Background: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.
View Article and Find Full Text PDFBackground: Diagnosing rare genetic disorders relies on precise phenotypic and genotypic analysis, with the Human Phenotype Ontology (HPO) providing a standardized language for capturing clinical phenotypes. Traditional HPO tools, such as Doc2HPO and ClinPhen, employ concept recognition to automate phenotype extraction but struggle with incomplete phenotype assignment, often requiring intensive manual review. While large language models (LLMs) hold promise for more context-driven phenotype extraction, they are prone to errors and "hallucinations," making them less reliable without further refinement.
View Article and Find Full Text PDFPurpose: The variome of the Turkish (TK) population, a population with a considerable history of admixture and consanguinity, has not been deeply investigated for insights on the genomic architecture of disease.
Methods: We generated and analyzed a database of variants derived from exome sequencing data of 773 TK unrelated, clinically affected individuals with various suspected Mendelian disease traits and 643 unaffected relatives.
Results: Using uniform manifold approximation and projection, we showed that the TK genomes are more similar to those of Europeans and consist of 2 main subpopulations: clusters 1 and 2 ( = 235 and 1181, respectively), which differ in admixture proportion and variome (https://turkishvariomedb.
Background: Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style functional data may help resolve variant classification disparities between populations, especially for Variants of Uncertain Significance (VUS).
Methods: We analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database.
Background: Copy number variation (CNV) is a class of genomic Structural Variation (SV) that underlie genomic disorders and can have profound implications for health. Short-read genome sequencing (sr-GS) enables CNV calling for genomic intervals of variable size and across multiple phenotypes. However, unresolved challenges include an overwhelming number of false-positive calls due to systematic biases from non-uniform read coverage and collapsed calls resulting from the abundance of paralogous segments and repetitive elements in the human genome.
View Article and Find Full Text PDFIntroduction: Systemic lupus erythematosus is a multi-faceted autoimmune disorder of complex etiology. Pre-pubertal onset of pediatric systemic lupus erythematosus (pSLE) is uncommon and should raise suspicion for a genetic driver of disease. Autosomal recessive p40 deficiency is a rare immunologic disorder characterized by defective but not abolished NADPH oxidase activity with residual production of reactive oxygen species (ROS) by phagocytic cells.
View Article and Find Full Text PDFThe duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes.
View Article and Find Full Text PDFPrimary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy.
View Article and Find Full Text PDFChildhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
April 2024
Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear.
View Article and Find Full Text PDFBackground: Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style data may help resolve variant classification disparities between populations, especially for variants of uncertain significance (VUS).
Methods: We analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from and the Genome Aggregation Database.
Background: Multilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context.
View Article and Find Full Text PDFBackground: NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects.
View Article and Find Full Text PDFInborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants.
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