Dr Ray O’Connor takes a look at the latest clinical articles in the field of genetics, which has seen large-scale collaborative efforts yield fundamental milestones and results
Some of the most significant discoveries in the life sciences over the last 50 years stem from genetics and genomics. This topic was the subject of a recent editorial in the journal Cell.1 The paper gives an excellent overview and summary of the topic of genetics from inception to date. Some of the salient points are summarised here.
Dr Ray O’Connor
The field has seen large-scale collaborative efforts yield fundamental milestones and results, such as the Human Genome Project. Progress in both basic and clinical genetics now drive efforts to cure complex human ailments such as blood and psychiatric disorders, metabolic diseases, cancer and neurodegeneration.
Genetics has grown from a largely focused topic of research to yielding one of the most ubiquitous methodological toolboxes used in nearly every life science discipline. From drug discovery to human evolution, from conservation to gene-editing, genetics is foundational to the study of living systems.
From viral vectors, engineered proteins, and fly, worm, zebrafish, and rodent models, the authors argue that genetics is a foundational methodology, on par with microscopy.
Beyond the lab, as emerging technology extends our ability to direct our own biology at its deepest level, it is important to understand the risk, ethics, and benefits of genetic research. This has come even further into focus in 2023 as both US and UK authorities have approved “clustered interspaced short palindromic repeats” (better known by its abbreviation CRISPR)-based gene therapies to treat disease. CRISPR is an extremely interesting discovery which is very well explained by the ‘Stanford Report’.2
Basically, CRISPR is an immune system used by microbes to find and eliminate unwanted invaders. Biologists use the term to describe the ‘genetic appearance’ of a system that was discovered in microbes – including bacteria and archaea – as early as 1987. When a virus infects a bacterial cell, CRISPR helps establish a memory – a genetic one.
The bacterium takes a piece of the virus’s genome and inserts the DNA into its own genome. From that newly acquired DNA sequence, CRISPR creates a new ‘guide RNA’, a sequence that helps CRISPR find the invader via sequence complementarity (i.e., A binds to T and C binds to G).
So, the next time when the virus infects that bacteria cell, the guide RNA rapidly recognizes the virus DNA sequence, binds to it, and destroys it. Gene therapy can mean using CRISPR as a macromolecule drug to either fix a mutated gene, or regulate a defective gene to treat a disease. Cell therapy means using CRISPR to make your body’s cells attack toxic cells or regenerate beneficial cells.
Carrier screening has historically assessed a relatively small number of autosomal recessive and X-linked conditions whose selection is based on frequency in a specific subpopulation and association with severe morbidity or mortality. Advances in genomic technologies enable simultaneous screening of individuals for several conditions.
In 2021, the American College of Medical Genetics and Genomics (ACMG) published a clinical practice resource3 that presents a framework when offering screening for autosomal recessive and X-linked conditions during pregnancy and preconception and recommends a tier-based approach when considering the number of conditions to screen for based on their frequency within the US population in general.
This more-recently published laboratory technical standard4 aims to complement the practice resource and to put forth considerations for clinical laboratories and clinicians who offer preconception/prenatal carrier screening.
The authors conclude that a wide array of high-throughput carrier screening assays for a large number of genes, identifying reproductive risks for dozens to hundreds of diseases, are now available based on next-generation sequencing (NGS) technologies. However, along with the capability to produce high-quality sequence data, NGS also brings new technical challenges that must be appreciated and addressed. This document provides technical guidelines for ACMG tier 3 genes, trying to ensure the achievement of maximum clinical sensitivity, specificity, and validity.
Osteoarthritis is the most prevalent whole-joint degenerative disorder and is characterized by the degradation of articular cartilage and the underlying bone structures. Almost 600 million people are affected by osteoarthritis worldwide.
No curative treatments are available, and management strategies focus mostly on pain relief. The authors of this review5 summarise the available human genetic and functional genomics studies for osteoarthritis to date and explain how these studies have helped shed light on disease etiopathology.
They highlight genetic discoveries from genome-wide association studies and provide a detailed overview of molecular-level investigations in osteoarthritis tissues, including methylation-, transcriptomics-, and proteomics-level analyses.
They review how functional genomics data from different molecular levels have helped to prioritize effector genes that can be used as drug targets or drug-repurposing opportunities. Finally, they discuss future directions with the potential to drive a step change in osteoarthritis research.
Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in approximately one per cent of populations across cultures. This review paper6 highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care.
The authors describe how there have been recent major advancements in the understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, so far, the impact of these findings on the clinical management of schizophrenia remains limited.
References:
- Cell Editorial Team. Five decades of genetics and genomics. Cell 2024; 187;1017-1018. https://doi.org/10.1016/j.cell.2024.01.051
- Qi S. What is CRISPR? A bioengineer explains. Stanford Report June 2024. https://news.stanford.edu/stories/2024/06/stanford-explainer-crispr-gene-editing-and-beyond#what-CRISPR (accessed 16/08/2025).
- Gregg AR, Aarabi M, Klugman S, et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(10):1793-1806. http://doi.org/10.1038/s41436-021-01203-z
- Guha S et al. ACMG TECHNICAL STANDARD. Laboratory testing for preconception/prenatal carrier screening: A technical standard of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine (2024) 26, 101137. https://doi.org/10.1016/j.gim.2024.101137
- Arruda AL et al. Annual Review of Genomics and Human Genetics. The Genetics and Functional Genomics of Osteoarthritis. Annu. Rev. Genom. Hum. Genet. 2024. 25:239–57 https://doi.org/10.1146/annurev-genom-010423-095636
- Besterman AD. A genetics-guided approach to the clinical management of schizophrenia. Schizophrenia Research 267 (2024) 462–469. https://doi.org/10.1016/j.schres.2023.09.042