Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

Background:Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown. Methods:We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual disability harboring apparent de novo SVs, most with an inconclusive diagnosis after regular genetic testing. Results: In 7 of these cases (18%), whole-genome sequencing analysis revealed disease-relevant complexities of the SVs missed in routine microarray-based analyses. We developed a computational tool to predict the effects on genes directly affected by SVs and on genes indirectly affected likely due to the changes in chromatin organization and impact on regulatory mechanisms. By combining these functional predictions with extensive phenotype information, candidate driver genes were identified in 16/39 (41%) patients. In 8 cases, evidence was found for the involvement of multiple candidate drivers contributing to different parts of the phenotypes. Subsequently, we applied this computational method to two cohorts containing a total of 379 patients with previously detected and classified de novo SVs and identified candidate driver genes in 189 cases (50%), including 40 cases whose SVs were previously not classified as pathogenic. Pathogenic position effects were predicted in 28% of all studied cases with balanced SVs and in 11% of the cases with copy number variants. Conclusions:These results demonstrate an integrated computational and experimental approach to predict driver genes based on analyses of WGS data with phenotype association and chromatin organization datasets. These analyses nominate new pathogenic loci and have strong potential to improve the molecular diagnosis of patients with de novo SVs

Panel 7: otitis media:treatment and complications

Objective: We aimed to summarize key articles published between 2011 and 2015 on the treatment of (recurrent) acute otitis media, otitis media with effusion, tympanostomy tube otorrhea, chronic suppurative otitis media and complications of otitis media, and their implications for clinical practice. Data Sources: PubMed, Ovid Medline, the Cochrane Library, and Clinical Evidence (BMJ Publishing). Review Methods: All types of articles related to otitis media treatment and complications between June 2011 and March 2015 were identified. A total of 1122 potential related articles were reviewed by the panel members; 118 relevant articles were ultimately included in this summary. Conclusions: Recent literature and guidelines emphasize accurate diagnosis of acute otitis media and optimal management of ear pain. Watchful waiting is optional in mild to moderate acute otitis media; antibiotics do shorten symptoms and duration of middle ear effusion. The additive benefit of adenoidectomy to tympanostomy tubes in recurrent acute otitis media and otitis media with effusion is controversial and age dependent. Topical antibiotic is the treatment of choice in acute tube otorrhea. Symptomatic hearing loss due to persistent otitis media with effusion is best treated with tympanostomy tubes. Novel molecular and biomaterial treatments as adjuvants to surgical closure of eardrum perforations seem promising. There is insufficient evidence to support the use of complementary and alternative treatments. Implications for Practice: Emphasis on accurate diagnosis of otitis media, in its various forms, is important to reduce overdiagnosis, overtreatment, and antibiotic resistance. Children at risk for otitis media and its complications deserve special attention

Skin cancer in skin of color transplant patients

Objectives: 1. Use UNOS/OPTN to establish a cohort of HFHS patients who received heart, lung, liver, pancreas or kidney organ transplants between January 1, 1990 and December 31, 2011 2. Explore racial differences in histologically-confirmed skin cancer for OTRs: calculate the incidence of skin cancer by race; calculate the cumulative incidence of skin cancer in the cohort using person-years at risk; compare, by race, the rates of skin cancer for OTRs in our cohort to that of the general population to determine if the difference in rates observed by race in the general population is similar to the difference in rates by race among OTRs. The racial difference in skin cancer between whites and nonwhites in our cohort of OTRs will be of a lesser magnitude (eg, \u3c70) than that reported for the general population. 3. Explore racial differences in indicators of severity/poor outcomes for squamous cell carcinoma, including number of lesions, recurrence of cancer, metastasis and death. H2: Among transplant patients with SCC, nonwhites will have worse outcomes, indicated by number of cancers, recurrence of cancer, metastasis, and death. Organ transplant patients are required to take lifelong immunosuppressant medications, resulting in a higher risk of developing skin cancer. In addition, patients with skin of color who develop skin cancer often have worse outcomes (ie, spread of cancer to other organs and death) when compared to white patients with a similar diagnosis. These differences in outcomes are likely due to delays in skin cancer diagnosis and treatment. This chart review aims to study three types of skin cancer (basal cell, squamous cell, and melanoma skin cancer) in a group of individuals who are both non-white and have received organ transplants. The goal is to explore racial differences in skin cancer outcomes, including the number of skin cancers, spread of cancer to other organs, and death from skin cancer. Information was obtained from a national database, United Network of Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) and from the Henry Ford Health System electronic medical record. Based on preliminary findings, we expect the nonwhite organ transplant patients to have worse outcomes. References to be provided once accepted

Disseminated pruritic papules

A 60-year-old Arabic man with a medical history of diabetes mellitus was admitted to the hospital for an unprovoked deep vein thrombosis with pruritus, nonproductive cough, and abdominal pain. His pruritus had been ongoing over the preceding four months and he has developed diffuse erythematous to hyperpigmented papules with some having a central keratotic core and others with hemorrhagic crusting. He had minimal to no improvement in his pruritus on mid-potency topical corticosteroids in combination with antihistamines. Over the course of his hospitalization, the patient had a cat scan that demonstrated hepatocellular carcinoma with metastatic pulmonary disease and peritoneal carcinomatosis. A biopsy was performed of his skin lesions that demonstrated acquired perforating disorder. Acquired perforating dermatosis is a disease of adults most commonly seen in patients with acute renal failure or diabetes mellitus. Here, we describe the case of a patient who developed acquired perforating dermatosis in the setting of devastating liver disease due to hepatocellular carcinoma. In addition, acquired perforating dermatosis is most commonly seen on the lower extremities but in this case we describe a patient with disseminated lesions. The patient’s treatment was escalated to high-potency topical corticosteroids and hydroxyzine; however, given his underlying malignancy, his prognosis is quite poor

Photodermatoses in skin of colour

Photodermatoses represent a heterogeneous collection of disorders unified by the characteristic of being provoked through exposure to ultraviolet radiation. Generally, these conditions are classified into the following categories: immunologically mediated photodermatoses, chemical- and drug-induced photosensitivity, photoaggravated dermatoses and photosensitivity associated with defective DNA repair mechanisms or chromosomal instabilities. The list of photodermatoses is extensive, and each individual photodermatosis is understood to a different extent. Regardless, there exists a paucity of information with regards to the clinical presentation among those with skin of colour. With ever-changing global demographics, recognition of photosensitive disorders in a diverse population is essential for accurate diagnoses and therapeutic guidance. The scope of this article seeks to review the epidemiology and clinical variability in presentation of such photodermatoses in patients with skin of colour