Sarah E. Topol

Comparison of 24-hour Holter Monitoring with 14-day Novel Adhesive Patch Electrocardiographic Monitoring

BACKGROUND Cardiac arrhythmias are remarkably common and routinely go undiagnosed because they are often transient and asymptomatic. Effective diagnosis and treatment can substantially reduce the morbidity and mortality associated with cardiac arrhythmias. The Zio Patch (iRhythm Technologies, Inc, San Francisco, Calif) is a novel, single-lead electrocardiographic (ECG), lightweight, Food and Drug Administration-cleared, continuously recording ambulatory adhesive patch monitor suitable for detecting cardiac arrhythmias in patients referred for ambulatory ECG monitoring. METHODS A total of 146 patients referred for evaluation of cardiac arrhythmia underwent simultaneous ambulatory ECG recording with a conventional 24-hour Holter monitor and a 14-day adhesive patch monitor. The primary outcome of the study was to compare the detection arrhythmia events over total wear time for both devices. Arrhythmia events were defined as detection of any 1 of 6 arrhythmias, including supraventricular tachycardia, atrial fibrillation/flutter, pause greater than 3 seconds, atrioventricular block, ventricular tachycardia, or polymorphic ventricular tachycardia/ventricular fibrillation. McNemars tests were used to compare the matched pairs of data from the Holter and the adhesive patch monitor. RESULTS Over the total wear time of both devices, the adhesive patch monitor detected 96 arrhythmia events compared with 61 arrhythmia events by the Holter monitor (P < .001). CONCLUSIONS Over the total wear time of both devices, the adhesive patch monitor detected more events than the Holter monitor. Prolonged duration monitoring for detection of arrhythmia events using single-lead, less-obtrusive, adhesive-patch monitoring platforms could replace conventional Holter monitoring in patients referred for ambulatory ECG monitoring.

Gain‐of‐function ADCY5 mutations in familial dyskinesia with facial myokymia

To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).

Characterization of Circulating Endothelial Cells in Acute Myocardial Infarction

Features of endothelial cells in blood samples may eventually permit prediction of atherosclerotic plaque rupture events. Tell-Tale Cells In Edgar Allan Poe’s short story The Tell-Tale Heart, the narrator murders an old man and hides the body under the floorboards. The guilty murderer imagines that he hears the beating of the dead man’s heart emanating from the corpse underfoot—unwanted evidence of his guilt. But what if the body could leak evidence of a fragile condition before suffering a heart attack? The tale told could be frightening, yes, but the information may allow intervention at a crucial time in the pathophysiological process of heart disease. Now, Damani et al. take crucial first steps toward defining a clinical measure that could predict a thus-far unpredictable, myocardial infarction (MI)–associated event: acute atherosclerotic plaque rupture. Many people tell a personal story of a friend or relative who had a normal stress test just weeks before suffering a heart attack as a result of plaque rupture. Indeed, diagnosis of stable coronary artery disease (CAD) is now possible using stress tests and coronary artery imaging. In contrast, there are no clinically useful tests that warn of impending cardiovascular maladies caused by atherosclerotic plaque rupture. Physicians thus require a noninvasive, clinically feasible assay for a macromolecule or cell in blood that can identify people at risk for this condition, which is increasing in incidence as the population ages and widens. Endothelial cells (ECs) are normally found lining the blood vessels, and leakage into the circulation is evidence of ongoing injury to arteries that occurs on the way to potentially lethal plaque rupture. Elevated amounts of circulating endothelial cells (CECs) were previously linked to acute arterial catastrophes, but these measures have not yet made it into the clinic. Using automated, clinically feasible, three-channel fluorescence microscopy technology that can detect and permit isolation of rare cells, the authors measured and characterized CECs in healthy subjects and in patients who had experienced a type of heart attack known to manifest after acute arterial plaque rupture. CECs were elevated significantly in patients, relative to controls, and this elevation was not correlated with other measures of heart tissue death. Damani et al. also found that acute MI patients specifically displayed multicellular, multinuclear EC clusters and ECs with larger cellular and nuclear areas, relative to age-matched controls and patients with peripheral vascular disease (narrowing of arteries in the legs and feet). Although the study must be conducted in more patients and validated in an independent cohort, the new work suggests that tell-tale CECs may be useful in the clinic as evidence of ongoing plaque rupture and as a warning of possible heart attack in the near future. Acute myocardial infarction (MI), which involves the rupture of existing atheromatous plaque, remains highly unpredictable despite recent advances in the diagnosis and treatment of coronary artery disease. Accordingly, a clinical measurement that can predict an impending MI is desperately needed. Here, we characterize circulating endothelial cells (CECs) using an automated and clinically feasible CEC three-channel fluorescence microscopy assay in 50 consecutive patients with ST-segment elevation MI and 44 consecutive healthy controls. CEC counts were significantly elevated in MI cases versus controls, with median numbers of 19 and 4 cells/ml, respectively (P = 1.1 × 10−10). A receiver-operating characteristic (ROC) curve analysis demonstrated an area under the ROC curve of 0.95, suggesting near-dichotomization of MI cases versus controls. We observed no correlation between CECs and typical markers of myocardial necrosis (ρ = 0.02, creatine kinase–myocardial band; ρ = −0.03, troponin). Morphological analysis of the microscopy images of CECs revealed a 2.5-fold increase (P < 0.0001) in cellular area and a twofold increase (P < 0.0001) in nuclear area of MI CECs versus healthy controls, age-matched CECs, as well as CECs obtained from patients with preexisting peripheral vascular disease. The distribution of CEC images that contained from 2 to 10 nuclei demonstrates that MI patients were the only subject group to contain more than 3 nuclei per image, indicating that multicellular and multinuclear clusters are specific for acute MI. These data indicate that CEC counts may serve as a promising clinical measure for the prediction of atherosclerotic plaque rupture events.

A genome sequencing program for novel undiagnosed diseases

Purpose:The Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene–disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study.Methods:A total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician–scientist review panel, and 17 patients (14.0%) and their family members were enrolled.Results:60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene–disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings.Conclusion:Genome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking.Genet Med 17 12, 995–1001.

Patient perspectives on whole-genome sequencing for undiagnosed diseases

This study assessed perspectives on whole-genome sequencing (WGS) for rare disease diagnosis and the process of receiving genetic results. Semistructured interviews were conducted with adult patients and parents of minor patients affected by idiopathic diseases (n = 10 cases). Three main themes were identified through qualitative data analysis and interpretation: perceived benefits of WGS; perceived drawbacks of WGS; and perceptions of the return of results from WGS. Findings suggest that patients and their families have important perspectives on the use of WGS in diagnostic odyssey cases. These perspectives could inform clinical sequencing research study designs as well as the appropriate deployment of patient and family support services in the context of clinical genome sequencing.

Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy

&NA; Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans‐mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole‐exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore‐forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange.

Corrigendum: Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key?

[This corrects the article on p. 72 in vol. 4, PMID: 29181379.].

Mutation of WIF1: a potential novel cause of a Nail-Patella-like disorder

Purpose:Nail-Patella syndrome is a dominantly inherited genetic disorder characterized by abnormalities of the nails, knees, elbows, and pelvis. Nail abnormalities are the most constant feature of Nail-Patella syndrome. Pathogenic mutations in a single gene, LMX1B, a mesenchymal determinant of dorsal-ventral patterning, explain approximately 95% of Nail-Patella syndrome cases. However, 5% of cases remain unexplained.Methods:Here, we present exome sequencing and analysis of four generations of a family with a dominantly inherited Nail-Patella-like disorder (nail dysplasia with some features of Nail-Patella syndrome) who tested negative for LMX1B mutation.Results:We identify a loss-of-function mutation in WIF1 (NM_007191 p.W15*), which is involved in mesoderm segmentation, as the suspected cause of the Nail-Patella-like disorder observed in this family.Conclusions:Mutation of WIF1 is a potential novel cause of a Nail-Patella-like disorder. Testing of additional patients negative for LMX1B mutation is needed to confirm this finding and further clarify the phenotype.Genet Med advance online publication 06 April 2017

Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key?

The Scripps molecular autopsy study seeks to incorporate genetic testing into the postmortem examination of cases of sudden death in the young (<45 years old). Here, we describe the results from the first 2 years of the study, which consisted of whole exome sequencing (WES) of a cohort of 50 cases predominantly from San Diego County. Apart from the individual description of cases, we analyzed the data at the cohort-level, which brought new perspectives on the genetic causes of sudden death. We investigated the advantages and disadvantages of using WES compared to a gene panel for cardiac disease (usually the first genetic test used by medical examiners). In an attempt to connect complex clinical phenotypes with genotypes, we classified samples by their genetic fingerprint. Finally, we studied the benefits of analyzing the mitochondrial DNA genome. In this regard, we found that half of the cases clinically diagnosed as sudden infant death syndrome had an increased ratio of heteroplasmic variants, and that the variants were also present in the mothers. We believe that community-based data aggregation and sharing will eventually lead to an improved classification of variants. Allele frequencies for the all cases can be accessed via our genomics browser at https://genomics.scripps.edu/browser.