Notable Genomics Research

This study focuses on the pathogenic mechanisms of MED13L missense variants, revealing differential impacts on protein stability, cellular localization, and interactions within the CDK8 kinase module. The findings highlight the complexity of MED13L-related intellectual disability syndrome and suggest novel functional roles for specific MED13L domains.

Functional assays provide valuable evidence for variant classification, but they are underutilized. Our survey of genetics professionals showed varied confidence in evidence evaluation and identified education, recommendations, and resources as facilitators of evidence use. We collated ClinGen expert-recommended assays to highlight existing guidance and emerging issues requiring improved guidance.

Variant-level functional data are emerging as a powerful tool for reducing the clinical burden of variants of uncertain significance. This comprehensive needs assessment survey explores how genomic medicine providers currently use functional evidence in variant interpretation and ways to improve the uptake of these data types in clinical genomic medicine.

Analysis of 230,016 genomes in the All of Us Research Program revealed substantial variation in continental and subcontinental ancestry within self-reported race and ethnicity across the US. Subcontinental ancestry was associated with body mass index and height, underscoring the importance of fine-scale ancestry resolution in genetic research and precision medicine.

Within the field of prenatal genetic diagnosis, there is ongoing debate about whether fetal genomic sequencing (GS) should be offered for all pregnancies or only when a genetic disorder is suspected. Currently, the International Society of Prenatal Diagnosis recommends exome sequencing (ES) only in the presence of sonographic abnormalities. However, many treatable genetic disorders do not present with ultrasound abnormalities. In fact, recent studies have found that 0.6%–2.7% of sonographically normal fetuses harbor pathogenic or likely pathogenic variants expected to cause genetic disease, making a case for offering fetal GS to all pregnant individuals.

Multiplex assays of variant effects provide data for thousands of genetic variations, but robust clinical validation remains a barrier to clinical adoption. This was reflected in our November 2024 survey of UK NHS clinical scientists; their key recommendation was for clinical validation to be performed by a trusted central body.

We quantify differences in the predictive value of polygenic scores (PGSs) across the phenotypic range using quantile regression and non-equivalence tests of quantile-specific effect sizes. We demonstrate that heterogeneity can arise from gene-by-environment interactions. Our approach finds traits with evidence of interactions and heterogeneous PGS performance without specifying the relevant environmental exposures.

This paper examines the impact of rare variants and sex on gene expression across the X chromosome and autosomes, ultimately identifying over 700 rare variants with predicted functional differences between males and females. Their role in transcription factor binding and pharmacogenetics is further explored.

We identified the RP1L1 c.133C>T (R45W) mutation as the primary pathogenic variant in occult macular dystrophy (OMD). Functional analysis showed that R45W disrupts RP1L1 and RP1 localization, affects cell viability in vitro, and downregulates MEG3 and the PI3K/Akt pathway in iPSC-derived photoreceptor-like cells, advancing OMD pathogenesis understanding.

Trzupek et al. describe a rare disease Open Science Data Challenge, using data collected systematically on RARE-X across 27 neurodevelopmental disorders. Clinical diagnoses, symptoms, genetic data, and PROs were included. Researchers and statisticians generated solutions that identified previously underappreciated symptoms and used machine learning to test predictive models for diagnosis.

(Human Genetics and Genomics Advances 5, 100306; July 18, 2024)

Workplace genetic testing is a model where employees are offered genetic testing through wellness programs. However, the potential harms, benefits, and best implementation practices have yet to be defined. From a modified Delphi process, we identified 12 key characteristics for implementation. These findings help inform the establishment of a normative framework.

A multi-level genome-wide interaction study in 200,060 UK Biobank participants identified two loci around FADS1-FADS2 and GPR12 whose genotypes modify the associations of fish oil supplementation with the circulating levels of polyunsaturated fatty acids. Individuals with different genotypes need different doses of fish oil to achieve the same circulating levels.

We used an emerging functional assay to identify inhibitor-resistant MGMT protein variants that can potentially be generated via base editing. These MGMT variants could be introduced into engineered hematopoietic stem cells without viral transduction to facilitate their enrichment under alkylating-agent treatments that ablate the native hematopoietic stem cells.

We identify 14 individuals with de novo variants in BSN, a gene encoding the presynaptic protein Bassoon, linked to NDD and epilepsy. Detailed phenotypic analysis revealed a broad range of clinical features in individuals with BSN variants. Phenotypic expression varies significantly between pediatric and adult cohorts, suggesting an age-specific signature.