Genetic disease risks of under-represented founder populations in New York City.

The detection of founder pathogenic variants, those observed in high frequency only in a group of individuals with increased inter-relatedness, can help improve delivery of health care for that community. We identified 16 groups with shared ancestry, based on genomic segments that are shared through identity by descent (IBD), in New York City using the genomic data of 25,366 residents from the All Of Us Research Program and the Mount Sinai Bio biobank. From these groups we defined 8 as founder populations, mostly communities currently under-represented in medical genomics research, such as Puerto Rican, Garifuna and Filipino/Pacific Islanders.

rare variant augments aortic growth and induces cardiac hypertrophy and heart failure with pressure overload.

Smooth muscle cell-specific myosin heavy chain, encoded by , is selectively expressed in smooth muscle cells (s). Pathogenic variants in predispose to a number of disorders, including heritable thoracic aortic disease associated with patent ductus arteriosus, visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Rare variants of uncertain significance occur throughout the gene, including p.

Evaluating parental personal utility of pediatric genetic and genomic testing in a diverse, multilingual population.

There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results.

Physician and informal care use explained by the Pediatric Quality of Life Inventory (PedsQL) in children with suspected genetic disorders.

Purpose: To examine associations between Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and PedsQL Infant Scales with formal health care resource utilization (HCRU) and informal caregiver burden.

Methods: We studied a pediatric cohort of 837 patients (median age: 8.

Regulatory landscape enrichment analysis (RLEA): a computational toolkit for non-coding variant enrichment and cell type prioritization.

Background: As genomic studies continue to implicate non-coding sequences in disease, testing the roles of these variants requires insights into the cell type(s) in which they are likely to be mediating their effects. Prior methods for associating non-coding variants with cell types have involved approaches using linkage disequilibrium or ontological associations, incurring significant processing requirements. GaiaAssociation is a freely available, open-source software that enables thousands of genomic loci implicated in a phenotype to be tested for enrichment at regulatory loci of multiple cell types in minutes, permitting insights into the cell type(s) mediating the studied phenotype.

Evidence review and considerations for use of first line genome sequencing to diagnose rare genetic disorders.

Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included.

Aspirin-exacerbated respiratory disease is associated with variants in filaggrin, epithelial integrity, and cellular interactions.

Background: Previous studies have determined that up to 6% of patients with aspirin-exacerbated respiratory disease (AERD) have family history of AERD, indicating a possible link with genetic polymorphisms. However, whole exome sequencing (WES) studies of such associations are currently lacking.

Objectives: We sought to examine whether WES can identify pathogenic variants associated with AERD.

Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour.

Sex differences are found in brain structure and function across species, and across brain disorders in humans. The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan. Specifically, ovarian hormones oestrogens and progesterone are known to dynamically change structure and function of the adult female brain, having a major impact on psychiatric risk.

The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic results disclosure in diverse families.

Digital solutions are needed to support rapid increases in the application of genetic/genomic tests (GTs) in diverse clinical settings and patient populations. We developed GUÍA, a bilingual digital application that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GTs.

Regulatory Landscape Enrichment Analysis (RLEA) using gaiaAssociation.

Motivation: To understand whether sets of genomic loci are enriched at the regulatory loci of one or more cell types, we developed the gaiaAssociation package to perform Regulatory Landscape Enrichment Analysis (RLEA). RLEA is a novel analytical process that tests for enrichment of sets of loci in cell type-specific open chromatin regions (OCRs) in the genome.

Results: We demonstrate that the application of RLEA to genome-wide association study (GWAS) data reveals cell types likely to be mediating the phenotype studied, and clusters OCRs based on their shared regulatory profiles.

Physician services and costs after disclosure of diagnostic sequencing results in the NYCKidSeq program.

Purpose: To better understand the effects of returning diagnostic sequencing results on clinical actions and economic outcomes for pediatric patients with suspected genetic disorders.

Methods: Longitudinal physician claims data after diagnostic sequencing were obtained for patients aged 0 to 21 years with neurologic, cardiac, and immunologic disorders with suspected genetic etiology. We assessed specialist consultation rates prompted by primary diagnostic results, as well as marginal effects on overall 18-month physician services and costs.

Urine Proteomics Link Complement Activation with Interstitial Fibrosis/Tubular Atrophy in Lupus Nephritis Patients.

Background: Intrarenal complement activation has been implicated in the pathogenesis of tubulointerstitial fibrosis in lupus nephritis (LN) based on prior animal studies. The assembly of the membrane attack complex (MAC) by complement C5b to C9 on the cell membrane leads to cytotoxic pores and cell lysis, while CD59 inhibits MAC formation by preventing C9 from joining the complex. We hypothesize that complement activation and imbalance between complement activation and inhibition, as defined by increased production of individual complement components and uncontrolled MAC activation relative to CD59 inhibition, are associated with interstitial fibrosis and tubular atrophy (IFTA) in LN and correlate with the key mediators of kidney fibrosis- transforming growth factor receptors beta (TGFRβ), platelet-derived growth factor beta (PDGFβ) and platelet-derived growth factor receptor beta (PDGFRβ).

Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine.

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here, we reveal molecular substrates in the reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine. We find shared involvement of X chromosome inactivation-related and estrogen signaling-related gene regulation in enhanced conditioning responses following early-life stress and during the low-estrogenic state in females.

Prenatal vitamin D deficiency alters immune cell proportions of young adult offspring through alteration of long-term stem cell fates.

Vitamin D deficiency is a common deficiency worldwide, particularly among women of reproductive age. During pregnancy, it increases the risk of immune-related diseases in offspring later in life. However, exactly how the body remembers exposure to an adverse environment during development is poorly understood.

The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic counseling in racially and ethnically diverse families.

Background: Digital solutions are needed to support rapid increases in the application of genetic and genomic tests (GT) in diverse clinical settings and patient populations. We developed GUÍA, a bi-lingual web-based platform that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial evaluated GUÍA's impact on understanding of GT results.

Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program.

Copy number variations (CNVs) play a significant role in human disease. While chromosomal microarray has traditionally been the first-tier test for CNV detection, use of genome sequencing (GS) is increasing. We report the frequency of CNVs detected with GS in a diverse pediatric cohort from the NYCKidSeq program and highlight specific examples of its clinical impact.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

Purpose: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions.

Methods: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing.

An optimized approach for multiplexing single-nuclear ATAC-seq using oligonucleotide-conjugated antibodies.

Background: Single-cell technologies to analyze transcription and chromatin structure have been widely used in many research areas to reveal the functions and molecular properties of cells at single-cell resolution. Sample multiplexing techniques are valuable when performing single-cell analysis, reducing technical variation and permitting cost efficiencies. Several commercially available methods have been used in many scRNA-seq studies.