Human Genetics and Genomics Advances

Microtia is a common congenital craniofacial malformation characterized by the partial or complete absence of the external ear structure. Despite its relatively high incidence, the pathogenesis of microtia remain poorly understood. In this study, we analyzed both single-cell and bulk RNA sequencing data from microtia cases and identified a population of COL1+HES1+ mesenchymal stem cell in perichondrium with significantly higher expression of the CRABP2 gene, a gene that encodes a nuclear transpo...

Several lines of evidence suggest that normal-range facial features and nonsyndromic orofacial clefts (OFCs) exhibit a shared genetic basis. Approaches designed to leverage this relationship hold the possibility of revealing new OFC risk loci by boosting discovery power. To test this idea, we applied a pleiotropy-informed GWAS method (cFDR-GWAS) with summary statistics from large, independent European GWASs of normal facial shape (n=4,680; n=3,566) and nonsyndromic cleft lip with or without clef...

ObjectiveOur understanding of the genetic causes of non-syndromic orofacial clefts (OFCs) is based largely upon genetic studies of common and rare nucleotide variants. Less is known about the role of copy number variations (CNVs) and the studies published to date have been limited to either small samples or targeted genomic regions. The objective of our study is to investigate the contribution of CNVs spread across the entire genome to OFC risk in a large multi-ancestry cohort. MethodsWe utiliz...

India harbors one of the most complex demographic and genetic landscapes globally, comprising more than 4600 endogamous ethnolinguistic groups shaped by multiple waves of migration, prolonged isolation and deep social stratification. Odisha, an eastern state of India, is home to 62 indigenous tribal groups, including 13 Particularly Vulnerable Tribal Groups (PVTGs), many of which remain genetically understudied. These populations provide a unique opportunity to explore fine-scale population stru...

Study questionDo variants in HSP90AA1 cause human male infertility? Summary answerVariants in HSP90AA1 appear as a possible autosomal dominant cause of human male infertility. What is known alreadyMale infertility is a highly heterogeneous condition, with so far over 300 genes described in this context. HSP90AA1 appears as a promising candidate gene for human male infertility, because the gene is highly conserved between species and knock-out of Hsp90aa1 in mice results in male-specific infert...

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...

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...

Genetic studies have largely focused on homogeneous populations, limiting our understanding of the genetic architecture of complex traits in admixed individuals. The advent of diverse biobanks like the All of Us Research Program (AoU) and computationally efficient local ancestry inference (LAI) methods now enable admixture mapping (ADM) at biobank scale. Here, we used two orthogonal LAI methods (GNOMIX and FLARE) to characterize local ancestry in the entire AoU v7.1 cohort (n=230,019). We then u...

Antisense oligonucleotides (ASO) are versatile disease modifying therapies for genetic diseases. An accelerated FD) pathway enables ASO treatment trial initiation in single patients within a year. However, this rapid N-of-1 pathway lacks extensibility to broad use necessary for sustainability. Individualized ASOs bind pre-mRNAs encompassing an entire locus. Thus, ASOs targeting common heterozygous polymorphisms (SNPs) are potentially haplospecific in many patients with dominant disorders. We dev...

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...

Age-related hearing loss (ARHL) is a progressive, bilateral decline in hearing ability that affects one in four individuals over 60 years of age worldwide. While previous genome-wide association studies (GWAS) have identified distinct single-nucleotide variants (SNVs) associated with metabolic and sensory ARHL phenotypes, the contribution of short tandem repeats (STRs) - a neglected yet important class of genetic variants - remains poorly understood. To address this gap, TRTools was used to impu...

Metabolite genome-wide association studies have identified hundreds of variants, many of which play intermediate roles linking genotype and phenotype with downstream diseases. However, the majority of metabolite GWAS have been published in self-identified Non-Hispanic White (NHW) populations, greatly limiting inference to other populations. Here we report the results of a GWAS of 7,522 untargeted metabolite peaks in 2,183 participants of the Coronary Artery Risk Development in Young Adults (CARD...

Disease-causing genetic variants can be found in a subset of individuals with cerebral palsy (CP), with variants deemed causal of CP having been published for at least 515 genes. We develop a statistical approach that treats CP as a phenotypic feature for which some genetic disorders confer an increased risk. Based on comprehensive literature curation we show that the null hypothesis of no CP association can be rejected for only 89 of the 515 genes. We applied these findings to the analysis of a...

Menieres disease (MD) is a chronic inner ear disorder characterized by recurrent vertigo, fluctuating sensorineural hearing loss, and tinnitus. Despite these distinctive symptoms, its etiology remains poorly understood. We performed a genome-wide meta-analysis of 8,969 cases and 1,962,542 controls across five large biobanks, identifying five independent genome-wide significant loci and estimating an observed-scale SNP heritability of 7% (SE 0.8%), consistent with a modest but significant genetic...

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...

Defects in motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD), and primary ciliary dyskinesia (PCD). Although these conditions often co-occur, the genetic and mechanistic bases for tissue-specific manifestations remain poorly understood. Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with HTX and complex congenital heart disease but no clinical signs of PCD. Whole-genome sequencing revealed a m...

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental disorders (NDDs), a relationship likely driven by multiple interacting factors, including shared genetic influences, the underlying cardiac malformation, and risks associated with medical and surgical care. To investigate the genetic component of this association, we analyzed genome-wide association study (GWAS) summary statistics for CHD from the UK Biobank and FinnGen, focusing on two phenotypes presen...

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...

PTEN hamartoma tumor syndrome (PHTS) is a cancer predisposition disorder caused by germline PTEN variants, yet its full clinical spectrum remains poorly defined due to reliance on highly selected cohorts. Accordingly, PHTS is underrecognized and its prevalence underestimated. Leveraging genomic and electronic health record data from 414,830 participants in the All of Us (AoU) Research Program, we identified 55 individuals with pathogenic or likely pathogenic PTEN variants, the majority of whom l...