Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood

Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment. © 2019 Author(s)National Human Genome Research Institute (1K08HG0101)Wellcome Trust (202802/Z/16/Z)University of Bristol NIHR Biomedical Research Centre (S- BRC-1215-20011)National Human Genome Research Institute (HG008895)National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300025CNational Heart, Lung, and Blood Institute (NHLBI) HHSN268201300026CNational Heart, Lung, and Blood Institute (NHLBI) HHSN268201300027CNational Heart, Lung, and Blood Institute (NHLBI) HHSN268201300028CNational Heart, Lung, and Blood Institute (NHLBI) HHSN268201300029CNational Heart, Lung, and Blood Institute (NHLBI) HHSN268200900041CNational Institute on Aging (AG0005)NHLBI (AG0005)National Human Genome Research Institute (U01-HG004729)National Human Genome Research Institute (U01-HG04424)National Human Genome Research Institute (U01-HG004446)Wellcome (102215/2/13/2

Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1

Abstract Background RASopathies are a group of disorders caused by disruptions to the RAS‒MAPK pathway. Despite being in the same pathway, Neurofibromatosis Type 1 (NF1) and Legius syndrome (LS) typically present with phenotypes distinct from Noonan spectrum disorders (NSDs). However, some NF1/LS individuals also exhibit NSD phenotypes, often referred to as Neurofibromatosis‐Noonan syndrome (NFNS), and may be mistakenly evaluated for NSDs, delaying diagnosis, and affecting patient management. Methods A derivation cohort of 28 patients with a prior negative NSD panel and either NFNS or a suspicion of NSD and café‐au‐lait spots underwent NF1 and SPRED1 sequencing. To further determine the utility and burden of adding these genes, a validation cohort of 505 patients with a suspected RASopathy were tested on a 14‐gene RASopathy‐associated panel. Results In the derivation cohort, six (21%) patients had disease‐causing NF1 or SPRED1 variants. In the validation cohort, 11 (2%) patients had disease‐causing variants and 15 (3%) had variants of uncertain significance in NF1 or SPRED1. Of those with disease‐causing variants, 5/17 only had an NSD diagnosis. Conclusions Adding NF1 and SPRED1 to RASopathy panels can speed diagnosis and improve patient management, without significantly increasing the burden of inconclusive results

Training the Future Leaders in Personalized Medicine

The era of personalized medicine has arrived, and with it a need for leaders in this discipline. This generation of trainees requires a cadre of new skill sets to lead the implementation of personalized medicine into mainstream healthcare. Traditional training programs no longer provide trainees with all the skills they will need to optimize implementation of this revolution now underway in medicine. Today’s trainees must manage clinical teams, act as clinical and molecular diagnostic consultants, train other healthcare professionals, teach future generations, and be knowledgeable about clinical trials to facilitate genomic-based therapies. To prepare trainees for the transition to junior faculty positions, contemporary genomic training programs must emphasize the development of these management, teaching, and clinical skills

Combined X-linked familial exudative vitreoretinopathy and retinopathy of prematurity phenotype in an infant with mosaic turner syndrome with ring X chromosome

Retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR) are two distinct pathologies of retinal angiogenesis with overlapping clinical features. Examination, multimodal imaging, and genetic testing were used to guide diagnosis and treatment. We report a combined phenotype of X-linked FEVR and ROP in a 4-month-old girl with mosaic Turner syndrome with ring X chromosome born at 26 weeks gestational age. She was initially diagnosed with atypical ROP with a vitreous band causing a localized traction retinal detachment, inferotemporal to the macula in the right eye, vessels to posterior zone 2 with no clear ridge temporally in the left eye, and fluorescein leakage in both eyes. Due to the suspicion of concurrent FEVR, genetic testing using a vitreoretinopathy panel was performed which revealed a mosaic Turner syndrome associated with 45,X/46,X,r(X), subsequently confirmed by chromosome analysis. The deleted region in the ring X chromosome included the NDP and RS1 genes. The patient was treated with laser photocoagulation of the peripheral avascular retina and sub-Tenon's triamcinolone injection in both eyes, intravitreal injection of bevacizumab in the left eye, and pars plicata vitrectomy in the right eye. In premature neonates with atypical ROP, a clinical suspicion of concurrent FEVR or similar vasculopathy is important and genetic testing may elucidate a genetic etiology, which could influence management and prognosis. Turner syndrome can be connected with co-occurring Mendelian gene disorders, particularly in individuals with mosaicism. The concurrence of FEVR and ROP appears to result in atypical and possibly more severe phenotypes

Rare Genetic Variants Associated With Sudden Cardiac Death in Adults

Background: Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. Objectives: This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. Methods: The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. Results: Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death—corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). Conclusions: Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.National Heart, Lung, and Blood Institute (Grants HL-03783, HL-26490, HL-34595, HL-34594, HL-35464, HL-043851, HL-46959, HL-099355 and HL-080467)National Cancer Institute (Grants CA-167552, CA-186107, CA-49449CA-34944, CA-40360, CA-47988, CA-55075, CA-87969 and CA-97193

Electronic Health Record Phenotype in Subjects with Genetic Variants Associated with Arrhythmogenic Right Ventricular Cardiomyopathy: A Study in 30,716 Subjects with Exome Sequencing: Genotype-Phenotype Association in Incidental ARVC Genetic Findings

Purpose Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained. Methods: 30,716 individuals underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes. Results: 18 subjects had pLOF variants; none had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram (ECG), one had a minor diagnostic criterion, 13 were normal. 184 subjects had VUSs; none had an ARVC diagnosis. In subjects with VUSs, there was no difference in the proportion with major (4%) or minor (13%) ECG diagnostic criteria compared to variant-negative controls. ICD-9 codes showed no difference in defibrillator utilization, electrophysiologic abnormalities or non-ischemic cardiomyopathies in patients with pLOF or VUSs compared to controls. Conclusion: pLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain