Functional Characterization of ABCA4 Missense Variants Aids Variant Interpretation and Phenotype Prediction in Patients With ABCA4-Retinal Dystrophies.

Purpose: Biallelic pathogenic variants in the gene encoding the ATP-binding cassette transporter ABCA4 are the leading cause of irreversible vision loss in inherited retinal dystrophies (IRDs). Interpretation of ABCA4 variants is challenging, due to cis-modifying and hypomorphic variants. We have previously detected 10 missense variants of unknown significance (VUS) in patients with suspected ABCA4-retinal dystrophies (ABCA4-RDs) in Norway.

Long-Term Follow-Up of Pediatric Excimer Laser-Assisted Penetrating Keratoplasty for Congenital Stromal Corneal Dystrophy.

Purpose: The purpose of this study was to highlight characteristic clinical and microscopic findings and report the long-term follow-up of pediatric excimer laser-assisted penetrating keratoplasty (excimer-PKP) for congenital stromal corneal dystrophy (CSCD).

Methods: A 2-year-old Greek child presented with CSCD at our department. Clinical examination showed bilateral flake-like whitish corneal opacities affecting the entire corneal stroma up to the limbus.

A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms.

Functional Analyses of Rare Germline Missense Variants Located within and outside Protein Domains with Known Functions.

The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in focus on variants located within the Really Interesting New Gene (RING), coiled-coil and BRCA1 C-terminal (BRCT) domains, and several missense variants in these regions have been shown to be pathogenic. However, the majority of these studies focus on domain specific assays, and have been performed using isolated protein domains and not the full-length BRCA1 protein.

Screening patients with autoimmune endocrine disorders for cytokine autoantibodies reveals monogenic immune deficiencies.

Background: Autoantibodies against type I interferons (IFN) alpha (α) and omega (ω), and interleukins (IL) 17 and 22 are a hallmark of autoimmune polyendocrine syndrome type 1 (APS-1), caused by mutations in the autoimmune regulator (AIRE) gene. Such antibodies are also seen in a number of monogenic immunodeficiencies.

Objectives: To determine whether screening for cytokine autoantibodies (anti-IFN-ω and anti-IL22) can be used to identify patients with monogenic immune disorders.

The SH3PXD2A-HTRA1 fusion transcript is extremely rare in Norwegian sporadic vestibular schwannoma patients.

Introduction: Vestibular schwannoma (VS) is a benign intracranial tumor in which the underlying genetics is largely uncertain, apart from mutations in the tumor suppressor gene NF2. Alternative tumorigenic mechanisms have been proposed, including a recurrent in-frame fusion transcript of the HTRA1 and SH3PXD2A genes. The gene product of the SH3PXD2A-HTRA1 fusion has been shown to promote proliferation, invasion and resistance to cell death in vitro and tumor growth in vivo.

Genetic Dominant Variants in Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Variants in cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant variants.

GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility.

Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10).

Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison's Disease.

Background: No reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison's disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal.

Objective: To explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD.

Methods: Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD.

Clinical features and molecular genetics of patients with ABCA4-retinal dystrophies.

Purpose: Pathogenic variations in the ABCA4 gene are a leading cause of vision loss in patients with inherited retinal diseases. ABCA4-retinal dystrophies are clinically heterogeneous, presenting with mild to severe degeneration of the retina. The purpose of this study was to clinically and genetically characterize patients with ABCA4-retinal dystrophies in Norway and describe phenotype-genotype associations.

Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents.

Recurrent copy number variations (CNVs) are common causes of neurodevelopmental disorders (NDDs) and associated with a range of psychiatric traits. These CNVs occur at defined genomic regions that are particularly prone to recurrent deletions and duplications and often exhibit variable expressivity and incomplete penetrance. Robust estimates of the population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders (NDD CNVs) are lacking.

Shared genetic background between children and adults with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls.

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23-a likely pathogenic variant with reduced penetrance?

Rare sequence variants in the non-coding part of the BRCA genes are often reported as variants of uncertain significance (VUS), which leave patients and doctors in a challenging position. The aim of this study was to determine the pathogenicity of the BRCA1 c.5407-25T>A variant found in 20 families from Norway, France and United States with suspected hereditary breast and ovarian cancer.

The quaternary structure of human tyrosine hydroxylase: effects of dystonia-associated missense variants on oligomeric state and enzyme activity.

Tyrosine hydroxylase (TH) is a multi-domain, homo-oligomeric enzyme that catalyses the rate-limiting step of catecholamine neurotransmitter biosynthesis. Missense variants of human TH are associated with a recessive neurometabolic disease with low levels of brain dopamine and noradrenaline, resulting in a variable clinical picture, from progressive brain encephalopathy to adolescent onset DOPA-responsive dystonia (DRD). We expressed isoform 1 of human TH (hTH1) and its dystonia-associated missense variants in E.

Genetic and transcriptional analysis of inflammatory bowel disease-associated pathways in patients with GUCY2C-linked familial diarrhea.

Objective: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients.

Early Stage Discovery and Validation of Pharmacological Chaperones for the Correction of Protein Misfolding Diseases.

Pharmacological chaperones are small molecular weight molecules that bind specifically to protein targets and stabilize unstable and misfolded conformations. In particular, there is an increasing interest in the application of this type of compounds for the correction of genetic conformational disorders, which are caused by mutations leading to protein instability. The discovery of compounds with pharmacological chaperone ability is customarily initiated by a high-throughput screening of chemical libraries searching for stabilizing binders.

Rare genetic variation in mitochondrial pathways influences the risk for Parkinson's disease.

Background: Mitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein-altering variation in nuclear genes controlling mitochondrial structure and function.

Objective: The objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD.

Beta-propeller protein-associated neurodegeneration: a case report and review of the literature.

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare disorder, which is increasingly recognized thanks to next-generation sequencing. Due to a highly variable phenotype, patients may present to pediatrics, neurology, psychiatry, or internal medicine. It is therefore essential that physicians of different specialties are familiar with this severe and debilitating condition.

Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1.

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.