Publications by authors named "Evan Baugh"

Article Synopsis
  • DExD/H-box RNA helicases (DDX/DHX) are a large gene family linked to neurodevelopmental disorders and cancer, with DHX9 being a key member associated with various phenotypes.
  • Analysis of individuals with rare DHX9 variants revealed a range of neurodevelopmental disorder traits and the genetic basis for these phenotypes correlated with the type of variant.
  • Experimental investigations showed that DHX9 variants impact its cellular localization and function, linking them to conditions like Charcot-Marie-Tooth disease and highlighting DHX9's role in neurodevelopment and neuronal stability.
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Objective: Idiopathic sudden sensorineural hearing loss (ISSNHL) affects 66,000 patients per year in the United States. Genetic mutations have been associated with progressive hearing loss; however, genetic mutations associated with ISSNHL have not been identified.

Methods: A prospective cohort study of adults older than 18 years presenting with ISSNHL at a tertiary academic medical center.

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Purpose: Next-generation sequencing (NGS) has revolutionized the diagnostic process for rare/ultrarare conditions. However, diagnosis rates differ between analytical pipelines. In the National Institutes of Health-Undiagnosed Diseases Network (UDN) study, each individual's NGS data are concurrently analyzed by the UDN sequencing core laboratory and the clinical sites.

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Genomic regions subject to purifying selection are more likely to carry disease-causing mutations than regions not under selection. Cross species conservation is often used to identify such regions but with limited resolution to detect selection on short evolutionary timescales such as that occurring in only one species. In contrast, genetic intolerance looks for depletion of variation relative to expectation within a species, allowing species-specific features to be identified.

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Article Synopsis
  • Nuclear deubiquitinase BAP1 is a crucial part of protein complexes that help regulate gene transcription by reversing the ubiquitination of histone 2A, and its loss can lead to cancer.
  • This study identified 11 rare, de novo germline BAP1 variants associated with a unique neurodevelopmental disorder, where most of these variants demonstrated a loss-of-function effect.
  • Functional analyses showed these variants impaired histone modifications, leading to significant changes in chromatin states and contributing to dysregulation of genes essential for development.
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Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48).

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Osteoporosis in premenopausal women with intact gonadal function and no known secondary cause of bone loss is termed idiopathic osteoporosis (IOP). Women with IOP diagnosed in adulthood have profound bone structural deficits and often report adult and childhood fractures, and family history of osteoporosis. Some have very low bone formation rates (BFR/BS) suggesting osteoblast dysfunction.

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AIM To determine which patients with cerebral palsy (CP) should undergo genetic testing, we compared the rate of likely causative genetic variants from whole-exome sequencing in individuals with and without environmental risk factors. METHOD Patients were part of a convenience and physician-referred cohort recruited from a single medical center, and research whole-exome sequencing was completed. Participants were evaluated for the following risk factors: extreme preterm birth, brain bleed or stroke, birth asphyxia, brain malformations, and intrauterine infection.

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Purpose: In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants.

Methods: Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER).

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CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes.

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Macular telangiectasia type 2 (MacTel) is a progressive, late-onset retinal degenerative disease linked to decreased serum levels of serine that elevate circulating levels of a toxic ceramide species, deoxysphingolipids (deoxySLs); however, causal genetic variants that reduce serine levels in patients have not been identified. Here we identify rare, functional variants in the gene encoding the rate-limiting serine biosynthetic enzyme, phosphoglycerate dehydrogenase (PHGDH), as the single locus accounting for a significant fraction of MacTel. Under a dominant collapsing analysis model of a genome-wide enrichment analysis of rare variants predicted to impact protein function in 793 MacTel cases and 17,610 matched controls, the PHGDH gene achieves genome-wide significance (P = 1.

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Purpose: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome).

Methods: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers.

Results: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript.

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Schinzel-Giedion syndrome (SGS; OMIM 269150) is an ultra-rare genetic disorder associated with a distinctive facial gestalt, congenital malformations, severe intellectual disability, and a progressive neurological course. The prognosis for SGS is poor, with survival beyond the first decade rare. Germline, de novo heterozygous variants in the SETBP1 gene cause SGS with the pathogenic variants associated with the SGS phenotype missense and confined to exon 4 of the gene, clustered in a four amino acid (12 bp) hotspot in the SKI homologous region of the SETBP1 protein.

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Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant () strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment.

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Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance.

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Tardive dyskinesia (TD) is an adverse movement disorder induced by chronic treatment with antipsychotics drugs. The contribution of common genetic variants to TD susceptibility has been investigated in recent years, but with limited success. The aim of the current study was to investigate the potential contribution of rare variants to TD vulnerability.

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NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene.

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Objective: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD.

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Background: Oligodontia is a severe form of tooth agenesis characterized by the absence of six or more permanent teeth. Oligodontia has complex etiology and variations in numerous genes have been suggested as causal for the condition.

Methods: We applied whole-exome sequencing (WES) to identify the cause of oligodontia in a 9-year-old girl missing 11 permanent teeth.

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The p53 gene contains homozygous mutations in ~50-60% of human cancers. About 90% of these mutations encode missense mutant proteins that span ~190 different codons localized in the DNA-binding domain of the gene and protein. These mutations produce a protein with a reduced capacity to bind to a specific DNA sequence that regulates the p53 transcriptional pathway.

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Existing methods for interpreting protein variation focus on annotating mutation pathogenicity rather than detailed interpretation of variant deleteriousness and frequently use only sequence-based or structure-based information. We present VIPUR, a computational framework that seamlessly integrates sequence analysis and structural modelling (using the Rosetta protein modelling suite) to identify and interpret deleterious protein variants. To train VIPUR, we collected 9477 protein variants with known effects on protein function from multiple organisms and curated structural models for each variant from crystal structures and homology models.

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Cutinases are esterases of industrial importance for applications in recycling and surface modification of polyesters. The cutinase from Thielavia terrestris (TtC) is distinct in terms of its ability to retain its stability and activity in acidic pH. Stability and activity in acidic pHs are desirable for esterases as the pH of the reaction tends to go down with the generation of acid.

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Computational structure prediction and design of proteins and protein-protein complexes have long been inaccessible to those not directly involved in the field. A key missing component has been the ability to visualize the progress of calculations to better understand them. Rosetta is one simulation suite that would benefit from a robust real-time visualization solution.

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