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.

Mutational Landscape of Autism Spectrum Disorder Brain Tissue.

Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism from peripheral samples. In this study, we undertook whole exome sequencing on brain tissue from 26 ASD brain donors from the Harvard Brain Tissue Resource Center (HBTRC) and ascertained the presence of post-zygotic and germline mutations categorized as pathological, including those impacting known ASD-implicated genes.

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.

Clinical and molecular significance of genetic loci associated with psoriatic arthritis.

Psoriatic arthritis (PsA) is caused by a combination of environmental and multiple genetic factors, with clear evidence for a strong genetic basis. The remarkable accumulation of knowledge gained from genetic, pharmacogenetic, and therapeutic response of biologic agents in PsA has fundamentally changed and advanced our understanding of disease pathogenesis and has identified key signalling pathways. However, only one-quarter of the genetic contribution of PsA has been accounted for; and dissecting the genetic contributors of the cutaneous disease from those that would identify joint disease has been challenging.

Genetic Epidemiology of Complex Phenotypes.

Genetic and environmental factors are critical elements in most common complex disease. Genetics is increasingly being recognized to play a substantive role in the susceptibility, prognosis, and treatment of common diseases. Due to recent and rapid advancements in characterization of genetic variants and large-scale genotyping platforms, multiple genes and genetic variants have now been identified for common, complex diseases.

Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh.

Collectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet-Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh.

Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis.

Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40-50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA.

An Exploration of Physical and Phenotypic Characteristics of Bangladeshi Children with Autism Spectrum Disorder.

This study explored the physical and clinical phenotype of Bangladeshi children with autism spectrum disorder (ASD). A totally of 283 children who were referred for screening and administered Module 1 of the Autism Diagnostic Observation Schedule (ADOS) were included. Overall, 209 met the ADOS algorithmic cutoff for ASD.

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.

Quantifying Differences in Heritability among Psoriatic Arthritis (PsA), Cutaneous Psoriasis (PsC) and Psoriasis vulgaris (PsV).

Chronic plaque psoriasis and psoriatic arthritis are multifactorial inter-related diseases with strong genetic contributions. Better elucidation of the heritability of psoriatic disease subsets is important for identifying novel genes, risk stratification and potential clinical applications. In this study, we used two mixed-effect modelling methodologies to assess the additive contribution of common single nucleotide polymorphisms from genome-wide association studies to estimate the heritability of cutaneous psoriasis, psoriasis vulgaris and psoriatic arthritis.

Complexities in Genetics of Psoriatic Arthritis.

Purpose Of The Review: To provide a general overview and current challenges regarding the genetics of psoriatic disease. With the use of integrative medicine, multiple candidate loci identified to date in psoriatic disease will be annotated, summarized, and visualized. Recent studies reporting differences in genetic architecture between psoriatic arthritis and cutaneous-only psoriasis will be highlighted.

A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect.

Background: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer.

Methods: Five female HBOC probands sequenced negative for moderate- and high-risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.

The Genetics of Psoriasis and Psoriatic Arthritis.

Psoriatic arthritis (PsA) is an inflammatory arthritis that manifests in 20-30% of patients diagnosed with psoriasis. Epidemiologic studies suggest a substantial genetic contribution to PsA. There is a strong need for genome-wide association studies on patients with PsA, including PsA-weighted or specific variants, and a need for a better understanding of the relevance of HLA alleles in disease expression.

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.

A review of ixekizumab in the treatment of psoriatic arthritis.

Psoriatic arthritis (PsA) is a heterogeneous inflammatory disorder with articular, peri-articular, and extra-articular features along with selected co-morbidities as a sequela to chronic inflammation. There is accumulating evidence that the Th-17 signaling pathway is of critical importance in PsA pathogenesis. Areas covered: Ixekizumab (IXE) is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody directed against IL-17A.

Ustekinumab in psoriatic arthritis and related phenotypes.

Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The T-helper (Th)-17 pathway and the interleukin (IL)-23/IL-17 axis have become prominent players in PsA and considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the emerging role of IL-12/23 and its blockade, in the pathogenesis and management of PsA as well as of psoriasis and inflammatory bowel disease.

Expression and Metabolomic Profiling in Axial Spondyloarthritis.

Purpose Of Review: The purpose of this review is to highlight recent evidence with respect to expression and metabolomic profiling in axial spondyloarthritis (axSpA) that included ankylosing spondylitis (AS).

Recent Findings: AxSpA is not only characterized by the strongest genetic contribution for any complex rheumatic disease but is also influenced by environmental and immunological factors. Large-scale association-based studies have identified over 100 genetic variants contributing to 30% of the genetic risk of ankylosing spondylitis.

A review of ustekinumab in the treatment of psoriatic arthritis.

Psoriatic arthritis is an inflammatory arthritis associated with psoriasis. The IL-23/IL-17 axis is an important pathway in the development of psoriatic disease. Ustekinumab is a fully human monoclonal IgG1 antibody that binds to the p40 subunit of IL-12 and IL-23, which, in turn, inhibits downstream signaling pathways.

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect.

Genetic isolates provide unprecedented opportunities to identify pathogenic mutations and explore the full natural history of clinically heterogeneous phenotypes such as hearing loss. We noticed a unique audioprofile, characterized by prelingual and rapid deterioration of hearing thresholds at frequencies >0.5 kHz in several adults from unrelated families from the island population of Newfoundland.

Pharmacogenetics and pharmacogenomics in psoriasis treatment: current challenges and future prospects.

Introduction: Topical, systemic, oral disease modifying, and biologic agents are part of the armamentarium to manage psoriatic disease. The choice of therapy depends upon disease severity, relevant co-morbidities and patient preference. There is great variability in patient response with these agents, and there is still no clear method of selecting the preferred therapeutic agent for efficacy or lack of adverse events.

Ankylosing spondylitis: beyond genome-wide association studies.

Purpose Of Review: This article discusses genomic investigations in ankylosing spondylitis (AS) beyond genome-wide association (GWA) studies, but prior to this, genetic variants achieving genome-wide significance will be summarized highlighting key pathways contributing to disease pathogenesis.

Recent Findings: Evidence suggests that disease pathogenesis is attributed to a complex interplay of genetic, environmental and immunological factors. GWA studies have greatly enhanced our understanding of AS pathogenesis by illuminating distinct immunomodulatory pathways affecting innate and acquired immunity, most notably the interleukin-23/interleukin-17 pathway.