Somatic Variants Acquired Later in Life Associated with Thoracic Aortic Aneurysms: V617F.

The V617F somatic variant is a well-known driver of myeloproliferative neoplasms (MPN) associated with an increased risk for athero-thrombotic cardiovascular disease. Recent studies have demonstrated its role in the development of thoracic aortic aneurysm (TAA). However, limited clinical information and level of V617F burden have been provided for a comprehensive evaluation of potential confounders.

Maternal Uniparental Isodisomy of Chromosome 2 Leading to Homozygous Variants in and : A Case Report and Review of the UPD2 Literature.

We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in , and a variant of uncertain significance in . Biallelic pathogenic variants in lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD.

Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group.

Purpose: Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.

Trp719Arg Genetic Variant Increases Risk for Thoracic Aortic Dissection.

Background: KIF6 (kinesin family member 6), a protein coded by the gene, serves an important intracellular function to transport organelles along microtubules. In a pilot study, we found that a common Trp719Arg variant increased the propensity of thoracic aortic aneurysms (TAA) to suffer dissection (AD). The present study aims for a definite investigation of the predictive ability of 719Arg vis à vis AD.

Detecting regions of homozygosity improves the diagnosis of pathogenic variants and uniparental disomy in pediatric patients.

Chromosomal microarray analysis using single nucleotide polymorphism probes can detect regions of homozygosity (ROH). This confers a potential utility in revealing autosomal recessive (AR) diseases and uniparental disomy (UPD). Results of genetic testing among pediatric patients from 2015 to 2019 were evaluated.

A de novo 10.79 Mb interstitial deletion at 2q13q14.2 involving PAX8 causing hypothyroidism and mullerian agenesis: a novel case report and literature review.

Reports of interstitial deletions involving proximal long arm of chromosome 2 are limited. Based on early chromosomal analysis studies, the phenotypic consequence of deletions at the ancestral chromosome fusion site at chromosome 2q13q14.1 remains unclear.

The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1.

The methyl-CpG-binding domain (MBD) gene family was first linked to autism over a decade ago when Rett syndrome, which falls under the umbrella of autism spectrum disorders (ASDs), was revealed to be predominantly caused by MECP2 mutations. Since that time, MECP2 alterations have been recognized in idiopathic ASD patients by us and others. Individuals with deletions across the MBD5 gene also present with ASDs, impaired speech, intellectual difficulties, repetitive behaviors, and epilepsy.

Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways.

Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to <1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes.

Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci.

Background: Autism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism.

An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD.

Methods: We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set.

Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk.

Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility.

Microduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21.

Copy number variations (CNVs) play a crucial role in the intricate genetics of autism spectrum disorders. A region on chromosome 15q24 vulnerable to both deletions and duplications has been previously implicated in a range of phenotypes including autism, Asperger's syndrome, delayed development, and mild to severe mental retardation. Prior studies have delineated a minimal critical region of approximately 1.

A de novo 1.5 Mb microdeletion on chromosome 14q23.2-23.3 in a patient with autism and spherocytosis.

Autism is a neuro-developmental disorder characterized by deficits in social interaction and communication as well as restricted interests or repetitive behaviors. Cytogenetic studies have implicated large chromosomal aberrations in the etiology of approximately 5-7% of autism patients, and the recent advent of array-based techniques allows the exploration of submicroscopic copy number variations (CNVs). We genotyped a 14-year-old boy with autism, spherocytosis and other physical dysmorphia, his parents, and two non-autistic siblings with the Illumina Human 1M Beadchip as part of a study of the molecular genetics of autism and determined copy number variants using the PennCNV algorithm.

Genetic analysis of biological pathway data through genomic randomization.

Genome Wide Association Studies (GWAS) are a standard approach for large-scale common variation characterization and for identification of single loci predisposing to disease. However, due to issues of moderate sample sizes and particularly multiple testing correction, many variants of smaller effect size are not detected within a single allele analysis framework. Thus, small main effects and potential epistatic effects are not consistently observed in GWAS using standard analytical approaches that consider only single SNP alleles.

A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism.

Background: Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism.

A genome-wide association study of autism reveals a common novel risk locus at 5p14.1.

Although autism is one of the most heritable neuropsychiatric disorders, its underlying genetic architecture has largely eluded description. To comprehensively examine the hypothesis that common variation is important in autism, we performed a genome-wide association study (GWAS) using a discovery dataset of 438 autistic Caucasian families and the Illumina Human 1M beadchip. 96 single nucleotide polymorphisms (SNPs) demonstrated strong association with autism risk (p-value < 0.

Common genetic variants on 5p14.1 associate with autism spectrum disorders.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.

Variation in WNT genes is associated with non-syndromic cleft lip with or without cleft palate.

Non-syndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect. Genetic and environmental factors have been causally implicated and studies have begun to delineate genetic contributions. The Wnt genes are involved in regulating mid-face development and upper lip fusion and are therefore strong candidates for an etiological role in NSCLP.

Determinants of skeletal age deviation in a cross-sectional study.

Objective: Skeletal age deviation (SAD) is associated with bone mass and fracture risk in children, but factors determining this are unknown. The aim of this population-based cross-sectional study was to describe the factors associated with SAD.

Methods: A convenience sample of 640 male and female children aged 7-17 yr was studied.

Bone density interpretation and relevance in Caucasian children aged 9-17 years of age: insights from a population-based fracture study.

The interpretation of bone density measurement in children is difficult due to a number of factors including rapid change in body size and uncertain clinical significance of bone density in children. This study asked two questions. (1) Is there a preferred bone density measurement site or type for fracture risk in children? (2) What is the best way to interpret bone density in children? This population-based case control study included 321 upper limb fracture cases and 321 class- and sex- matched randomly selected controls.

Investigation of autism and GABA receptor subunit genes in multiple ethnic groups.

Autism is a neurodevelopmental disorder of complex genetics, characterized by impairment in social interaction and communication, as well as repetitive behavior. Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in autistic patients, indicate that the GABAergic system, which is responsible for synaptic inhibition in the adult brain, may be involved in autism. Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients.

Extension of multifactor dimensionality reduction for identifying multilocus effects in the GAW14 simulated data.

The multifactor dimensionality reduction (MDR) is a model-free approach that can identify gene x gene or gene x environment effects in a case-control study. Here we explore several modifications of the MDR method. We extended MDR to provide model selection without crossvalidation, and use a chi-square statistic as an alternative to prediction error (PE).

Synovial haemangioma of the knee: a case report.

Synovial haemangioma is a rare but important cause of knee symptoms, which, when undiagnosed, can lead to significant morbidity. Diagnosis is frequently difficult and delayed. We report on a case of synovial haemangioma, which demonstrates the difficulties inherent in diagnosis and the morbidity associated with diagnostic delay, in a young woman.

Skeletal age deviation assessed by the Tanner-Whitehouse 2 method is associated with bone mass and fracture risk in children.

The aim of this population-based case-control study was to describe the association among skeletal age deviation (SAD), bone density, and upper limb fracture risk in male and female children aged 9-16 years. A total of 321 fracture cases and 321 randomly selected individually matched controls were studied. Skeletal age was assessed by standard atlas.

Risk-taking, coordination and upper limb fractures in children: a population based case-control study.

The aim of this population based case-control study was to examine the association between risk-taking behaviour, motor coordination and upper limb fractures in children aged 9-16 years. A total of 321 fracture cases and 321 randomly selected individually matched controls were studied. The number for different types of upper limb fractures was 91 for hand, 190 for wrist and forearm and 40 for upper arm.