Crisper than CRISPR: Towards Greater Precision in the Diagnosis and Treatment of Genetic Disorders

The sky is the limit. Or maybe not! Every time a new breakthrough discovery is made, we think that we have reached the pinnacle of scientific achievement, and then along comes another more innovative development. This is particularly true about advances in the field of medicine and even more so in the field of medical genetics. A number of breakthroughs in recent years have led to rapid advances in the diagnosis and management of genetic disorders. Notable among them is the discovery of the Clustered regularly interspaced short palindromic repeats (CRISPR)-cas9 genome editing system and the development of high-fidelity long-read sequencing techniques. The CRISPR-cas9 genome editing system is considered to be a very promising modality for the treatment of genetic disorders. However, CRISPR-cas9, which involves the creation of double-stranded breaks in the gene and subsequent repair through either homology-directed repair or nonhomologous end joining, lacks precision and has limitations, especially in terms of unintended edits at off-target sites. To overcome these challenges, researchers are now developing higher precision techniques. One such method is the use of retrons, which has been discussed in the GenExpress of this issue. Retrons are part of the anti-phage defense mechanism of bacteria, which consist of a reverse transcriptase and a noncoding RNA, which together produce multicopy single-stranded DNA. The retron-derived single-stranded DNA can be used in combination with the CRISPR-cas9 system as a template for precise genome editing. The GenExpress also has an excerpt of a recent publication, which highlights the role of artificial intelligence (AI) in identifying potential rare diseases from retrospective electronic medical records. This AI-based search algorithm, called “ThinkRare” is an example of how the power of AI and machine-learning can be leveraged for early diagnosis and management of rare genetic disorders and for understanding the burden of rare diseases in a population. Another interesting development, also covered in the GenExpress, is the study on same-day genome sequencing in the neonatal intensive care setting, where advanced sequencing pipelines and precisely designed workflows have been demonstrated to generate genome sequencing results within a few hours, enabling accurate and rapid diagnosis for appropriate targeted treatment of sick newborns. These recent advances are very promising and will hopefully get translated into clinical practice very soon. The Optical Genome Mapping technique is a good example of a technological advancement being used for routine clinical diagnostics for conditions such as facioscapulohumeral muscular dystrophy, as outlined in the GeneVista review article in this issue, and for complex structural genomic variations. The recently concluded Tenth Annual Conference of the Society for the Indian Academy of Medical Genetics (2025), held in Pune, Maharashtra, showcased many such recent developments in the field of medical genetics. National and international faculty and delegates attended the event and actively participated in the scientific deliberations. The theme of the conference “From Rare Disorders to Common Diseases” aptly reflects the broad range of topics covered, from genetic risk stratification in common diseases and polygenic risk scores in diabetes to functional characterization of novel gene variants and emerging disease-specific therapies for monogenic disorders. The GenEvent segment of this issue covers the salient features of the conference. As we step into 2026, we hope that the New Year will usher in an era of improved diagnosis and more affordable, accessible, and precise disease-specific therapies for patients suffering from rare genetic disorders. Wishing all our readers a very happy New Year!