving the demographic and socio-economic problems of the state; c) propose a medical-genetic concept of quality of life and living environment, the implementation of which will enable the generation of a healthy heritage (physical and psychological), will allow to form potential and build up reserves for improving the quality of life. Taking into account resource limitations and the presence of threats and risks in the internal environment, medical genetic counseling and testing, the creation of satisfactory environmental conditions along with a living environment become necessary levers in the recovery of Ukraine. The constitution and importance of the impact of quality of life factors for Ukraine have been updated: heredity (32.0 %); environmental conditions and living environment (32.0 %); nature of the life and lifestyle of the individual (26.0 %); quality of medical care and socio-economic factors (10.0 %). Systemic conditions for the regeneration of the demographic and economic situation, improvement of the quality of life and well-being to proceed with the development of a healthy society have been formulated. A model for assessing the quality of life has been developed, enhancing the methodological approach in assessing the economic equivalent of the value of living, which also involves calculatiing the economic profit of the state from the preserved working capacity of a person as a result of successful treatment / prevention of a genetic anomaly. This becomes the basis for: substantiating the economic effectiveness of medical and genetic care and other treatment and preventive measures for patients with genetic pathologies; rationalization of pension payments; development of a new social policy. The practical significance of the results becomes the basis to improve: the national model of medical and genetic monitoring; a set of preventative measures within the population; analysis of aggressive environmental conditions and living environment; cost of living estimates; systems for managing loss risk factors.

An unusual diagnosis of small bowel bleeding: A case of hereditary hemorrhagic telangiectasia

In clinical practice, small bowel bleeding is primarily attributed to angiodysplasia associated with chronic kidney disease. Hereditary Hemorrhagic Telangiectasia (HHT) represents a relatively rare condition, which poses diagnostic challenges. Herein, we present the case of a 49-year-old male with chronic gastrointestinal bleeding. The diagnosis was established based on the patient’s medical history, imaging findings, and genetic testing.

Hereditary predisposition syndromes to myeloid neoplasms: diseases, genes and mechanisms of development

With the development of modern next generation sequencing based DNA diagnostic methods, it has become possible to study hereditary predisposition to oncohematological diseases. Germline variants (mutations) of RUNX1, CEBPA, GATA2, ANKRD26, DDX41, FANC- (Fanconi anemia), etc. genes, associated with the development of hereditary hematological malignancies, have been identified. Timely diagnosis of such diseases will allow for medical genetic counseling and testing of the patient’s relatives to identify or exclude the risk of developing the disease, select a donor for the patient (it is undesirable to use a mutation carrier relative as a donor), and personalize the choice of chemotherapy regimens (for example, patients with Fanconi anemia may experience increased sensitivity to chemotherapy). The aim of this review is to present a modern view of the genetic predisposition to the development of hematological malignancies.

Caregiver Burden with Duchenne and Becker Muscular Dystrophy in Japan: A Clinical Observation Study.

Objective Skeletal muscle weakness and cardiomyopathy can be seen in carriers of dystrophinopathy. Therefore, the health management of caregivers of Duchenne/Becker muscular dystrophy (DMD/BMD) patients who are themselves carriers is an important issue. However, few studies have focused on caregivers who have dystrophin mutations. Methods In this cross-sectional study conducted at five hospitals, the daily living, situation medical treatment status, genetic testing, physical assessment, care burden, and quality of life of caregivers of DMD/BMD patients were surveyed. Results The subjects were 36 main caregivers (mean age 55.7±8.4 years old), of whom 52.8% were diagnosed as carriers, 8.3% were noncarriers, and 38.9% were not confirmed. In addition, half of the caregivers were not examined regularly at medical institutions. Of all caregivers, 54.3% had muscle or cardiac symptoms, and 75% had elevated serum creatine kinase levels. The mean Zarit Caregiver Burden Interview (ZBI) total score of current caregivers was 20.9±13.1. The frequency of a ZBI total score ≥25 was significantly higher in caregivers diagnosed as carriers than in caregivers unexamined as carriers (p=0.04). The health-related quality of life score (Short Form 36; SF-36) in caregivers was slightly lower than the Japanese standard scores in the sections of physical functioning, role limitations-physical, bodily pain, and social functioning. Conclusion Some caregivers of DMD/BMD patients can themselves have muscular or cardiac symptoms and a heavy care burden. It is therefore necessary for carrier caregivers, especially women, to undergo regular health checkups and receive appropriate health management.

Features of genetic mutations in children with high myopia combined with peripheral retinal degenerations

The study investigates the features of genetic mutations in children with high myopia combined with peripheral retinal degenerations. Study group was formed from the database of genetic studies of the Scientific and Clinical Center OOO Oftalmic, which consists of 4362 patients referred for medical genetic counseling and molecular genetic testing from 2016 to 2021. Selection criteria were: male and female patients, aged 5-18 years old, who had the following clinical signs: high myopia (>6.00 D) and the presence of peripheral retinal degenerations (PRD). The study considered both isolated cases of ophthalmic pathology, as well as its syndromic forms. The final selection included 40 children. All patients had consulted with a geneticist. Whole-exome sequencing (WES), next generation sequencing (NGS), and single gene sequencing were conducted by taking 5 mL of peripheral venous blood and extracting deoxyribonucleic acid (DNA). In patients with isolated cases of ophthalmic pathology (peripheral retinal degenerations and high myopia) with a confirmed genetic diagnosis, mutations in the COL2A1 gene were detected in 77.4% of cases, and in the COL11A1 gene - in 22.6% of cases. In Stickler syndrome with a confirmed genetic diagnosis, mutations in the COL2A1 gene were detected in 33.3% of cases. In Marshall syndrome, the mutation in the COL11A1 gene was detected in 11.1% of cases. In children with Ehlers-Danlos, Knobloch type 1, Cohen, Marfan, Wagner syndromes mutations in the genes COL5A1, COL18A1, VPS13B, FBN1, VCAN were detected in 55.6% of cases. In 33.3% of cases of Knobloch type 1, Cohen, Wagner syndromes the mutation is found in both copies of the gene (i.e., in both chromosomes), which leads to the development of peripheral retinal degenerations with high myopia. The results of the conducted molecular genetic testing expand our understanding of the mutation spectrum in the genes of children with both isolated cases of ophthalmic pathology, as well as syndromic pathology.

Abstract 12838: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) and m.3243A>G Mutations Have Higher Prevalence of Wolff-Parkinson-White Syndrome

Background: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the most common mitochondrial disorders. Cardiovascular involvement has been reported in up to 30% of MELAS patients with varying clinical presentations from non-specific cardiogenic abnormalities to conduction abnormalities, cardiomyopathies, heart failure, fatal arrhythmias and cardiac death. Although conduction defects are a known complication, the frequency of Wolff-Parkinson-White (WPW) Syndrome among MELAS patients and mutations associated with MELAS is uncertain, and their association with cardiomyopathy and treatment outcomes have rarely been reported. Methods: A retrospective chart review of 50 MELAS patients from January 2007 to December 2022 from the Neuroscience Institute at University of Texas Houston was conducted. Medical histories, genetic testing, electrocardiograms, echocardiograms, and electrophysiology studies were reviewed. Results: 43 patients were included (mean age 23.8, median age 18.5, range 2-58). Eight of 43 patients with MELAS (20 %), inclusive of one of 3 patients with m.4317A>G (33.3%) and seven of 40 patients with m.3243A>G variants had electrocardiographic findings consistent with WPW. Other conduction abnormalities were noted in ten of 20 patients (50%) with m.3243A>G with neurological involvement and six of 20 patients (30%) with m.3243A>G mutation without strokes. Four patients required electrophysiology studies with ablation (mean age 8.5, range 7-10), one for inappropriate sinus tachycardia resistant to several medications, and three patients with WPW syndrome all of whom required repeat ablations. Conduction abnormalities had a positive correlation with higher heteroplasmy levels (mean 35 % vs 51%, 95% CI -30.2 to -2.88, p=0.019). Six patients with MELAS had cardiomyopathy of varying severity which were all associated with conduction abnormalities, including two patients with WPW syndrome (p=0.014). Conclusion: The prevalence of WPW in patients with MELAS syndrome and the m.3243A>G variant appears much higher than in the normal population and may require multiple electrophysiology studies ablations to treat. Routine cardiology screening is recommended for early detection.

A mainstreaming oncogenomics model: improving the identification of Lynch syndrome.

"Mainstreaming" is a proposed strategy to integrate genomic testing into oncology. The aim of this paper is to develop a mainstreaming oncogenomics model by identifying health system interventions and implementation strategies for mainstreaming Lynch syndrome genomic testing. A rigorous theoretical approach inclusive of conducting a systematic review and qualitative and quantitative studies was undertaken using the Consolidated Framework for Implementation Research. Theory-informed implementation data were mapped to the Genomic Medicine Integrative Research framework to generate potential strategies. The systematic review identified a lack of theory-guided health system interventions and evaluation for Lynch syndrome and other mainstreaming programs. The qualitative study phase included 22 participants from 12 health organizations. The quantitative Lynch syndrome survey included 198 responses: 26% and 66% from genetic and oncology health professionals, respectively. Studies identified the relative advantage and clinical utility of mainstreaming to improve genetic test access and to streamline care, and adaptation of current processes was recognized for results delivery and follow-up. Barriers identified included funding, infrastructure and resources, and the need for process and role delineation. The interventions to overcome barriers were as follows: embedded mainstream genetic counselors, electronic medical record genetic test ordering, results tracking, and mainstreaming education resources. Implementation evidence was connected through the Genomic Medicine Integrative Research framework resulting in a mainstreaming oncogenomics model. The proposed mainstreaming oncogenomics model acts as a complex intervention. It features an adaptable suite of implementation strategies to inform Lynch syndrome and other hereditary cancer service delivery. Implementation and evaluation of the model are required in future research.

GENETIC EPILEPTIC AND DEVELOPMENTAL ENCEPHALOPATHIES OF THE EARLY AGE: FROM SYMPTOMS GENETIC TESTING TO DIAGNOSIS

Introduction. The problem of early diagnostics of orphan diseases is relevant for most countries of the world. The challenge for healthcare is to prevent new cases of orphan diseases by providing medical genetic testing and counseling at the stage of family planning. Department of psychoneurology of the State Intstitution "Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova National Academy of Medical Sciences of Ukraine" has been dealing with the problem of orphan diseases since 2012 and has significant experience in their diagnosis and treatment in children.The aim of paper: to develop an algorithm for the genetic diagnosis of epileptic and developmental encephalopathies in children with developmental delay and dimorphic features based on modern data on the application and interpretation of genetic methods. A case which demonstrate the complexity of interpreting the results and algorithms for early diagnosis of patients and the importance of medical and genetic counseling is presentedMaterial and methods: clinical and neurological examination, sleep video-EEG monitoring during night sleep, brain magnetic resonance imaging (3.0T), whole-exome sequencing (WES).Results. The article presents the algorithm of genetic diagnosis of orphan diseases in children with developmental and epileptic encephalopathies, developmental delay, and dimorphic features. A clinical case of a boy with general developmental delay and atonic epileptic seizures is presented. Sleep EEG-monitoring showed epileptiform activity in the stage of slow-wave sleep localized in the central-parietal and left temporal areas in the form of benign childhood epileptiform patterns.Whole-exome sequencing detected a variant of uncertain significance (VUS) c.5887C>T(p.Arg1963Cys) of SON gene in a heterozygous state, which leads to the replacement of arginine to cysteine. Mutations in the SON gene in the heterozygous state have been described in patients with Zhu-Tokita-Takenouchi-Kim syndrome (OMIM: 617140).Conclusions: It is important for pediatricians and neurologists to be aware of orphan diseases in children with developmental and epileptic encephalopaties and developmental delay. Genetic tests are wide available but they require competent interpretation by clinicists. After obtaining the results, it is important to compare the obtained result with the phenotype of patient. In case the phenotype of patient match and the results of genetic test, (detected VUS) this mutation could be etiological factor of the disease. In our case, the clinical signs coincided with those described in 2015 by the authors of the first description of Zhu-Tokita-Takenuchi-Kim syndrome, and therefore genetic testing helped to verify the final diagnosis. Therefore genetic counseling is extremely important for detection of etiology and prognosis of early developmental and epileptic encephalopathies/

A new era of genetic diagnosis for short stature children: A review

Children with short stature are often presented to pediatric endocrinologists. Short stature is defined as the height that is more than two standard deviations below the corresponding mean height for a specific age and sex in a reference population. Endocrine dysfunctions, including growth hormone deficiency/insensitivity, hypothyroidism, cortisol excess, precocious puberty, chronic disease (renal disease, diabetes mellitus, or inflammatory disease), and genetic disorders, should be assessed in patients presenting with short stature. In addition to medical history, physical examination, endocrine study, skeletal survey, and genetic testing are important for identifying the cause of short stature. Based on the next-generation sequencing analysis in patients with short stature, different genes that are unrelated to syndromic or non-syndromic short stature were identified. In particular, the genetic causes of short stature disrupting the growth plates and the pituitary-insulin-like growth factor axis have expanded. In recent years, the molecular level of chondrogenesis in the growth plates, including paracrine signals, extracellular matrix, and fundamental intracellular signals, has been reported. Moreover, new insights into the molecular pathogenesis of short stature are emerging. This article aimed to review the genetic causes of primary growth impairment in idiopathic short stature conditions.

Optical coherence tomography findings in three patients with Werner syndrome

BackgroundWerner syndrome is a rare, autosomal recessive disorder characterised by premature aging. It is a typical hereditary progeroid syndrome that can be difficult to diagnose owing to its rarity and the similarity of some of its symptoms, such as juvenile cataracts, to other common ophthalmologic conditions. Early onset of bilateral cataracts is currently used as the ophthalmological feature for Werner syndrome; however, ophthalmologists often find performing a detailed examination of the medical history and genetic testing for Werner syndrome at the time of an ophthalmologic consultation challenging. If a unique ocular finding was observed on ocular examinations in cases of juvenile bilateral cataracts, we could consider Werner syndrome as a differential diagnosis. Case presentationWe documented the cases of three patients with Werner syndrome in whom thinning of the retina in the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were observed using optical coherence tomography (OCT). Visual field tests revealed the loss of visual field mainly owing to glaucoma.The thinnig of the choroidal thickness (CT) in three patients was also observed using enhanced depth imaging (EDI)-OCT.ConclusionsThree patients have thinning of the RNFL, GCC, and choroidal thickness and the loss of visual field. These findings suggest the need for including Werner syndrome in the differential diagnosis when patients presenting with juvenile cataracts of unknown cause also show abnormal retinal and choroidal thinning in the OCT images.

Intellectual Functioning of Children With Isolated PRS, PRS-Plus, and Syndromic PRS.

Describe the intelligence quotient (IQ) of children with Pierre Robin sequence (PRS). Prospective cohort study. Neurodevelopmental follow-up clinic within a hospital. Children with PRS (n = 45) who had been in the Neonatal Intensive Care Unit (NICU) were classified by a geneticist into 3 subgroups of isolated PRS (n = 20), PRS-plus additional medical features (n = 8), and syndromic PRS (n = 17) based on medical record review and genetic testing. Children with PRS completed IQ testing at 5 or 8 years of age with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III) or Fourth Edition (WPPSI-IV) or the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) or Fifth Edition (WISC-V). IQ scores were more than 1 to 2 standard deviations below the mean for 36% of the overall sample, which was significantly greater compared to test norms (binomial test P = .001). There was a significant association between PRS subtype and IQ (Fisher's exact P = .026). While only 20% of children with isolated PRS were within 1 standard deviation below average and 35% of children with syndromic PRS were below 1 to 2 standard deviations, 75% of PRS-plus children scored lower than 1 to 2 standard deviations below the mean. PRS subgroups can help identify children at risk for cognitive delay. The majority of children with PRS-plus had low intellectual functioning, in contrast to the third of children with syndromic PRS who had low IQ and the majority of children with isolated PRS who had average or higher IQ.

Noonan Syndrome and Pulmonary Valve Stenosis

Source: Bell JM, Considine EM, McCallen LM, et al. The prevalence of Noonan spectrum disorders in pediatric patients with pulmonary valve stenosis. J Pediatr. 2021;234:134–141.e5; doi:10.1016/j.jpeds.2021.03.050Investigators from the University of Colorado School of Medicine, Denver, CO, and University of Colorado College of Engineering and Applied Science, Boulder, CO, conducted a retrospective study to estimate the prevalence of Noonan spectrum disorders (NSD) in children with pulmonary valve stenosis (PVS), and to identify characteristics that predicted NSD in PVS patients. Study participants were identified using the “Slicer/Dicer” function of the EPIC electronic medical system and included children seen in the Children’s Hospital Colorado Cardiology clinic between 2009 and 2018. The medical records of the identified patients were reviewed, and data on clinical characteristics abstracted. The presence of PVS was confirmed by reviewing echocardiogram reports.Study patients were classified as having NSD based on clinical diagnosis made by a medical geneticist and/or genetic test results. Data on other syndromic conditions present in participants also were recorded. The association of specific other cardiac conditions, including atrial septal defect (ASD), supravalvar pulmonary stenosis (SVPS), ventricular septal defect, hypertrophic cardiomyopathy, and patent ductus arteriosus, with NSD in patients with PVS was assessed by chi square tests. A similar process was used for extracardiac characteristic statistically associated with NSD in children with PVS, including cryptorchidism, lymphedema, hearing loss, pectus deformity, feeding issues, failure to thrive (FTT), developmental delay, short stature, and ocular findings. Bayes rule was used to determine the conditional probability of NSD in patients with one or more of these findings.Data were analyzed on 686 patients with PVS. Of these, a diagnosis of NSD was made in 59 (8.6%), with the diagnosis confirmed by genetic testing in 52 children. Other syndromic conditions were identified in 50 study participants (7.3%); Williams syndrome (N = 8) and trisomy 21 (N = 7) were the most common non-NSD syndromic conditions found. Clinical characteristics statistically significantly associated with a diagnosis of NSD in patients with PVS included lymphedema, cryptorchidism, hearing loss, pectus deformity, feeding issues, FTT, developmental delay, short stature, ocular findings, SVPS, hypertrophic cardiomyopathy, and ASD. Among these characteristics, the strongest predictors of NDS were cryptorchidism (conditional probability, 0.70), pectus deformity (conditional probability, 0.66), and ocular findings (conditional probability, 0.48). For children with PVS, pectus deformity, and developmental delay, the conditional probability of NDS was 0.82.The authors conclude that the prevalence of NSD is high in children with PVS, and that a diagnosis of NSD should be considered in PVS patients with other, specific, clinical characteristics.Dr Spar has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.PVS is the most common type of pulmonary stenosis (characterized by fused commissures with thickened leaflets of the pulmonary valve) and accounts for 8–12% of all CHD.1 PVS can range from mild to critical, with critical being the most severe form of pulmonary stenosis (PS) with inadequate pulmonary blood flow. In NSD the pulmonary valve is dysplastic with prominent leaflet thickening, with a small valve annulus and reduced mobility.2 Typical physical examination findings include an audible click, splitting of S2 and a systolic ejection murmur heard at the second left intercostal space. Echocardiogram confirms diagnosis with visualization of the pulmonary valve anatomy and provides determination of severity of stenosis by measuring the pressure gradient over the pulmonary valve.NSD has autosomal dominant inheritance with significant genetic heterogeneity. The most common pathogenic variants include PTPN11 gene (50% of patients with NSD). There are also at least 17 genes related to encoding of protein of the Ras-MAPK signaling pathway associated with NSD.1,3 Typical clinical manifestations are heterogeneous, with common features including widely spaced eyes, low-set ears, short stature, and PVS.4 Greater than 80% of patients with NSD have cardiac involvement, with the majority having PS and hypertrophic cardiomyopathy.5 Other cardiac lesions seen include ASD, ventricular septal defect, tetralogy of Fallot, pulmonary artery stenosis, coarctation of aorta, and primum type atrial septal defect.3The investigators of the current study reviewed all patients with a diagnosis of PVS without other cardiac lesions over a 10-year period. Patients with a clinical diagnosis after evaluation by a geneticist or confirmed by molecular testing were identified as having NSD. The investigators found that 59 of 686 (8.6%) patients with PVS had NSD. Of the 59, there were 52 children who had a molecular diagnosis, and 6 had a clinical diagnosis. Of patients with PVS, those with NSD were commonly had ASD, hypertrophic cardiomyopathy, and SVPS.PVS is commonly seen in patients with NSD. Genetic evaluation is a consideration in patients with PVS and other features known to be associated with NSD.

Preparing genomic revolution: Attitudes, clinical practice, and training needs in delivering genetic counseling in primary care in Hong Kong and Shenzhen, China.

ABSTRACTPurposeThe aim was to evaluate knowledge, attitudes, and clinical practice concerning medical genetics, genetic testing, and counseling among primary care physicians (PCPs) in Hong Kong and Shenzhen, China.MethodsThe University of Hong Kong (HKU), HKU‐Shenzhen Hospital, and Shenzhen Health Capacity Building and Continuing Education Center invited PCPs from Hong Kong and Shenzhen to participate in an online survey.ResultsThe survey was completed by 151 PCPs and 258 PCPs from Hong Kong and Shenzhen, respectively. The majority agreed it was important to keep current with genetics (91%) and that personalized medicine was the future of healthcare (86%), yet only 10% reported that they had postgraduate training in genomic medicine. Seventeen percent of Hong Kong and 40% of Shenzhen's PCPs encountered genetic‐related cases in the past 6 months, and they identified insufficient knowledge, few training opportunities, and self‐rated low confidence in their skillsets as main barriers.ConclusionsOur survey shows that Hong Kong and Shenzhen's PCPs are not yet fully utilizing potential benefits of genomic medicine in their clinical practice, which could be addressed with a combination of easily accessible educational resources, clear referral pathways and guidelines on genetic diseases, and cross‐specialty collaboration between healthcare systems and professional bodies.

Economic impact of medical genetic testing on clinical applications in Thailand.

BackgroundAlthough the clinical benefits of medical genetic testing have been proven, there has been limited evidence on its economic impact in Thai setting. Thus, this study aimed to evaluate the economic impact of genetic testing services provided by the Center for Medical Genomics (CMG) in Thailand.MethodsCost-benefit analysis was conducted from provider and societal perspectives. Cost and output data of genetic testing services provided by the CMG during 2014 to 2018 and published literature reviews were applied to estimate the costs and benefits. Monetary benefits related to genetic testing services were derived through human capital approach.ResultsThe total operation cost was 126 million baht over five years with an average annual cost of 21 million baht per year. The net benefit, benefit-to-cost ratio, and return on investment were 5,477 million baht, 43 times, and 42 times, respectively. Productivity gain was the highest proportion (50.57%) of the total benefit.ConclusionsThe provision of genetic testing services at the CMG gained much more benefits than the cost. This study highlighted a good value for money in the establishment of medical genomics settings in Thailand and other developing countries.

1268A family with a novel variant in the SLC4A3 gene leading to short QT phenotype - the importance of whole-exome-sequencing and cascade screening

Abstract Funding Acknowledgements none Introduction Short QT syndrome (SQTS) is a rare, autosomal dominant disease causing ventricular fibrillation and sudden cardiac death. Genetic testing is recommended according to current guidelines. Mutations in KCNQ1, KCNH2, KCNJ2 and more recently SLC4A3 genes have been implicated in SQTS. These genes encode potassium channel subunits and a bicarbonate transporter regulating intracellular pH. A dominant mutation in this transporter can lead to increased intracellular pH and shortened action potential. Purpose We present a family with a short QT phenotype and recurrent syncope in whom a novel genetic variant was detected by whole-exome sequencing (WES), confirmed by cascade screening. Methods We performed a thorough work-up of the index patient including medical history, physical examination, 12-lead ECG, echocardiography, stress testing, coronary angiography, flecainide challenge, and genetic testing with NGS. QTc was determined using Bazett’s formula. CS of all 1° and two 2° relatives was performed. Results The ECG of the index patient showed a QTc of 340ms and characteristics compatible with a SQTS (figure). Clinical work-up was unremarkable. A first genetic search with next generation sequencing focusing on genes that have been previously involved in the pathogenesis of channelopathies detected a rare known heterozygous missense variant in the KCNH2 gene (Arg328Cys, frequency 0.053%), which was predicted to be pathogenic according to various prediction algorithms (Polyphen, SIFT, Align GVGD, mutation taster). ECG screening of all asymptomatic first-degree family members identified a SQT phenotype in the mother (QTc 355ms), but not in the father (QTc 380ms) and sister (410ms). The KCNH2 variant was found in the father and sister but not the affected mother, which excludes this variant as the causative mutation in this family. Therefore, reanalysis of WES data was performed and revealed a novel heterozygous missense variant p.(Arg370Cys) in the SLC4A3 gene, recently associated with SQTS. A mutation in this gene at the same position has been previously reported in SQTS. The p.(Arg370Cys) mutation was found in the mother but not in the unaffected father or sister. Furthermore the mutation was present in two affected maternal uncles (QTc 319ms and 342ms) supporting the assumption that this was the causative mutation in this family. Conclusions A novel genetic variant in the SLC4A3 gene leading to sQT phenotype could be detected using WES and cascade screening. Predictive bioinformatic algorithms to assess the pathogenicity of missense variants are of limited relevance, but genetic analysis of additional unaffected and affected family members may be instrumental to identify pathogenic DNA sequence variations. Abstract Figure. Pedigree and ECGs of the family

Neonatal Severe Primary Hyperparathyroidism: A Series of Four Cases and their Long-term Management in India.

Context:Neonatal severe primary hyperparathyroidism (NSPHPT) is an extremely rare autosomal recessive disorder, requiring a high index of suspicion. Infants affected with this disorder present with severe life-threatening hypercalcemia early in life, requiring adequate preoperative medical management followed by surgery.Aims:We report four newborns with NSPHPT who were managed over 10 years.Subjects and Methods:Demography, clinical presentation, treatment, and follow-up data were retrospectively studied with descriptive analysis to highlight the utility of long-term medical management, surgery, and genetic testing reported in the literature.Statistical Analysis Used:Descriptive Analysis.Results:We had three males and one female infant with a mean age of diagnosis at 28.7 days, calcium 29.2+/-2.8 mg/dL, and parathormone (PTH) 1963+/-270.4 pg/mL. All four infants presented with failure to thrive, hypotonia, and respiratory distress. All infants were treated medically followed by total parathyroidectomy plus transcervical thymectomy, with an additional hemithyroidectomy in one of them. Imaging was negative in all four cases. Three babies became hypocalcemic while the fourth infant had a drop in PTH and is on the tab. cinacalcet 30 mg/day. CaSR mutation was positive in three infants.Conclusions:Diagnosing NSPHPT needs expert clinical acumen. It requires emergency medical management to control calcium levels. The crisis may present later, necessitating parathyroidectomy in these cases once the child is fit for surgery. Surgery offers a cure for this unusual lethal hypercalcemia while the role of cinacalcet needs a special mention. Sound knowledge in endocrinology with parathyroid embryology and morphology is of paramount importance. Our case series might add a few insights into managing this unusual genetic disorder.

<p>Knowledge, Beliefs, and Attitudes Concerning Genetic Testing Among Young Jordanians</p>

BackgroundMedical genetic testing is an evolving side of clinical care that helps people to make informed medical and lifestyle decisions. The source of knowledge, personal beliefs, and attitude towards genetic testing are the main determinative factors of getting optimal utilization of such technology in reducing/prevention of diseases.MethodsA structured survey was used to assess the knowledge, beliefs, and attitude regarding genetic testing among 463 young adults aged 18 years or older living in the North of Jordan.ResultsMore than three-quarters (77.1%) of the respondents were familiar with the term genetic testing. The most common sources of knowledge were: education they received (44.8%), the internet (37.5%), and social media (17.2%). Most (93.9%) of the respondents believed that genetic testing is a useful tool to diagnose and prevent genetic diseases. Almost three-quarters (72.7%) of the respondents believed that the health care system provides advice or genetic counseling to those with a genetic disease. A total of 9.6% of the respondents thought that genetic testing might cause a physical risk to their lives. In addition, 11.3% of the respondents believed that genetic testing is forbidden and not permissible and about 6.3% did not agree in performing genetic testing in the future. Finally, about half (53.4%) of the respondents consider genetic testing affordable and the remainder consider it costly.ConclusionOur findings emphasize the importance of acquiring knowledge about genetic testing among young individuals, Issues related to knowledge were identified and should be further improved, such as cost prediction, safety, and the legitimacy of genetic testing to get better outcomes in the Jordanian community.

Abstract 2427: Patterns of BRCA testing by provider type based on biological and non-biological factors among a diverse sample of young breast cancer survivors

Abstract Introduction: Per national practice guidelines, pre-test genetic counseling through a provider experienced and proficient in genetics (such as a genetics health professional (GHP)) is recommended prior to genetic testing for hereditary cancer. We sought to determine if there are differences in clinical and demographic variables between young breast cancer (BC) survivors who saw a GHP prior to genetic testing compared to those tested without involvement of a GHP. Methods: A population-based sample of Black, Hispanic and non-Hispanic white (NHW) women diagnosed with invasive BC < age 50 in 2009-2012 was recruited through the Florida State Cancer Registry. Participants were asked to complete a questionnaire and medical records release to verify clinical information and genetic test results. Women tested through a GHP were compared to those tested through a non-GHP based on the following variables: 1) Socioeconomic status (SES) (income, college education and private insurance); 2) Racial group (Black, Hispanic and NHW); and 3) Clinical factors (age at diagnosis, family history (FH) of breast or ovarian cancer and triple negative breast cancer (TNBC) status) using Pearson chi-squared analyses. Results: Of 1618 study participants, 1080 reported genetic counseling and/or testing, of which provider information was verified on 981 based on documentation in medical record and/or genetic test result report. GHP involvement (either through consultation and/or test ordering) was reported in 193 women (19.7%) whereas the remaining 788 women (80.3%) had no documentation of GHP involvement. There was a significantly higher rate of GHP involvement among women with TNBC compared to those without TNBC (26.1% vs. 19.1%; p=0.05); and non-significant increases in those with and without a FH of BC (21.1% vs. 17.6%; p=0.17); and ovarian cancer (22.8% vs. 19.2%; p=0.34). GHP involvement did not vary among: 1) women diagnosed < or > age 45 (19.6% vs. 19.8%; p=0.96); 2) Blacks (20.1% vs. 19.6%; p=0.88); 3) Hispanics (23.5% vs. 18.8%; p=0.15); and 4) NHW (18.5% vs. 22%; p=0.19). Regarding SES-related indicators, GHP involvement was lower among women with private insurance versus those without (18.3% vs. 29.3%; p=0.002), annual household income > $25,000 versus those < $25,000 (18.8% vs. 30.8%; p=0.004) and a college education (55.4% vs. 60.9%; p=0.17). Conclusions: Our results demonstrate that TNBC status was associated with testing through a GHP, while other clinical and demographic variables were not associated with GHP involvement. This finding may be due to widespread recognition of a more aggressive disease phenotype and association of TNBC with hereditary disease. Furthermore, the inverse relationship between higher SES-related indicators and GHP involvement suggests that those with higher SES are less likely to receive care through a GHP, as recommended per national guidelines. Citation Format: Sonya Reid, Deborah Cragun, Ann Tezak, Anne Weidner, Ingrid Mayer, Xiao-ou Shu, Susan Vadaparampil, Tuya Pal. Patterns of BRCA testing by provider type based on biological and non-biological factors among a diverse sample of young breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2427.