Public Interest in Carrier Screening in the Brazilian Population

Brazil has a heterogeneous population comprising indigenous, European, and African ancestral roots that have contributed to carrier risks for certain autosomal recessive disorders, such as sickle-cell disease, thalassemias, cystic fibrosis, and (in the Ashkenazi Jewish Brazilian population) Tay-Sachs disease. An anonymous online survey was distributed to Brazilians using Facebook and Reddit. A total of 353 eligible participants responded. This study explored knowledge of these disorders, knowledge of autosomal recessive inheritance, perception of carrier risk, and interest in carrier screening. The mean knowledge score was 53% (range: 15% to 100%) and was not significantly associated with level of education. Physicians had significantly higher knowledge scores than all other professions. Non-physician healthcare professionals, however, did not have higher knowledge scores when compared to non-physician professionals. Overall, perception of carrier risk was low. Participants expressed high interest in carrier screening, regardless of demographic background. Seventy-eight percent of participants expressed high interest in carrier screening, and 91% expressed high interest specifically in carrier screening for life-threatening disorders if treatment were available. Participants preferred having carrier screening prior to pregnancy compared to during pregnancy or waiting for newborn screening (p<0.001). Additionally, 86% of participants were interested in carrier screening for disorders that are not typically included in newborn screening.Challenges to implementing a screening program in Brazil include the shortage of genetics-trained professionals and lack of infrastructure. The carrier risks for these disorders, and the interest presented here, justify a need for expansion of Brazil’s genetic services to include population-wide preconception and prenatal carrier screening

Public Interest in Carrier Screening in the Brazilian Population

Brazil has a heterogeneous population comprising indigenous, European, and African ancestral roots that have contributed to carrier risks for certain autosomal recessive disorders, such as sickle-cell disease, thalassemias, cystic fibrosis, and (in the Ashkenazi Jewish Brazilian population) Tay-Sachs disease. An anonymous online survey was distributed to Brazilians using Facebook and Reddit. A total of 353 eligible participants responded. This study explored knowledge of these disorders, knowledge of autosomal recessive inheritance, perception of carrier risk, and interest in carrier screening. The mean knowledge score was 53% (range: 15% to 100%) and was not significantly associated with level of education. Physicians had significantly higher knowledge scores than all other professions. Non-physician healthcare professionals, however, did not have higher knowledge scores when compared to non-physician professionals. Overall, perception of carrier risk was low. Participants expressed high interest in carrier screening, regardless of demographic background. Seventy-eight percent of participants expressed high interest in carrier screening, and 91% expressed high interest specifically in carrier screening for life-threatening disorders if treatment were available. Participants preferred having carrier screening prior to pregnancy compared to during pregnancy or waiting for newborn screening (p<0.001). Additionally, 86% of participants were interested in carrier screening for disorders that are not typically included in newborn screening.Challenges to implementing a screening program in Brazil include the shortage of genetics-trained professionals and lack of infrastructure. The carrier risks for these disorders, and the interest presented here, justify a need for expansion of Brazil’s genetic services to include population-wide preconception and prenatal carrier screening

Phenotypic diversity of patients diagnosed with VACTERL association.

The combination of vertebral, anal, cardiac, tracheo-esophageal, renal and limb anomalies termed VACTERL association, also referred to as VATER, has been used as a clinical descriptor and more recently, a diagnosis of exclusion, for a specific group of phenotypic manifestations that have been observed to co-occur non-randomly. Though the causes remain elusive and poorly understood in most patients, VACTERL association is thought to be due to defects in early embryogenesis and is likely genetically heterogeneous. We present data on 36 patients diagnosed with VACTERL association in addition to describing the phenotypic diversity of each component feature. Unique cases in our cohort include a patient with a 498.59 kb microdeletion in the 16p11.2 region and another with a 215 kb duplication in the 3p25.2 region. Our findings expand upon the current understanding of VACTERL association and guide future research aimed at determining its etiology

A Transposon-Mediated System for Flexible Control of Transgene Expression in Stem and Progenitor-Derived Lineages

Precise methods for transgene regulation are important to study signaling pathways and cell lineages in biological systems where gene function is often recycled within and across lineages. We engineered a genetic toolset for flexible transgene regulation in these diverse cellular contexts. Specifically, we created an optimized piggyBac transposon-based system, allowing for the facile generation of stably transduced cell lineages in vivo and in vitro. The system, termed pB-Tet-GOI (piggyBac-transposable tetracycline transactivator-mediated flexible expression of a genetic element of interest), incorporates the latest generation of tetracycline (Tet) transactivator and reverse Tet transactivator variants—along with engineered mutants—in order to provide regulated transgene expression upon addition or removal of doxycycline (dox). Altogether, the flexibility of the system allows for dox-induced, dox-suppressed, dox-resistant (i.e., constitutive), and dox-induced/constitutive regulation of transgenes. This versatile strategy provides reversible temporal regulation of transgenes with robust inducibility and minimal leakiness

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A due to mutations in the GLA gene. This leads to an accumulation of globotriaosylceramide (GL-3) in many tissues, which results in progressive damage to the kidneys, heart, and nervous system. We present the molecular and clinical characteristics and long-term outcomes of FD patients from a multidisciplinary clinic at the University of California, Irvine treated with agalsidase beta enzyme replacement therapy (ERT) for 2-20 years. This cohort comprised 24 adults (11 males, 13 females) and two male children (median age 45; range 10-68 years). Of the 26 patients in this cohort, 20 were on ERT (12 males, 8 females). We describe one novel variant not previously reported in the literature in a patient with features of 'classic' FD. The vast majority of patients in this cohort presented with symptoms of 'classic' FD including peripheral neuropathic pain, some form of cardiac involvement, angiokeratomas, corneal verticillata, hypohidrosis, tinnitus, and gastrointestinal symptoms, primarily abdominal pain. The majority of males had clinically evident renal involvement. An annual eGFR reduction of -1.88 mL/min/1.73 m2/yr during the course of ERT was seen in this cohort. The most common renal presentation was proteinuria, and one individual required a renal transplant. Other common findings were pulmonary involvement, lymphedema, hearing loss, and significantly, three patients had strokes. Notably, there was a high prevalence of endocrine dysfunction and low bone mineral density, including several with osteoporosis. While enzyme replacement therapy (ERT) cleared plasma GL-3 in this cohort, there was limited improvement in renal function or health-related quality of life based on the patient-reported SF-36 Health Survey. Physical functioning significantly declined over the course of ERT treatment, which may be, in part, due to the late initiation of ERT in several patients. Further delineation of the phenotypic and genotypic spectrum in patients with FD and the long-term outcome of ERT will help improve management and treatment options for this disease

Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma

SummaryAs the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma