Notable Genomics Research

When I assumed the role of editor-in-chief of the American Journal of Human Genetics (AJHG) in January 2018, I introduced myself in an editorial entitled “Transitions in an era of disruptive change.”1 That proved to be an apt title, as will be outlined below. Nevertheless, during this time, The Journal celebrated its 75th anniversary, and we have strived to maintain its status as the flagship journal of the American Society of Human Genetics (ASHG) known for scientific rigor and relevance to human genetics researchers everywhere.

Starting in 2019, AJHG has published an annual feature1,2,3,4,5,6 identifying ten key advances in applying genomic information to clinical care that were reported in the previous 12 months of published literature. The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research of the National Human Genome Research Institute (NHGRI) has authored these reviews based on its broader effort to identify notable accomplishments in genomic medicine on a monthly basis and post them on a searchable website (see web resources).

EEPRS integrates electronic health record-derived phenotype embeddings with GWAS summary statistics to improve polygenic risk prediction. Using embedding methods such as Word2Vec and GPT, EEPRS enhances both single- and multi-trait PRS performance and reveals interpretable phenotype clusters, offering a scalable, interpretable framework for integrating clinical and genetic information.

Through paleogenomics, the study of ancient DNA (aDNA), scientists have been able to construct chronologies of human evolution, detailing interactions between Homo sapiens, other species, and past environments. Paleogenomics differs from modern genomics in that aDNA is typically extracted from skeletal remains and other finite organic sources, often destroying irreplaceable samples. Once destroyed, recovery of additional endogenous aDNA is not possible, and re-analysis is limited to the reprocessing of raw data sequence.

Using CRISPR-edited CD34+ cells differentiated into megakaryocytes, CRIMSON HD models Glanzmann thrombasthenia phenotypes, providing a robust, lineage-relevant framework for functional testing and reclassification of clinically ambiguous variants in inherited platelet disorders.

Loss-of-function variants in genes linked to haploinsufficient Mendelian diseases have unexpectedly low rates of phenotypic expression in population-scale biobanks. Using statistical modeling and machine learning, we demonstrate that many of these variants likely harbor residual allelic activity, allowing them to remain unexpressed in many individuals.

Large-scale data sharing is indispensable for advancing human genetics and genomics (HGG) research and medicine. The willingness of study participants and researchers to share data has been the foundation of rapid advancements of the HGG field for decades. If the potential benefits of HGG research are to be fully realized, maintaining a broad data-sharing ethos and policy environment is vital. ASHG reasserts the HGG community’s commitment to responsible data stewardship and emphasizes the role of researchers in working alongside other interested parties to create a secure research enterprise without imposing undue restrictions on researchers’ ability to collaborate, share data, and advance knowledge while also protecting the will and privacy of participants.

As genomics becomes increasingly embedded in research, healthcare, and society, training programs must adapt. Through focus groups with leaders across public health genetics subfields, we developed updated competencies reflecting the skills future practitioners need, emphasizing foundational knowledge, analytical proficiency, interdisciplinary application, and cross-sector collaboration.

Heterozygous variants in ESRRG are associated with an autosomal-dominant, non-progressive congenital movement disorder. Clinical characterization of eight individuals, supported by in silico modeling and cell-based functional assays, defines a recurrent phenotype with congenital ataxia, hypotonia, and ocular motor abnormalities, expanding the genetic landscape of early-onset motor disorders.

Bi-allelic loss-of-function variants in protein arginine methyltransferase 9 (PRMT9) cause a neurodevelopmental disorder with variable severity. Affected individuals have mild to severe intellectual disability, global developmental delay, autism spectrum disorder, epilepsy, and hypotonia. Functional studies on patients’ cells reveal a possible functional impact on ciliary functions.

This study provides an unbiased genomic characterization of polyglutamine (polyQ) disorder genes, revealing widespread pleiotropy and genomic features linked to clinical trial failure. These findings highlight potential safety risks of directly targeting polyQ genes and emphasize the value of other approaches, such as targeting genetic modifiers or employing allele-selective strategies.

We conducted a protein quantitative trait locus (pQTL) study in 3,707 Greenlanders, identifying 251 associations, including 70 novel signals. We compared variance explained with Europeans from the UK Biobank, linked pQTLs to cardiovascular outcomes, and uncovered protein associations with Arctic-enriched variants, underscoring the importance of pQTL studies in diverse populations.

Current methods for detecting splicing quantitative trait loci (sQTLs) miss many disease-associated genetic variants. MAJIQTL introduces improved statistical modeling and comprehensive splicing representation, discovering significantly more functionally relevant sQTLs that explain neurodegenerative disease GWAS signals, including identifying the role of rs528823 in Alzheimer disease through MS4A3 splicing regulation.

This study applies a shared genomic segments analysis in high-risk pedigrees to identify chromosomal regions linked to stillbirth, offering insights into inherited contributors to obstetric complications.

(The American Journal of Human Genetics 109, 944–952; May 5, 2022)