Genomics Moves From Variant Discovery to Precision Diagnosis Across Rare and Common Disease

Human genetics is undergoing a period of unusually rapid consolidation, and a new editorial surveying a collection of studies on the genetics of common and rare diseases argues that the field has crossed a practical threshold: genomic technologies are no longer confined to research laboratories but are increasingly woven into everyday clinical practice. The editorial, authored by Jordi Pérez-Tur of the Institute of Biomedicine of Valencia and the Spanish National Research Council, Mara Marongiu of the Institute of Genetic and Biomedical Research in Cagliari, and Erica E. Davis of the Stanley Manne Children's Research Institute and Northwestern University, organizes the collected work into three broad and partially overlapping themes: genomic medicine, rare disease discovery, and the mechanisms of translational biology. Together, the editors contend, these studies offer a snapshot of a discipline shifting from the simple identification of genetic variants toward integrated strategies that combine genomic, transcriptomic, functional, and clinical evidence to inform diagnosis, prognosis, and patient management.

The first theme, genomic medicine, is illustrated most vividly by the diagnostics cluster, where several studies demonstrate how newer sequencing approaches can outperform established methods in specific clinical settings. Lan and coworkers applied long-read sequencing to the detection and characterization of variants in the CYP21A2 gene, which underlies 21-hydroxylase deficiency, a form of congenital adrenal hyperplasia. The long-read approach substantially improved variant detection and characterization, and the authors further showed that a next-generation sequencing-based technique can serve as an efficient diagnostic route for affected patients.

In parallel, Malmgren and collaborators assessed the diagnostic yield of parent-proband trio exome and genome sequencing in individuals presenting with a wide variety of clinical symptoms, providing evidence for the clinical utility of comprehensive genomic testing and reinforcing that trio analysis achieves a higher diagnostic yield than singleton analysis of the affected individual alone. Other diagnostic studies show how sampling and screening innovations can bring molecular testing to previously difficult contexts. Fang and colleagues conducted an observational study of a mitochondrial DNA variant associated with mitochondrial diabetes mellitus and demonstrated that a minimally invasive collection technique yielded patient samples suitable for diagnosis, an advance with obvious implications for conditions in which tissue access has historically been a barrier.

At the population scale, Zhang and coworkers combined tandem mass spectrometry with molecular testing in a newborn screening program covering more than 1.4 million newborns in Xinjiang, China, to determine the incidence and genetic basis of inborn errors of metabolism. Large-scale screening also featured in the work of Gui and collaborators, who identified the rare hemoglobin variants Hb O-Arab and Hb D-Punjab in Guangxi, China, expanding the known hemoglobinopathy spectrum across diverse ancestries within the country. These population genomics efforts, the editors note, have closed knowledge gaps for specific rare conditions in large cohorts.

Population-based molecular epidemiology is also extending into complex, multifactorial disease. Mouawad and colleagues analyzed a Lebanese cohort and confirmed the association of a promoter variant in the MUC5B gene with idiopathic pulmonary fibrosis, a finding previously established in other populations that now has replication in a distinct ancestry group. In a large South Asian population, Menon and coworkers validated the utility of a polygenic risk score for body-mass index as a predictor of obesity risk, an example of the field's movement toward what the editors describe as a predictive era for complex diseases.

Taken together, the editors argue, these advances demonstrate the increasing integration of genomic technologies into routine medical practice and show how diagnostic approaches are being reshaped across distinct clinical settings, from newborn screening laboratories to adult pulmonary and metabolic clinics. A second substantial trend identified in the collection is the refinement of genotype-phenotype relationships, in which detailed clinical characterization combined with genetic analysis moves beyond diagnosis toward prognosis and counseling. Bi and colleagues showed that individuals carrying pathogenic variants in PCDH15, a gene implicated in inherited deafness, derived marked benefit from cochlear implantation regardless of whether their phenotype was isolated deafness or Usher syndrome, a result with direct implications for therapeutic decision-making.

Feghali and coworkers characterized MEFV variants in familial Mediterranean fever within a Lebanese population, defining the genetic landscape of the disease across different geographic subpopulations, while Orozco and collaborators characterized variants linked to Duchenne muscular dystrophy in Guatemala, emphasizing the need for easy and fast access to genetic infrastructure in regions where such resources remain limited. The genotype-phenotype theme extends across a striking range of clinical presentations. Wei and colleagues reported marked clinical heterogeneity in Shwachman-Diamond syndrome, a rare inherited multisystem disorder, with manifestations spanning pancreatic insufficiency, neutropenia, developmental anomalies, and neurocognitive features.

Chan and coworkers studied a cohort of rare forms of congenital adrenal hyperplasia, combining clinical observation with genetic analysis to show that genomic characterization is instrumental in defining subtypes of clinically overlapping endocrine disorders, and they described novel variants in steroidogenic genes. Xu and collaborators demonstrated that in Netherton syndrome the distribution of SPINK5 variants relates to disease severity, including infant mortality, nutritional status, and dermatological manifestations. Gupta and colleagues probed the spectrum of RASopathies in a large North Indian cohort and found a previously undescribed correlation between specific molecular defects and clinical presentations.

Collectively, the editors conclude, such studies show that genetic analysis of clinically characterized samples informs prognosis, therapeutic choices, and genetic counseling, not merely etiological confirmation. The collection also highlights the rapid integration of computational biology and systems-level approaches into human genetics. Ji and coworkers analyzed available datasets for polycystic ovary syndrome, now known as polyendocrine metabolic ovarian syndrome, and rheumatoid arthritis, and identified subsets of shared genes with dysregulated expression involved in cell death, inflammation, and redox pathways, suggesting overlapping molecular mechanisms of immune dysregulation between the two conditions.

Through a large meta-analysis, Zhu and collaborators refined the relationship between the TGF-β1 rs1982073 variant and susceptibility to autoimmune disease, with the signal particularly evident in Asian populations. In the structural variant domain, Fifirig and colleagues summarized the mechanistic evidence linking the 15q11.2 BP1-BP2 microdeletion to congenital heart disease, implicating the four genes within the deleted interval, TUBGCP5, CYFIP1, NIPA1, and NIPA2, in phenotype manifestation; the prevalence of the condition among deletion carriers ranges from 10 to 30 percent, a figure the authors attribute to the deletion's low penetrance and variable expressivity. These computational approaches, the editors observe, help delineate biological connections between apparently unrelated diseases while simultaneously identifying potentially promising therapeutic targets.

The expansion of the catalog of disease-associated genes remains one of the most prominent themes. Lucia-Campos and coworkers reported an association between an intragenic duplication in AFF2 and a Cornelia de Lange syndrome-like phenotype, extending the group of transcriptional regulators implicated in this family of disorders. Yang and collaborators described familial involvement of UBAP2L in a recently recognized neurodevelopmental disorder characterized by developmental delay, impaired language, behavioral abnormalities, seizures, and dysmorphic facies.

Xin and colleagues identified a pathogenic COL2A1 variant associated with acetabular dysplasia, and Lin and coworkers found pathogenic or likely pathogenic variants in PLOD1, COL1A1, COL5A2, and COL4A1 in four families affected with keratoconus, connecting connective tissue biology to this corneal condition. Ma and collaborators, working with a zebrafish model, uncovered a previously unrecognized role for MFSD3 in auditory development and the maintenance of sensory hair cells. The editors stress that these reports reflect the challenges posed by genetic heterogeneity and the importance of thorough clinical and genetic investigation in unresolved cases, and that they support the field's growing capacity not only to identify disease genes but also to influence patient management.

Functional studies in the collection push beyond gene discovery toward molecular and cellular pathology. Zhang and colleagues showed that variants in CFTR, the gene mutated in cystic fibrosis, may exert their pathogenic effects by altering RNA splicing rather than through an altered protein-dependent mechanism, broadening the mechanistic repertoire attributed to this well-studied gene. Li and coworkers found that a marked proportion of variants in COL4A5 induced aberrant transcripts and were usually associated with more severe renal outcomes, linking transcript-level consequences to clinical severity.

Na and collaborators used transcriptomic analysis with functional validation to implicate AURKA, BUB1, CDK1, RAD51, and TOP2A in the pathogenesis of biliary atresia. The editors highlight these manuscripts as evidence of a strengthened interest and capacity to move from variant identification to functional validation in pursuit of mechanistic understanding. A broad-reaching group of studies spans all three themes in the area of prenatal and developmental genetics.

Cai and colleagues showed that combining exome sequencing with microarray analysis in fetuses with hyperechoic kidneys can inform choices in pregnancy management. Wang and coworkers found highly variable prenatal phenotypes together with incomplete penetrance in fetuses with recurrent 1q21.1 copy number variants, reporting phenotypes associated with both the 1q21.1 deletion and duplication syndromes and exemplifying the challenges of prenatal diagnosis and counseling. Zhao and collaborators described a multigenerational family carrying a balanced t(5;9)(p15;p24) translocation that produced unbalanced chromosomal rearrangements and Cri-du-chat syndrome in some offspring, work the editors note may have high clinical relevance for reproductive counseling and risk assessment.

Yin and colleagues identified SLC23A2 as a significant genetic risk factor for non-syndromic cleft lip, with experimental evidence implicating increased oxidative stress and apoptosis in oral epithelial cells and zebrafish models, and demonstrating an interaction between SLC23A2 function, oxidative stress, and ascorbic acid availability. Finally, Xu and coworkers showed that neonatal-onset methylmalonic acidemia often presents with non-specific symptoms that can delay disease-specific care, with most affected individuals in their small cohort carrying recurrent variants in MMACHC and MMUT. Looking forward, the editors argue that the distinction between rare and common diseases is increasingly blurred, as similar genomic, analytical, and functional approaches are applied across both and progressively incorporated into routine care, pointing the field toward a more integrative, mechanistically informed, and translationally oriented paradigm that brings precision medicine closer to everyday clinical practice.

Subject of Research: Integration of genomic medicine, rare disease gene discovery, and functional genomics across common and rare diseases

Article Title: Editorial: Insights in genetics of common and rare diseases 2024–2025

Article References: Pérez-Tur, J., Marongiu, M., & Davis, E. E. (2026). Editorial: Insights in genetics of common and rare diseases 2024–2025. Frontiers in Genetics, 17, 1996785. https://doi.org/10.3389/fgene.2026.1996785

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1996785

Keywords: genomic medicine, rare disease, genotype-phenotype, long-read sequencing, newborn screening, population genomics, polygenic risk score, prenatal genetics, disease genes, functional genomics, precision medicine, copy number variants