American journal of human genetics最新文献

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments dedicated to each. Active involvement of consortium leadership, buy-in from its members at all levels, and support from NIH program staff at pivotal stages were essential to the success of this effort. The ClinGen JEDI action plan that resulted from our process is a living document and roadmap whose target goals and deliverables will continue to evolve. Here, we offer a transparent account of how a large, multi-site biomedical research consortium achieved this, as well as the challenges and opportunities we encountered on this first step in our journey toward enacting JEDI principles in our sphere of influence. We hope that others seeking to engage in this work will gain valuable insights from our process, experience, and lessons learned.

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.

Clinical short-read exome and genome sequencing approaches have positively impacted diagnostic testing for rare diseases. Yet, technical limitations associated with short reads challenge their use for the detection of disease-associated variation in complex regions of the genome. Long-read sequencing (LRS) technologies may overcome these challenges, potentially qualifying as a first-tier test for all rare diseases. To test this hypothesis, we performed LRS (30× high-fidelity [HiFi] genomes) for 100 samples with 145 known clinically relevant germline variants that are challenging to detect using short-read sequencing and necessitate a broad range of complementary test modalities in diagnostic laboratories. We show that relevant variant callers readily re-identified the majority of variants (120/145, 83%), including ∼90% of structural variants, SNVs/insertions or deletions (indels) in homologous sequences, and expansions of short tandem repeats. Another 10% (n = 14) was visually apparent in the data but not automatically detected. Our analyses also identified systematic challenges for the remaining 7% (n = 11) of variants, such as the detection of AG-rich repeat expansions. Titration analysis showed that 90% of all automatically called variants could also be identified using 15-fold coverage. Long-read genomes thus identified 93% of challenging pathogenic variants from our dataset. Even with reduced coverage, the vast majority of variants remained detectable, possibly enhancing cost-effective diagnostic implementation. Most importantly, we show the potential to use a single technology to accurately identify all types of clinically relevant variants.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.

Alzheimer disease (AD) is a complex and progressive neurodegenerative disorder that accounts for the majority of individuals with dementia. Here, we aim to identify causal plasma proteins for AD, shedding light on the etiology of AD. We utilized the latest large-scale plasma proteomic data from the UK Biobank Pharma Proteomics Project (UKB-PPP) and AD genome-wide association study (GWAS) summary data from the International Genomics of Alzheimer's Project (IGAP). Via a robust univariate instrumental variable (IV) regression method, we identified causal proteins through cis-protein quantitative trait loci (pQTLs) and (both cis- and trans-)pQTLs. To further reduce potential false positives due to high linkage disequilibrium (LD) of some pQTLs and high correlations among some proteins, we developed a robust multivariate IV regression method, called two-stage constrained maximum likelihood (MV-2ScML), to distinguish direct and confounding/mediating effects of proteins; some key features of the method include its robustness to invalid IVs and applicability to GWAS summary data. Our work highlights some differences between using cis-pQTLs and trans-pQTLs and critical values of multivariate analysis for fine-mapping causal proteins, providing insights into plasma protein pathways to AD.

Analysis of exome data from the latest release of the Genome Aggregation Database (gnomAD v.4.1.0) revealed a significant carrier burden of pathogenic/likely pathogenic (P/LP) variants in genes associated with autosomal-recessive conditions across diverse ancestral populations. Carrier screening panels are routinely offered to reproductive partners to inform their risk of having an affected child. Current guidelines from the American College of Medical Genetics and Genomics (ACMG) recommend screening for genes with a carrier frequency of at least 1/200 and associated with moderate/severe conditions. Here, we systematically analyzed >700,000 gnomAD v.4.1.0 exomes spanning eight ancestries to estimate the carrier frequency of P/LP variants in 2,987 genes associated with autosomal-recessive conditions. After expert curation for clinical severity, we identified 286 genes meeting the criteria for carrier screening. The number of genes exceeding the 1/200 threshold varied across populations, with 40 in the South Asian ancestry and up to 119 in the Ashkenazi Jewish population. Simulations showed that pan-ethnic screening panels offer advantages for individuals of diverse or admixed ancestry, while ancestry-specific panels may be preferable for genetically homogeneous populations. This study leveraged the most comprehensive genomic dataset to date to provide an updated candidate gene list for equitable carrier screening across diverse populations. Our findings highlight the need for continued expansion of genomic resources to better understand rare disease risk and inform screening efforts in underrepresented groups.

The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with bi-allelic variants in death-associated protein 3 (DAP3), a nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modeling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated that DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability, and DAP3 GTPase activity. Our study presents genetic and functional evidence that bi-allelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD.

Available large-scale genome-wide association study (GWAS) summary datasets predominantly stem from European populations, while sample sizes for other ethnicities, notably Central/South Asian, East Asian, African, Hispanic, etc., remain comparatively limited, resulting in low precision of causal effect estimations within these ethnicities when using Mendelian randomization (MR). In this paper, we propose a trans-ethnic MR method, TEMR, to improve the statistical power and estimation precision of MR in a target population that is underrepresented, using trans-ethnic large-scale GWAS summary datasets. TEMR incorporates trans-ethnic genetic correlation coefficients through a conditional likelihood-based inference framework, producing calibrated p values with substantially improved MR power. In the simulation study, compared with other existing MR methods, TEMR exhibited superior precision and statistical power in causal effect estimation within the target populations. Finally, we applied TEMR to infer causal relationships between concentrations of 16 blood biomarkers and the risk of developing five diseases (hypertension, ischemic stroke, type 2 diabetes, schizophrenia, and major depression disorder) in East Asian, African, and Hispanic/Latino populations, leveraging biobank-scale GWAS summary data obtained from individuals of European descent. We found that the causal biomarkers were mostly validated by previous MR methods, and we also discovered 17 causal relationships that were not identified using previously published MR methods.