Highly variable hearing loss due to POU4F3 (c.37del) is revealed by longitudinal, frequency specific analyses.

Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES).

Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene.

Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.

A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified.

Psychological Distress and Quality of Life in Participants Undergoing Genetic Testing for Arrhythmogenic Right Ventricular Cardiomyopathy Caused by TMEM43 p.S358L: Is It Time to Offer Population-Based Genetic Screening?

Purpose: We have identified 27 families in Newfoundland and Labrador (NL) with the founder variant TMEM43 p.S358L responsible for 1 form of arrhythmogenic right ventricular cardiomyopathy. Current screening guidelines rely solely on cascade genetic screening, which may result in unrecognized, high-risk carriers who would benefit from preemptive implantable cardioverter-defibrillator therapy.

Next-generation humanized patient-derived xenograft mouse model for pre-clinical antibody studies in neuroblastoma.

Faithful tumor mouse models are fundamental research tools to advance the field of immuno-oncology (IO). This is particularly relevant in diseases with low incidence, as in the case of pediatric malignancies, that rely on pre-clinical therapeutic development. However, conventional syngeneic and genetically engineered mouse models fail to recapitulate the tumor heterogeneity and microenvironmental complexity of human pathology that are essential determinants of cancer-directed immunity.

The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate.

Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 variants in trans, which is complicated by extreme allelic and clinical heterogeneity. We report the genetic architecture of STGD1 in the young genetically isolated population of Newfoundland, Canada.

Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss.

Background: Usher syndrome, the most common form of inherited deaf-blindness, is unlike many other forms of syndromic hereditary hearing loss in that the extra aural clinical manifestations are also detrimental to communication. Usher syndrome patients with early onset deafness also experience vision loss due to progressive retinitis pigmentosa that can lead to legal blindness in their third or fourth decade.

Methods: Using a multi-omic approach, we identified three novel pathogenic variants in two Usher syndrome genes (USH2A and ADGRV1) in cases initially referred for isolated vision or hearing loss.

The role of interleukin-2, all-trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma.

Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. Nevertheless, these mechanisms are not fully understood.

TOX2 regulates human natural killer cell development by controlling T-BET expression.

Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA-binding domain with the other TOX members. Although TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells (mNK) and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)-derived CD34(+) cells.

Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL.

Autosomal dominant sensorineural hearing loss (ADSNHL) is extremely genetically heterogeneous, making it difficult to molecularly diagnose. We identified a multiplex (n=28 affected) family from the genetic isolate of Newfoundland, Canada with variable SNHL and used a targeted sequencing approach based on population-specific alleles in WFS1, TMPRSS3 and PCDH15; recurrent mutations in GJB2 and GJB6; and frequently mutated exons of KCNQ4, COCH and TECTA. We identified a novel, in-frame deletion (c.

Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada.

Aims: Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.

A novel deletion in SMPX causes a rare form of X-linked progressive hearing loss in two families due to a founder effect.

X-linked hearing loss is the rarest form of genetic hearing loss contributing to <1% of cases. We identified a multiplex family from Newfoundland (Family 2024) segregating X-linked hearing loss. Haplotyping of the X chromosome and sequencing of positional candidate genes revealed a novel point deletion (c.

Selection of stem cells by using antibodies that target different CD34 epitopes yields different patterns of T-cell differentiation.

The objective of this study was to compare the patterns of T-cell differentiation from CD34(+) human stem cells selected with different classes of antibody targeting the CD34 molecule. We compared signal-joint T-cell receptor excision circle (sjTREC) production in thymocytes selected with different classes of anti-CD34 antibody. Based on these results, we studied immune reconstitution in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice using human stem cells selected with the same antibodies that yielded variation in the thymocytes.

Human gammadelta T cells from G-CSF-mobilized donors retain strong tumoricidal activity and produce immunomodulatory cytokines after clinical-scale isolation.

Human gammadelta T cells are a small fraction of T cells that have been shown to exert major histocompatibility (MHC)-unrestricted natural cytotoxicity against a variety of solid tumors and some subsets of leukemias and lymphomas. They are also involved in the immune response to certain bacterial, viral, and parasitic infections and expand significantly in CMV- or HSV-infected organ allografts. They are able to mediate antibody-dependent cytotoxicity and are not alloreactive, which makes them attractive candidates for cell-based immunotherapy.