Big leaps in diagnostics, small steps in therapeutics
Editorial
Correct diagnosis is the first step to treatment. Treatment is aimed at cure. DNA based diagnosis of monogenic
disorders has been established and more diagnostic tests are being added rapidly. Gone is the era of linkage based
diagnosis; today, in most centers DNA-based diagnosis is done by mutation detection only. This is due to improvement in
the technology of sequencing as well as the development of newer techniques like multiplex ligation probe amplification
(MLPA), etc. The problem with large sized genes and genetically heterogeneous disorders has been tackled by the high
throughput technique of next generation sequencing (NGS). NGS technology has also been instrumental in identifying
causative genes of many rare disorders. Though the pace of diagnostics is far more as compared to that of
development of novel treatments and cures, research in the area of treatments is showing great promise. Duchenne
muscular dystrophy (DMD) is one such example of a genetic disorder for which many novel therapeutic
strategies are being explored and the review article in this issue discusses many of the conventional as well
as newer diagnostic and therapeutic aspects related to Duchenne muscular dystrophy. One of the latest
treatment strategies showing promise is use of an internal ribosome entry site (IRES), the article about which is
mentioned in the Genexpress of this issue. The treatment strategies being innovated and tried are novel
and varied. But all of them depend on better understanding of the pathophysiology based on the function
of the causative gene and the different degrees of effects of various mutations on protein expression and
function.
The story of most of the monogenic disorders e.g. cystic fibrosis, Marfan syndrome, etc., is the same. Identification of
the causative gene and understanding of its function and of the pathophysiology of the disease has lead to development of
novel treatment strategies for each of them, gene therapy being the common final goal for all. It is becoming obvious that
though gene therapy may take longer than was expected, other strategies to manipulate other genes, proteins or pathways
may be equally successful in ameliorating symptoms of diseases as has been seen for some diseases like
Marfan syndrome, RASopathies, etc. Early diagnosis becomes important for timely intervention for such
treatable disorders. For early diagnosis of these disorders newborn screening by sequencing the exome or
whole genome of a neonate is an option and technically feasible today. It is being done in clinical settings
in patients with difficult clinical diagnoses. One of the articles mentioned in Genexpress of this issue has
reported the diagnostic yield of whole exome sequencing to be 25%. Of course analysis of sequence data and
interpretation regarding the pathogenic nature of sequence variations are demons arising from the huge
NGS data and the bioinformatician’s fight against these demons has begun. The tools used in this war
are discussed in the article on ‘Prediction of Pathogenicity of Sequence Variations’ in this issue. Not only
laboratory personnel and geneticists but clinicians will need to be well conversant with these tools as they
now need to participate in the analysis and interpretation of result data and not limit themselves to only
communication of the results to the patients / families. The size of the demon of “variations of uncertain
significance” will continue to shrink and whole genome / exome sequencing will become a technique for
presymptomatic diagnosis; genetic medicine may then take the form of preventive medicine in the real sense. And,
embryonic diagnosis and nonsurgical treatment of congenital malformations such as duodenal atresia or
transposition of great vessels or cure for major defects such as holoprosencephaly may not remain just a science
fiction.
