The American Journal of Human Genetics

Pharmacogenomics is an essential component of precision medicine; however, most existing knowledge has been derived from populations of European ancestry, limiting the understanding of pharmacogenomic diversity in East Asian populations. In this study, we applied genotype imputation to the Korea Biobank Array v2.0 using a reference panel of 8,062 Korean whole-genome sequencing (WGS) samples and analyzed pharmacogenomic variants and phenotypes in 14,490 Korean individuals. To assess the accuracy ...

MAP2K4 encodes a kinase that activates the c-Jun N-terminal kinase (JNK) pathway, which is essential for human neurodevelopment. While somatic MAP2K4 loss has been observed in cancer, germline variants have not previously been linked to human disease. We describe ten individuals with de novo or presumed de novo MAP2K4 variants who present with a novel syndromic neurodevelopmental disorder. Shared features include developmental delay or intellectual disability, epilepsy, and variable congenital m...

Exome sequencing (ES) is a cornerstone of clinical genetic diagnosis, yet its application in pharmacogenomics remains limited. While some pharmacogenetic variants are detectable by ES, clinically relevant loci such as CYP2D6, UGT1A1, and HLA remain challenging. We present a robust, comprehensive method to derive a complete pharmacogenomic profile directly from standard ES data. Our method addresses primary limitations of ES for pharmacogenomics, including low coverage and structural complexity a...

BackgroundThe transport of transfer RNAs (tRNAs) from the nucleus to the cytoplasm is a crucial step in the regulation of gene expression and protein synthesis. This process is mediated by specialized export molecules, among which XPOT (Exportin-t, XPO3) plays a central role by recognizing and transporting mature tRNAs through the nuclear pore complex. XPOT is not essential in RNA trafficking in the simple organisms, however the potential impact of XPOT deficiency in human health remains unresol...

BackgroundGenetic studies have disproportionately focused on populations of European ancestry, limiting the generalizability of allele-frequency references and genetic associations to underrepresented groups, including South American populations. This gap is particularly relevant for rare diseases and cancer, where accurate variant interpretation depends in part on appropriate population context. In addition, population-specific haplotype structure influence genome-wide association analyses and ...

TUBB2B encodes a {beta}-tubulin isotype essential for neuronal proliferation, migration, and organization during brain development. Pathogenic heterozygous variants in TUBB2B have been associated with a range of neurodevelopmental disorders, with phenotypes including polymicrogyria and corpus callosum abnormalities. However, the phenotypic spectrum remains heterogeneous, likely influenced by variant-specific effects on microtubule formation and stability, an area that warrants further investigat...

We report a previously undescribed genotypic configuration identified in twins with HNRNPU-related neurodevelopmental disorder. Both twins have two closely spaced mosaic variants on the same allele that never co-occur on any single DNA molecule, resulting in three distinct cell lineages within each individual. We define this genotypic configuration as clustered monoallelic mosaicism (cMoMa). Recognizing the extreme improbability of such a configuration, we systematically explore two potential me...

BackgroundMost rare coding variants in monogenic disease genes remain classified as Variants of Uncertain Significance (VUS), limiting their use in clinical care. Many variant classifications have been submitted to ClinVar, often with rich free-text summaries of the evidence underlying each classification. These narratives are not standardized and are difficult to mine systematically, making it challenging to identify variants that might be reclassified as new evidence becomes available. Method...

Cohesin is a fundamental genome-organizing complex that orchestrates three-dimensional chromosome folding and gene expression via DNA loop extrusion. Alterations to genes encoding cohesin subunits and cohesin loaders cause Mendelian disorders, including Cornelia de Lange syndrome (CdLS). By contrast, disruption of factors that remove cohesin from DNA, including WAPL and its binding partners PDS5A and PDS5B, have not yet been associated with human disease. Here, we explored the relevance of these...

Biobanks with longitudinal measurements have advanced our understanding of time-to-event (TTE) traits including age-of-onset and disease progression. However, limited work has characterized the heritability of TTE traits, a key parameter for comparisons of total association and predictive power. Here, we present COXMM, a Cox proportional hazard mixed model for estimating TTE heritability. Simulations show our model achieves nearly unbiased results, whereas non-TTE approaches severely underestima...

BackgroundDespite their profound impact on patients lives, most rare and intractable diseases still lack established treatments. Genomic variants that disrupt normal splicing by creating novel splice sites (splice-site creating variants, SSCVs) substantially contribute to the pathogenesis of those conditions. Deep intronic SSCVs are particularly amenable to antisense oligonucleotide (ASO)-mediated splice modulation, yet many of them remain undetected by conventional genomic analyses. Existing ap...

We report an autosomal recessive neurodevelopmental disorder exclusively affecting females carrying biallelic loss-of-function variants in CIZ1, a gene encoding a nuclear matrix protein essential for the maintenance of X-chromosome inactivation. Eight unrelated affected females were identified, whereas male siblings with biallelic variants were asymptomatic. We showed that loss of CIZ1 compromises the maintenance of X-chromosome inactivation, leading to an abnormal overexpression of a subset of ...

BackgroundMitochondrial diseases are the most common inherited metabolic disorders, characterized by pronounced clinical and genetic heterogeneity that complicates molecular diagnosis. Although DNA-based sequencing approaches have become standard in genetic testing, up to half of patients remain without a definitive diagnosis. RNA sequencing (RNA-seq) provides a complementary layer of evidence by revealing functional consequences of genetic variation, thereby improving diagnostic yield. Methods...

Understanding genetic architectures of disease is fundamental to partitioning heritability, polygenic risk prediction, and statistical fine-mapping. Genetic architectures of disease in European populations have been shown to depend on European minor allele frequency (MAF): SNPs with lower MAF have larger per-allele effects, due to the action of negative selection. However, we hypothesized that African MAF (defined using African-ancestry segments in African Americans), which is not distorted by t...

Protocadherin-12 (PCDH12), a cell-adhesion protein belonging to the non-clustered protocadherin family, plays a crucial role in the establishment and regulation of neuronal connections and communication. Bi-allelic loss-of-function (LoF) variants in the PCDH12 gene have been associated with several neurodevelopmental disorders (NDDs) such as diencephalic-mesencephalic junction dysplasia (DMJD) syndrome, cerebral palsy, and cerebellar ataxia, often accompanied by ocular abnormalities. However, ge...

The Clinical Pharmacogenetics Implementation Consortium (CPIC) bases its drug-gene recommendations on the assignment of star alleles, which map known genotypes to defined functional categories and corresponding drug dosage guidelines. The star allele framework, first proposed in 1996 for the CYP gene family and later formalized with CPICs establishment in 2010 [1, 2], remains foundational to pharmacogenomics. However, this system has notable limitations. Its dependence on a restricted set of ben...

Age-related hearing loss is a widespread sensory impairment affecting a significant proportion of the elderly population, yet the genetic underpinnings of this condition remain incompletely understood. In this study, we investigate a non-synonymous variant (rs2242416) in the CRIP3 gene, which is expressed in auditory hair cells, in the context of hearing loss. Firstly, we find the variant shows strong and consistent association with hearing loss across multiple genome-wide association studies. S...

XRN1 encodes a highly conserved cytoplasmic 5-3 exoribonuclease involved in mRNA decay and quality control. It localizes to transient ribonucleoprotein aggregates, P-bodies and stress granules, where it interacts with other mRNA decay proteins and is involved in various cellular responses, including an emerging role in viral infection responses. Complete knockout of XRN1 in multicellular organisms is lethal, most likely due to its central role in mRNA homeostasis, with no prior human disease ass...

Gain-of-function (GoF) missense variants in the Two-Pore Domain (K2P) K+ channel TASK-1 (KCNK3) result in Developmental Delay with Sleep Apnea (DDSA), a neurodevelopmental channelopathy, whilst loss-of-function (LoF) variants cause a hypertensive disorder. However, for the related TASK-3 channel (KCNK9), both LoF and GoF variants underlie a distinct neurodevelopmental disorder, KCNK9 Imprinting Syndrome (KIS). The relationship between genotype and phenotype in these disorders is further complica...

Next-generation sequencing has unraveled the genetic cause for many individuals with a rare disease, but a significant number of individuals remain undiagnosed using standard of care tests. It is anticipated that structural variants (SVs) have not been fully assessed in this context. Here, we performed optical genome mapping (OGM) for 57 trios and prioritized SVs using a two-step approach. First, we systematically identified all de novo SVs, and subsequently we studied all rare inherited SVs. Po...