Developing a community-led rare disease ELSI research agenda.

Background: Research priorities are best defined through engagement with communities who will be impacted by the research and have lived experience of the topics to be studied. We aimed to establish a pediatric rare disease community stakeholder group and empower them in (1) eliciting perspectives from affected families in the wider region and (2) synthesizing collective ideas into a research agenda focused on shared ethical, legal, and social implications (ELSI) across rare disease.

Methods: This two-year project utilized a community-centered approach to engage rare disease community members as equal partners in developing a research agenda for ELSI in rare disease.

Landscape Analysis of Neurodevelopmental Comorbidities in Newborn Screening Conditions: Challenges and Opportunities.

Newborn screening (NBS) is a large-scale public health program in the US that screens 3.8 million newborns for up to 81 genetic conditions each year. Many of these conditions have comorbidities, including neurodevelopmental disorders (NDDs).

microRNA as a Maternal Marker for Prenatal Stress-Associated ASD, Evidence from a Murine Model.

Autism Spectrum Disorder (ASD) has been associated with a complex interplay between genetic and environmental factors. Prenatal stress exposure has been identified as a possible risk factor, although most stress-exposed pregnancies do not result in ASD. The serotonin transporter (SERT) gene has been linked to stress reactivity, and the presence of the SERT short (S)-allele has been shown to mediate the association between maternal stress exposure and ASD.

microRNAs and Gene-Environment Interactions in Autism: Effects of Prenatal Maternal Stress and the Gene on Maternal microRNA Expression.

Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children.

The AutGO Initiative: A Conceptual Framework for Developing Genetics-Outcomes Research Hypotheses.

The increasing emphasis on translational approaches to complex neuropsychiatric and neurodevelopmental conditions research requires scientists from a broad range of disciplines to build dynamic collaborations when formulating hypotheses and framing study designs. The need to integrate the knowledge and perspectives not only from multiple scientific silos but also from the populations impacted by these conditions presents a significant challenge to researchers, particularly for a heterogeneous condition like autism. As one path toward addressing these challenges, we have previously introduced Autism Genetics Outcomes (AutGO), an initiative to support broad stakeholder partnerships and promote a new integrated concept called GO (i.

The potential role of a retrotransposed gene and a long noncoding RNA in regulating an X-linked chromatin gene (KDM5C): Novel epigenetic mechanism in autism.

A growing body of evidence supports the potential role of the circadian system and chromatin remodeling genes in autism. Considering the heterogeneity and gender discrepancy in autism, and the complex nature of the epigenetic landscape, identification of biologically relevant epigenetic factors requires reducing heterogeneity using proper subtyping. For this study, we used X chromosome inactivation (XCI) status in females with autism as an epigenetic marker for subtyping and examined the expression level of members of KDM5, a chromatin remodeling gene family.

Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37.

Purpose: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family.

Methods: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family.

Results: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration.

Building a Bridge Between Genetics and Outcomes Research: Application in Autism (The AutGO Study).

Background: Concerns over the need to improve translational aspects of genetics research studies and engaging community members in the research process have been noted in the literature and raised by patient advocates. In addition to the work done by patient advocacy groups, organizations such as the Patient-Centered Outcomes Research Institute advocate for a change in the culture of research from being researcher-driven to becoming more patient-driven.

Objective: Our project, Autism Genetics and Outcomes (AutGO), consists of two phases.

A Novel Stratification Method in Linkage Studies to Address Inter- and Intra-Family Heterogeneity in Autism.

Most genome linkage scans for autism spectrum disorders (ASDs) have failed to be replicated. Recently, a new ASD phenotypic sub-classification method was developed which employed cluster analyses of severity scores from the Autism Diagnostic Interview-Revised (ADI-R). Here, we performed linkage analysis for each of the four identified ADI-R stratified subgroups.

A proof-of-concept study: exon-level expression profiling and alternative splicing in autism using lymphoblastoid cell lines.

Objective: Autism is a complex, heterogeneous neurobehavioral disorder with many causes and varying degrees of severity. Some genetic implications related to autism may involve gene-regulatory processes such as alternative splicing. Here, we assess the feasibility of profiling exon-level gene expression in autism using the Affymetrix Human exon 1.

Genetic studies of complex human diseases: characterizing SNP-disease associations using Bayesian networks.

Background: Detecting epistatic interactions plays a significant role in improving pathogenesis, prevention, diagnosis, and treatment of complex human diseases. Applying machine learning or statistical methods to epistatic interaction detection will encounter some common problems, e.g.

FEPI-MB: identifying SNPs-disease association using a Markov Blanket-based approach.

Background: The interactions among genetic factors related to diseases are called epistasis. With the availability of genotyped data from genome-wide association studies, it is now possible to computationally unravel epistasis related to the susceptibility to common complex human diseases such as asthma, diabetes, and hypertension. However, the difficulties of detecting epistatic interaction arose from the large number of genetic factors and the enormous size of possible combinations of genetic factors.

Autism Genetic Database (AGD): a comprehensive database including autism susceptibility gene-CNVs integrated with known noncoding RNAs and fragile sites.

Background: Autism is a highly heritable complex neurodevelopmental disorder, therefore identifying its genetic basis has been challenging. To date, numerous susceptibility genes and chromosomal abnormalities have been reported in association with autism, but most discoveries either fail to be replicated or account for a small effect. Thus, in most cases the underlying causative genetic mechanisms are not fully understood.

Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism.

To assess the feasibility and relevance of using lymphoblastoid cell lines to study the role of noncoding RNAs in the etiology of autism, we evaluated global expression profiling of 470 mature human microRNAs from six subjects with autism compared with six matched controls. Differential expression (either higher or lower) for 9 of the 470 microRNAs was observed in our autism samples compared with controls. Potential target genes for these microRNAs were identified using computer tools, which included several autism susceptibility genes.

snoTARGET shows that human orphan snoRNA targets locate close to alternative splice junctions.

Among thousands of non-protein-coding RNAs which have been found in humans, a significant group represents snoRNA molecules that guide other types of RNAs to specific chemical modifications, cleavages, or proper folding. Yet, hundreds of mammalian snoRNAs have unknown function and are referred to as "orphan" molecules. In 2006, for the first time, it was shown that a particular orphan snoRNA (HBII-52) plays an important role in the regulation of alternative splicing of the serotonin receptor gene in humans and other mammals.

Body composition and fatness patterns in Prader-Willi syndrome: comparison with simple obesity.

Objective: To characterize the body composition of Prader-Willi syndrome (PWS) subjects and compare with simple obesity.

Research Methods And Procedures: Seventy-two individuals (27 PWS deletion, 21 PWS uniparental disomy, and 24 obese controls) 10 to 49 years old were studied with the use of DXA. Body composition measures were obtained, and regional fat and lean mass patterns were characterized.

X-chromosome inactivation patterns in females with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by loss of paternally expressed genes from the 15q11-q13 region generally due to a paternally-derived deletion of the 15q11-q13 region or maternal disomy 15 (UPD). Maternal disomy 15 is usually caused by maternal meiosis I non-disjunction associated with advanced maternal age and after fertilization with a normal sperm leading to trisomy 15, a lethal condition unless trisomy rescue occurs with loss of the paternal chromosome 15. To further characterize the pathogenesis of maternal disomy 15 process in PWS, the status of X-chromosome inactivation was calculated to determine whether non-random skewing of X-inactivation is present indicating a small pool of early embryonic cells.

X chromosome gene expression in human tissues: male and female comparisons.

About 25% of X-linked genes may escape inactivation at least to some degree. However, in vitro results from somatic cell hybrids may not reflect what happens in vivo. Therefore, we analyzed the female/male (F/M) gene fold expression ratio for 299 X-linked and 7795 autosomal genes from 11 different tissues from an existing in vivo microarray database.

Ghrelin, peptide YY and their receptors: gene expression in brain from subjects with and without Prader-Willi syndrome.

Ghrelin and peptide YY (PYY) are peptides generally produced by the gastrointestinal organs which are involved in appetite regulation via highly specialized centers in the brain. Abnormal plasma ghrelin and PYY levels compared with controls have been reported for subjects with Prader-Willi syndrome (PWS) which is characterized by infantile hypotonia, poor suck reflex and failure to thrive followed by hyperphagia and marked obesity in early childhood. We studied gene expression of ghrelin, peptide YY, and their receptors (i.

Microarray analysis of gene/transcript expression in Angelman syndrome: deletion versus UPD.

Angelman syndrome (AS) is a neurodevelopmental disorder due to a functional deficit, usually a deletion, of the UBE3A gene located in the 15q11-q13 chromosome region. We report the first microarray analysis of gene expression in AS using a custom cDNA microarray to compare expression patterns from lymphoblastoid cell lines from control males and AS subjects with a 15q deletion or uniparental paternal disomy 15. Expression patterns of genes known to be biallelically expressed or paternally or maternally expressed were consistent with expectations.

Plasma peptide YY and ghrelin levels in infants and children with Prader-Willi syndrome.

An insatiable appetite is a cardinal feature of Prader-Willi syndrome (PWS) with stomach rupturing as a reported consequence. Peptide YY, secreted by the intestine and released post-prandially, inhibits appetite, while ghrelin, secreted by the stomach during mealtime hunger, stimulates appetite. Both peptide YY and ghrelin act at the brain level, particularly the hypothalamus.

Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy.

Objective: To determine whether phenotypic differences exist among individuals with Prader-Willi syndrome with either type I or type II deletions of chromosome 15 or maternal disomy 15 leading to a better understanding of cause and pathophysiology of this classical genetic syndrome.

Methods: We analyzed clinical, anthropometric, and behavioral data in 12 individuals (5 men, 7 women; mean age: 25.9 +/- 8.