Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data.

Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting.

Thoracic Aortic Aneurysmal Disease: Comprehensive Recommendations for the Primary Care Physician.

Thoracic aortic aneurysm (TAA) is a commonly encountered disease that is defined as aortic dilation with an increase in diameter of at least 50% greater than the expected age- and sex-adjusted size. Thoracic aortic aneurysms are described by their size, location, morphology, and cause. Primary care clinicians and other noncardiologists are often the first point of contact for patients with TAA.

Impact of Genetic Disorders in the Surgical Management of Congenital Heart Disease.

The congenital heart surgeon frequently encounters patients with various genetic disorders requiring surgical intervention. Although the specifics of the genetics for these patients and their families lie in the purview of specialists in genetics, the surgeon is well-served to be familiar with aspects of specific syndromes that impact surgical management and perioperative care. This aids in counseling families in expectations for the hospital course and recovery as well as can impact intraoperative and surgical management.

TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability.

Purpose: TRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.

Methods: Exome sequencing was performed in 3 individuals with ID and dysmorphic features.

Early and Late Outcomes of Cardiovascular Surgery in Patients With Ehlers-Danlos Syndrome.

Background: Cardiovascular surgical outcomes reports are few for vascular type IV of Ehlers- Danlos Syndrome (vEDS) compared to non-vascular types I-III (nEDS).

Methods: To define cardiovascular surgical outcomes among adult patients (≥18 years) with EDS types, a review of our institution's in-house STS Adult Cardiac Surgery Database-compliant software and electronic medical records from Mayo Clinic (1993-2019) was performed. Outcomes were compared for vEDS patients and nEDS patients.

Case Report: Early-Onset Behavioral Variant Frontotemporal Dementia in Patient With Retrotransposed Full-Length Transcript of Variant 5.

Frontotemporal dementia (FTD) rarely occurs in individuals under the age of 30, and genetic causes of early-onset FTD are largely unknown. The current report follows a 27 year-old patient with no significant past medical history presenting with two years of progressive changes in behavior, rushed speech, verbal aggression, and social withdrawal. MRI and FDG-PET imaging of the brain revealed changes maximally in the frontal and temporal lobes, which along with the clinical features, are consistent with behavioral variant FTD.

Impact of integrated translational research on clinical exome sequencing.

Purpose: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing.

Generation of Induced Pluripotent Stem Cells.

Induced pluripotent stem cells (iPSCs) are generated from somatic cells that have been reprogrammed by the ectopic expression of defined embryonic transcription factors. This technology has provided investigators with a powerful tool for modeling disease and developing treatments for human disorders. This chapter will provide the researcher with some background on iPSCs and details on how to produce MEF-conditioned medium, prepare mitotically arrested mouse embryonic fibroblasts (MEFs), create iPSCs using viral vectors, passage iPSCs, and cryopreserve iPSCs.

Three Patient Kindred with a Novel Phenotype of Osteogenesis Imperfecta due to a Variant.

Osteogenesis imperfecta (OI) is characterized by fractures and progressive bone deformities. Fracture rates peak during the toddler and adolescent years and decline during adulthood but do not stop entirely. We describe a kindred, the affected members of which were the mother and two sons, who presented with an apparently unique phenotype of OI.

Functional expression of ZNF467 and PCBP2 supports adipogenic lineage commitment in adipose-derived mesenchymal stem cells.

Bone marrow-derived mesenchymal stromal/stem cells (BMSCs) have the potential to be employed in many different skeletal therapies. A major limitation to utilizing BMSCs as a therapeutic strategy in human disease and tissue regeneration is the low cell numbers obtained from initial isolation necessitating multiple cell passages that can lead to decreased cell quality. Adipose-derived mesenchymal stromal/stem cells (AMSCs) have been proposed as an alternative cell source for regenerative therapies; however the differentiation capacity of these cells differs from BMSCs.

Oncolytic Measles Virotherapy and Opposition to Measles Vaccination.

Recent measles epidemics in US and European cities where vaccination coverage has declined are providing a harsh reminder for the need to maintain protective levels of immunity across the entire population. Vaccine uptake rates have been declining in large part because of public misinformation regarding a possible association between measles vaccination and autism for which there is no scientific basis. The purpose of this article is to address a new misinformed antivaccination argument-that measles immunity is undesirable because measles virus is protective against cancer.

Fracture incidence in Ehlers-Danlos syndrome - A population-based case-control study.

Background: The differential diagnosis of non-accidental injury during childhood includes medical conditions that predispose to skeletal fragility. Ehlers-Danlos syndrome (EDS) has been proposed as one such condition despite little objective evidence in the medical literature.

Objective: To investigate if EDS causes increased bone fragility during infancy and childhood.

Correction: Arterial tortuosity syndrome: 40 new families and literature review.

In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.

Validation of Osteogenic Properties of Cytochalasin D by High-Resolution RNA-Sequencing in Mesenchymal Stem Cells Derived from Bone Marrow and Adipose Tissues.

Differentiation of mesenchymal stromal/stem cells (MSCs) involves a series of molecular signals and gene transcription events required for attaining cell lineage commitment. Modulation of the actin cytoskeleton using cytochalasin D (CytoD) drives osteogenesis at early timepoints in bone marrow-derived MSCs and also initiates a robust osteogenic differentiation program in adipose tissue-derived MSCs. To understand the molecular basis for these pronounced effects on osteogenic differentiation, we investigated global changes in gene expression in CytoD-treated murine and human MSCs by high-resolution RNA-sequencing (RNA-seq) analysis.

Arterial tortuosity syndrome: 40 new families and literature review.

Purpose: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.

Methods: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.

Aortic Root Dilation: Do Patients With Marfan Syndrome Fare Worse Than Those With Marfanoid Features?

Objective: To discover whether patients with aortic root dilation and leptosomic features but without a diagnosis of Marfan syndrome (MFS) fare similarly to patients with MFS.

Methods: Of 124 patients with aortic root dilation identified from August 1, 1994, through October 31, 2012, 66 had MFS and 58 had leptosomic features but did not meet the Ghent criteria. Genetic testing was performed in 35% of patients (n=43).

Functional validation reveals the novel missense V419L variant in associated with Loeys-Dietz syndrome (LDS) impairs canonical TGF-β signaling.

TGF-β-related heritable connective tissue disorders are characterized by a similar pattern of cardiovascular defects, including aortic root dilatation, mitral valve prolapse, vascular aneurysms, and vascular dissections and exhibit incomplete penetrance and variable expressivity. Because of the phenotypic overlap of these disorders, panel-based genetic testing is frequently used to confirm the clinical findings. Unfortunately in many cases, variants of uncertain significance (VUSs) obscure the genetic diagnosis until more information becomes available.

Histone H4 Methyltransferase Suv420h2 Maintains Fidelity of Osteoblast Differentiation.

Osteogenic lineage commitment and progression is controlled by multiple signaling pathways (e.g., WNT, BMP, FGF) that converge on bone-related transcription factors.

Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience.

Objective: To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic odyssey in the first 18 months of an individualized medicine clinic (IMC).

Patients And Methods: The IMC offered WES to physicians of Mayo Clinic practice for patients with suspected genetic disease. DNA specimens of the proband and relatives were submitted to WES laboratories.

Spontaneous coronary artery dissection and its association with heritable connective tissue disorders.

Objective: Spontaneous coronary artery dissection (SCAD) is an under-recognised but important cause of myocardial infarction and sudden cardiac death. We sought to determine the role of medical and molecular genetic screening for connective tissue disorders in patients with SCAD.

Methods: We performed a single-centre retrospective descriptive analysis of patients with spontaneous coronary artery disease who had undergone medical genetics evaluation 1984-2014 (n=116).