American journal of human genetics最新文献

Regulatory single-nucleotide variants (rSNVs) in noncoding regions of the genome play a crucial role in gene transcription by altering transcription factor (TF) binding, chromatin states, and other epigenetic modifications. Existing expression quantitative trait locus (eQTL) methods identify genomic loci associated with gene-expression changes, but they often fall short in pinpointing causal variants. We introduce reg-eQTL, a computational method that incorporates TF effects and interactions with genetic variants into eQTL analysis. This approach provides deeper insights into the regulatory mechanisms, bringing us one step closer to identifying potential causal variants by uncovering how TFs interact with SNVs to influence gene expression. This method defines a trio consisting of a genetic variant, a target gene, and a TF and tests its impact on gene transcription. In comprehensive simulations, reg-eQTL shows improved power of detecting rSNVs with low population frequency, weak effects, and synergetic interaction with TF as compared to traditional eQTL methods. Application of reg-eQTL to GTEx data from lung, brain, and whole-blood tissues uncovered regulatory trios that include eQTLs and increased the number of eQTLs shared across tissue types. Regulatory networks constructed on the basis of these trios reveal intricate gene regulation across tissue types.

In two unrelated families with X-linked inherited retinal dystrophy, identification of the causative variants was elusive. Interrogation of the next-generation sequencing (NGS) data revealed a "dark" intergenic region on Xq27.1 with poor coverage. Long-range PCR and DNA walking across this region revealed different inter-chromosomal insertions into the human-specific palindrome on Xq27.1: a 58 kb insertion of 9p24.3 [der(X)dir ins(X;9)(q27.1;p24.3)] in family 1 and a 169 kb insertion of 3p14.2 [der(X)inv ins(X;3)(q27.1;p14.2)] in family 2. To explore the functional consequence of these structural variants in genomic and cellular contexts, induced pluripotent stem cells were derived from affected and control fibroblasts and differentiated to retinal organoids (ROs) and retinal pigment epithelium. Transcriptional dysregulation was evaluated using RNA sequencing (RNA-seq) and RT-qPCR. A downstream long non-coding RNA, LINC00632 (Xq27.1), was upregulated in ROs from both families compared to control samples. In contrast, the circular RNA CDR1as/ciRS-7 (circular RNA sponge for miR-7), spliced from linear LINC00632, was downregulated. To investigate this tissue-specific dysregulation, we interrogated the landscape of the locus using Hi-C and cleavage under targets and tagmentation sequencing (CUT&Tag). This revealed active retinal enhancers within the insertions within a topologically associated domain that also contained the upstream promoter of LINC00632, permitting ectopic contact. Furthermore, CDR1as/ciRS-7 acts as a "sponge" for miR-7, and target genes of miR-7 were also dysregulated in ROs derived from both families. We describe a new genomic mechanism for retinal dystrophy, and our data support a convergent tissue-specific mechanism of altered regulation of LINC00632 and CDR1as/ciRS-7 as a consequence of the insertions within the palindrome on Xq27.1.

The five authors recently discovered their misattributed paternity (MP), two ascertaining that, decades ago, their pediatricians abetted the paternity deception. From their unique perspective, the authors critique medical organizations' current MP discovery guidance, identifying shortcomings, contradictions, and clinical and legal hazards. They also discuss opportunities to improve MP discovery management.

Various scientific and professional groups, including the American Medical Association (AMA), American Society of Human Genetics (ASHG), American College of Medical Genetics (ACMG), and the National Academies of Sciences, Engineering, and Medicine (NASEM), have appropriately clarified that certain population descriptors, such as race and ethnicity, are social and cultural constructs with no basis in genetics. Nevertheless, these conventional population descriptors are routinely collected during the course of clinical genetic testing and may be used to interpret test results. Experts who have examined the use of population descriptors, both conventional and ancestry based, in human genetics and genomics have offered guidance on using these descriptors in research but not in clinical laboratory settings. This perspective piece is based on a decade of experience in a clinical genomics laboratory and provides insight into the relevance of conventional and ancestry-based population descriptors for clinical genetic testing, reporting, and clinical research on aggregated data. As clinicians, laboratory geneticists, genetic counselors, and researchers, we describe real-world experiences collecting conventional population descriptors in the course of clinical genetic testing and expose challenges in ensuring clarity and consistency in the use of population descriptors. Current practices in clinical genomics laboratories that are influenced by population descriptors are identified and discussed through case examples. In relation to this, we describe specific types of clinical research projects in which population descriptors were used and helped derive useful insights related to practicing and improving genomic medicine.

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.