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We sought to understand how the coronavirus disease 2019 (COVID-19) pandemic has affected the well-being, clinical training, and medical education for clinical trainees in medical genetics and genomics residency and fellowship programs. All clinical genetics trainees in the Accreditation Council for Graduate Medical Education (ACGME)-accredited training programs were invited to complete a survey. 31 out of 174 trainees completed the survey. With regards to well-being, 18 trainees reported increased anxiety, 10 had increased depression, 3 increased financial strain, 13 worsening work-life balance, and 13 worsening physical health. There was increased telehealth utilization in both outpatient (3% before the pandemic vs. 67% during the pandemic) and inpatient clinical encounters (0% vs. 29%). The most commonly reported challenges in telehealth use were inadequate physical examination and technical problems during visits. Twenty trainees believed that the pandemic has negatively impacted overall clinical training while none reported a positive impact. We concluded that the COVID-19 pandemic has negatively impacted most clinical genetics trainees in ACGME-accredited training programs. Telehealth has been increasingly used with some challenges. Further studies are needed on how to optimally integrate what we have learned into the training of medical genetics and genomics in the post-pandemic era.

Activating variants in the platelet-derived growth factor receptor β gene (PDGFRB) have been associated with Kosaki overgrowth syndrome, infantile myofibromatosis, and Penttinen premature aging syndrome. A recently described phenotype with fusiform aneurysm has been associated with mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant. Few reports however have examined the vascular phenotypes and mosaic effects of PDGFRB variants. We describe clinical characteristics of two patients with a recurrent mosaic PDGFRB p.(Tyr562Cys) variant identified via next-generation sequencing-based genetic testing. We observed intracranial fusiform aneurysm in one patient and found an additional eight patients with aneurysms and phenotypes associated with PDGFRB-activating variants through literature search. The conditions caused by PDGFRB-activating variants share overlapping features including overgrowth, premature aged skin, and vascular malformations including aneurysms. Aneurysms are progressive and can result in morbidities and mortalities in the absence of successful intervention. Germline and/or somatic testing for PDGFRB gene should be obtained when PDGFRB activating variant-related phenotypes are present. Whole-body imaging of the arterial tree and echocardiography are recommended after diagnosis. Repeating the imaging study within a 6- to 12-month period after detection is reasonable. Finally, further evaluation for the effectiveness and safety profile of kinase inhibitors in this patient population is warranted.

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.

We aim to assess residents’ perspectives and clinical utility of obtaining family history (FH) as well as to improve the rate of FH documentation in electronic medical record (EMR) at an internal medicine resident continuity clinic at a community hospital. The residents’ perspectives were assessed with questionnaires. The study period was divided into the first 10-week Phase 1 in which genetic education interventions were delivered by residents, and the second 10-week Phase 2 with minimal intervention. FH documentation in EMR was reviewed and compared to a 4-week baseline (Phase 0). We found that time constraint was the most reported barrier. We reviewed 1197 patient visits; FH was recorded in 34% (67/200), 52% (272/522), and 50% (239/475) during Phase 0, Phase1, and Phase 2, respectively. Genetic education significantly increased the rate of FH documentation in Phase 1 from baseline, which was maintained in Phase 2 despite removal of interventions. The mean age of patients with documented FH was younger than those without documentation (48 years vs 51 years; p

Additional file 4: Figure S2. De novo mosaicism in individual 6.

Additional file 6. Clinical reports of here presented individuals.

Additional file 5: Figure S3. Whole gene deletion in individual 24.

Additional file 8: Figure S5. Recombinant protein variants of DHX30 induce the formation of cytoplasmic clusters.

Additional file 1. Supplementary methods.

Additional file 7: Figure S4. DHX30 WT acts as an ATP-dependent RNA helicase.

Additional file 3: Figure S1. Identified missense variants affect highly conserved amino acids.

Additional file 9: Figure S6. Representative images of zebrafish embryos.

BackgroundWe aimed to define the clinical and mutational spectrum, and to provide novel molecular insights into DHX30-associated neurodevelopmental disorder.MethodsClinical and genetic data from affected individuals were collected through family support group, GeneMatcher and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.ResultsWe identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual bearing a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location and type we establish two distinct clinical subtypes. DHX30 loss-of-function mutations cause a milder phenotype whereas a severe phenotype is caused by HCM missense mutations that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of function with respect to SG formation. Behavioral characterization of dhx30 deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.ConclusionsOur study highlights the usefulness of social media in order to define novel Mendelian disorders, and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories and research laboratories.

BACKGROUND Life expectancy of individuals with Down syndrome (DS) has improved significantly over the past decades. However, there are sparse data documenting the co-morbidities and hospitalisation of adult patients with DS in the literature. The aim of this study was to characterise the co-morbidities and pattern of hospitalisation in adult patients with DS during a 10-year period at the community hospital as well as to compare hospitalisation parameters with the general adult population during the same years. METHOD We reviewed the medical records of 81 hospitalisations from 37 patients with DS aged 21 to 68 years at Metrowest Medical Center during a 10-year period and compared with those of the general adult population during the same time. Co-morbidities were also described. RESULTS Adults with DS had a mean age at admission of 48.6 ± 8.8 years with the median length of stay of 3 days (interquartile range 4 days). Male patients were hospitalised longer than female patients (mean 5.0 vs. 2.8 days; P

AIM To determine whether fasting C-peptide is an independent predictor for non-alcoholic fatty liver disease (NAFLD) in United States population. METHODS Using the National Health and Nutrition Examination Survey (NHANES) 1988-1994, NAFLD participants aged 20 or greater without any other liver diseases were included in this study. Excessive alcohol intake is defined as > 2 drinks per day for males and > 1 drink per day for females. C-peptide and 27 other factors known to be associated with NAFLD (e.g., age, gender, body mass index, waist circumference, race/ethnicity, liver chemistries, and other diabetes tests) were tested in both univariate and multivariate level using logistic regression with a P-value 0.05. RESULTS Of 18825 participants aged ≥ 20, 3235 participants (n = 3235) met inclusion criteria. There were 23 factors associated with NAFLD by univariate analysis. 9 factors, ranked by the highest change in pseudo R2, were found to be significant predictors of NAFLD in multivariate model: waist circumference, fasting C-peptide, natural log of alanine aminotransferase (ALT), total protein, being Mexican American, natural log of glycated hemoglobin, triglyceride level, being non-Hispanic white, and ferritin level. CONCLUSION Together with waist circumference and ALT, fasting C-peptide is among three most important predictors of NAFLD in United States population in the NHANES data set. Further study is needed to validate the clinical utility of fasting C-peptide in diagnosis or monitoring insulin resistance in NAFLD patients.

The incidence of hypocalcemia and bone mineral density (BMD) changes in end-stage renal disease (ESRD) patients on denosumab remains unclear. We performed this meta-analysis to assess the incidence of denosumab-associated hypocalcemia and effects of denosumab on BMD in ESRD patients. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through November 2017 to identify studies evaluating incidence of denosumab-associated hypocalcemia and changes in serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and BMD from baseline to post-treatment course of denosumab in ESRD patients. Study results were pooled and analyzed using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017081074). Six observational studies with a total of 84 ESRD patients were enrolled. The pooled estimated incidence of hypocalcemia during denosumab treatment was 42% (95% CI 29–55%, I2 = 0%). Hypocalcemia occurred approximately 7 to 20 days after the first dose and reached nadir of low calcium levels in the first 2 weeks up to 2 months. However, there were no significant changes in serum calcium or phosphate from baseline to post-treatment course (≥ 3 months after treatment) with mean differences [MDs] of 0.20 mg/dL (95% CI, − 0.30 to 0.69 mg/dL) and − 0.10 mg/dL (95% CI, − 0.70 to 0.49 mg/dL). There were significant reductions in ALP and PTH levels with standardized mean differences (SMDs) of − 0.65 (95% CI − 1.13 to − 0.16) and − 1.89 (95% CI − 3.44 to − 0.34), respectively. There were significant increases in T-scores with MDs of 0.39 (95% CI 0.10 to 0.69) and 0.79 (95% CI 0.60 to 0.98) for lumbar spine and femoral neck, respectively. Our study demonstrates the estimated incidence of denosumab-associated hypocalcemia in dialysis patients of 42%. From baseline to post-treatment course, although there are no differences in serum calcium and phosphate, our findings suggest significant reductions in ALP and PTH and a significant increase in BMD. Currently, denosumab should not be considered as the treatment of choice in ESRD patients until more safety and efficacy data are available.

This systematic review aims to assess the occurrence and risks of osteopenia and osteoporosis in patientswith Wilson's disease (WD). A literature search was conducted utilizing EMBASE and MEDLINE frominception through April 2017. Studies assessing the occurrence or risk of osteopenia and/or osteoporosis inWD patients were included. Effect estimates from the individual study were extracted and combined usingrandom-effect, generic inverse variance method of DerSimonian and Laird. Of 754 studies, four studies with283 WD patients met the eligibility criteria and were included in the data analysis. The pooled prevalencerates of osteopenia and osteoporosis in WD patients were 36.5% (95% confidence interval [CI]: 14.8%-65.7%) and 27.7% (95%CI: 8.6%-60.9%), respectively. When meta-analysis was limited only to adults, the estimated prevalence rates of osteopenia, osteoporosis, and vertebral fracture were 50.0% (95%CI: 42.0%-58.0%), 17.6% (95%CI: 6.7%-38.6%) and 8.01% (95%CI: 4.05%-15.2%), respectively. Meta-regressionshowed significant impacts of age (negative correlation; P=0.002) and male status (positive correlation;P

Arterial function is a marker of early atherosclerotic changes and cardiovascular disease. Several studies have suggested the possible association between nonalcoholic fatty liver disease (NAFLD) and increased arterial stiffness. Thus, we conducted a systematic review and meta-analysis to better characterize this association.A comprehensive search of the databases of the MEDLINE and EMBASE was carried out from inception through September 2016. All observational studies that compared arterial stiffness between NAFLD patients and healthy controls were included. Arterial stiffness was measured by pulse wave velocity (PWV) and augmentation index. We calculated pooled mean difference (MD) with 95% confidence intervals (CIs) using the random-effects model.Data were extracted from 12 studies involving 9351 NAFLD patients and 17 684 controls. NAFLD is significantly associated with increased arterial stiffness as determined by carotid-femoral PWV (MD=0.75 m/s, 95% CI: 0.43-1.07, I=88%), brachial-ankle PWV (MD=0.82 m/s, 95% CI: 0.57-1.07, I=92%), and augmentation index (pooled MD=2.54%, 95% CI: 0.07-5.01, I=73%) compared with healthy controls.In conclusion, our study demonstrated a higher degree of arterial stiffness in NAFLD patients compared with controls. However, this association might be related to the higher prevalence of cardiometabolic risk factors in NAFLD patients. Further studies are needed to determine an independent association between NAFLD and arterial stiffness adjusting to cardiometabolic risks.

Thyroid cancer (TC) is a known extra-intestinal manifestation and contributes to the mortality and morbidity in patients with familial adenomatous polyposis (FAP). Its exact prevalence is not well established and recent studies have shown an increasing number of TC in this patient population. The prevalence of benign thyroid masses and endocrinologic thyroid disorders are also poorly described. We conducted a systematic review and meta-analysis by using a random-effects model to characterize TC and estimated the prevalence of thyroid diseases in FAP patients. Twelve studies (n = 9821) were included. Pooled prevalence of TC, benign thyroid masses, and endocrinologic thyroid disorders in FAP were 2.6% [95% confidence interval (CI) 1.3–4.8], 48.8% [95% CI 33.8–64.0], and 6.9% [95% CI 4.5–10.3] respectively. Subgroup analyses revealed higher prevalence of TC in studies with fewer participants, studies that used screening ultrasound to diagnose TC, and studies that were published after 2002. TC diagnosis preceded the diagnosis of FAP in 34% of the patients. The means age at diagnosis of FAP and TC were 29 and 31 years, respectively. 95% of the patients were female and the most common pathology was of papillary subtype (83.3%). Most mutations (79.2%) were located at the 5′ end of APC gene. In summary, benign thyroid disorders are common in FAP, yet, TC is an uncommon phenomenon. Certain patient subset, such as young female with APC mutation at the 5′ end, might benefit from routine surveillance ultrasound.

BACKGROUND: Brugada syndrome (BrS) is an inherited arrhythmic disease linked to SCN5A mutations. It is controversial whether SCN5A mutation carriers possess a greater risk of major arrhythmic events (MAE). We examined the association of SCN5A mutations and MAE in BrS patients. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published cohort and case–control studies that compared MAE in BrS patients with and without SCN5A mutations. Data from each study were combined using the random‐effects model. Generic inverse variance method of DerSimonian and Laird was employed to calculate the risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Seven studies from March 2002 to October 2017 were included (1,049 BrS subjects). SCN5A mutations were associated with MAE in Asian populations (RR = 2.03, 95% CI: 1.37–3.00, p = 0.0004, I (2 )= 0.0%), patients who were symptomatic (RR = 2.66, 95% CI: 1.62–4.36, p = 0.0001, I (2 )= 23.0%), and individuals with spontaneous type‐1 Brugada pattern (RR = 1.84, 95% CI: 1.05–3.23, p = 0.03, I (2 )= 0.0%). CONCLUSIONS: SCN5A mutations in BrS increase the risk of MAE in Asian populations, symptomatic BrS patients, and individuals with spontaneous type‐1 Brugada pattern. Our study suggests that SCN5A mutation status should be an important tool for risk assessment in BrS patients.

A 52-year-old man was referred to an adult cardiovascular genetic clinic for lifelong venous tortuosity of the left leg. His medical history included recurrent deep venous thromboses of the left leg and pulmonary embolism complicated by oxygen-dependent chronic thromboembolic pulmonary hypertension and right-sided heart failure. He was taking warfarin and reported no family history of similar conditions. On examination, crackles were noted at bibasilar lungs. The left leg was slightly longer than the right leg, and giant tortuous veins were observed on the left side (figure 1A). MRI and angiography of the lower extremities revealed diffuse muscular hypertrophy (figure 1B) and bone elongation of the femur, tibia and fibula, as well as multiple capillary-venous malformations and tortuous deep and superficial …

Based on the location of training programs, internal applicants and local applicants were defined as applicants who attended the same training institution and trained in local areas (i.e., state, division, and region), respectively. While being an internal applicant does influence fellowship matching success for some specialties, gastroenterology fellowship program directors do not rank this consideration in the top half of their priority list. There is no published evidence about the frequency that internal applicants and local applicants match in US gastroenterology training program. To find the proportion of gastroenterologists who were internal applicants and local applicants during the graduation years 2010–2019. Online search in Doximity was conducted to obtain postgraduate training information of gastroenterologists with the graduation years 2010–2019. Programs were classified into nine divisions and four regions per United States Census Bureau. We used confidence level 95% and margin of error 2% to calculate sample size. In total, 1489 physicians (N = 1489) were included. The proportion of internal applicants was 39.56% of the sample size. The proportions of gastroenterologists who attended IM residency programs in the same state, same division, and same region were 53.06, 60.64, and 71.93%, respectively. A large proportion of gastroenterologists were either internal applicants or local applicants. Further research is necessary to better understand the reasons behind these trends and whether the bias against external or geographically distant fellowship candidates is intended or unintended, as these data have broad implications for GI fellowship candidate residency program and geography choices.

Background: Dialysis in older adults with chronic kidney disease (CKD) and comorbidities may not be associated with improved life expectancy compared to conservative management. To inform clinical practice, we performed a systematic review of all available studies examining this hypothesis. Methods: We performed a systematic review of retrospective and prospective cohort studies of older adults with stage-5 CKD who chose dialysis (hemodialysis or peritoneal dialysis) or opted for conservative management (including management of complications of CKD and palliative care). Outcomes of interest included hospitalizations and mortality. Results: Twelve cohort studies (11,515 patients) were identified with most of them focusing on older adults. Patients choosing dialysis were younger compared to those opting for conservative management and were less functionally impaired. Patients opting for conservative management received care in a multidisciplinary setting focusing on palliative care and management of complications of CKD. Patients choosing dialysis and conservative management had a median survival time of 8-67 and 6-30 months, respectively. In a subset of studies of patients 65 years and older with an estimated glomerular filtration rate 2, and where the multivariable analyses included age and comorbidities, by meta-analysis, patients choosing dialysis had a pooled adjusted hazard ratio for mortality of 0.53 (95% CI 0.30-0.91, p = 0.02) relative to those opting for conservative management; however, significant heterogeneity precluded definitive conclusions. Conclusions: When caring for older adults with advanced CKD who are contemplating dialysis therapy vs. conservative management, efforts must focus on promoting patient values and preferences, shared decision-making, and symptom burden alleviation.

Tracheobronchomegaly (Mounier-Kuhn syndrome) is a rare condition characterized by an abnormally enlarged trachea and main bronchi. Herein, we present a case of 79-year-old male with idiopathic pulmonary fibrosis and acute hypoxemic respiratory failure due to multilobar pneumonia. Computed tomography of the chest demonstrated a markedly dilated trachea, with the transverse diameter of 31mm and the sagittal diameter of 30mm. The clinical manifestations as well as its diagnosis, classification, and treatment are discussed.

Brugada syndrome (BrS) is an autosomal dominant inherited arrhythmic disease associated with the SCN5A mutation. Recent studies suggest that SCN5A mutation is associated with major arrhythmic events (MAE) in BrS which is controversial in previous studies. However, a systematic review and meta

Background Recent studies suggested that variants on chromosome loci 4q25, 1q21, and 16q22 were associated with atrial fibrillation recurrence after catheter ablation. In this study, we performed a systematic review and meta-analysis to explore the association between variants on chromosome loci 4q25, 1q21, and 16q22 and atrial fibrillation recurrence after catheter ablation. Methods We comprehensively searched the databases of MEDLINE and EMBASE from inception to January 2017. Included studies were published prospective or retrospective cohort and case control studies that compared the risk of atrial fibrillation recurrence after catheter ablation in AF patients with chromosome 4q25, 1q21, and 16q22 variants versus no variants. Single-nucleotide polymorphism rs1906617, rs2106261, rs7193343, rs2200733, rs10033464, rs13376333, and rs6843082 were included in this analysis. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate the risk ratios and 95% confidence intervals. Results Seven studies from January 2010 to June 2017 involving 3,322 atrial fibrillation patients were included in this meta-analysis. According to the pooled analysis, there was a strong independent association between chromosome 4q25 variant (rs2200733) and the risk of atrial fibrillation recurrence after catheter ablation (risk ratio 1.45 [95% confidence interval 1.15-1.83], P = 0.002). No association was found in other variants. Conclusion Our meta-analysis demonstrates a statistically significant increased risk of atrial fibrillation recurrence after catheter ablation in 4q25 variant (only in rs2200733) but not in 1q21 or 16q22 variants.