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Brazilian researchers described the case of a nine-year-old boy who was hospitalized with multiple symptoms and overlapping conditions that made diagnosis difficult, including short stature, thin tooth enamel (dental enamel hypoplasia ), moderate mental deficiency, speech delay, asthma. Minor changes in blood sugar, and a history of frequent infections in infancy. This article was published in the Journal of Pediatrics.
The scientists discovered the genetic changes in GCK and BCL11B using exome sequencing, which analyzes only the protein-coding region of the genome. He searched for them. As a result, monogenic diabetes and T-cell abnormalities syndromes were recognized as rare disorders. Identifying the real cause of the problem, as well as detecting blood sugar changes, had a substantial impact on their treatment decision.
This is one of six cases associated with syndromic growth disorders with multiple genetic diagnoses (two or more distinct genetic conditions in the same patient) described in the article, conducted by researchers at the Medical School of the University of São Paulo (FM-USP). Related to a study. ,
“Exome sequencing is a very useful technology to reduce what we call the diagnostic odyssey – the long journey that patients with rare or complex conditions have to go through until they get a proper diagnosis. Ten years ago, private laboratories would charge BRL 10,000. The price has now fallen to BRL 4,000. [about USD 800], This is still a lot of money for one test, but it has proven essential for accurate diagnosis and treatment in cases like this,” said Alexander Augusto de Lima Jorge, the last author of the article.
The team sequenced the exomes of 115 patients with syndromic developmental disorders that had hitherto unknown causes, diagnosing 63 based on genetic analysis; Of these, 9.5% had multiple diagnoses, which is much higher than previous studies.
“The cases involved two or more rare monogenic conditions in the same patient. Such cases are very difficult to diagnose, especially by clinical evaluation alone. Studies have been conducted to identify whole exome or whole genome sequences for these patients “highlights the need to use comprehensive genetic tests such as sequencing as the only way to identify rare diseases that explain such clusters of conditions,” said Lima George.
There are many rare diseases, including growth disorders, he said, so many of them are inherently difficult to identify. It is believed that 5% to 10% of the world’s population has this rare disease.
Short stature or tall stature is not a diagnosis but a clinical finding. “Short stature may have an external cause, such as infection or malnutrition. Nevertheless, genetic factors will always be important for growth. In healthy children with short or tall stature, it will probably have a polygenic basis [where stature is influenced by several genetic variants]But in syndromic growth disorders, in which short or tall stature is accompanied by other findings such as mental deficiency, deafness, autism spectrum disorder, or malformation, alterations in one or more genes are more likely to underlie the complex phenotype involved, ” Lima George said.
In light of the results, the researchers advocate the recognition of multiple genetic diagnoses as a possibility in complex cases of developmental disorder, opening new possibilities for treatment and genetic counseling for such patients, in place of the typical paradigm that models a single diagnosis. Demands diagnosis. Interpret all findings.
In the article, the researchers state that the development of next-generation sequencing technologies such as whole exome or whole genome sequencing has made it unnecessary to select a single gene as a candidate to explain a case. This special advantage has proven useful in research environments to promote the discovery of new disease-associated genes, advance the study of conditions with high levels of genetic diversity, and help in the care of patients with complex syndromic conditions where diagnosis can be done. Obtained by traditional clinical and genetic methods.
Many of the challenges noted by Lima George include the high cost of genetic tests and the fact that exome sequencing has a success rate of about 50% in diagnosing complex cases. In other words, approximately half of the patients presented for this type of analysis will remain in search of a conclusive diagnosis.
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