Exome sequencing reveals complex genetic diagnoses in developmental disorders

In an article published in Journal of PediatricsBrazil-based researchers describe the case of a nine-year-old boy who was admitted to the hospital with multiple symptoms and overlapping conditions that made diagnosis difficult, including short stature, thin tooth enamel (tooth enamel hypoplasia), moderate mental retardation, speech delay, asthma , mild change in blood sugar and a history of repeated infections in infancy.

The team used exome sequencing, in which only the portion of the genome that codes for the protein is analyzed, to look for genetic mutations and found them in GCK and BCL11B. As a result, the diagnosis was monogenic diabetes and T-cell abnormality syndrome, both of which are rare diseases. Identifying the exact cause of the problem and discovering the change in blood sugar significantly influenced their choice of treatment.

This is one of six cases involving syndromic growth disorders with multiple genetic diagnoses (two or more distinct genetic conditions in the same patient) described in the article, which is about a study conducted by researchers at the School of Medicine of the University of São Paulo ( FM-USP ) with the support of FAPESP.

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 undergo until they receive the correct diagnosis. Ten years ago, private labs charged BRL 10,000. The price has now dropped to BRL 4,000 [about USD 800]. That’s still a lot of money for a test, but it has proven to be essential for accurate diagnosis and treatment in cases of this nature.”

Alexander Augusto de Lima Jorge, last author of the article

The team sequenced the exomes of 115 patients with syndromic growth disorders that had so far unknown causes, diagnosing 63 based on genetic analysis. 9.5% of them had multiple diagnoses, much more than in previous studies.

“The cases involved two or more rare monogenic conditions in the same patient. Such cases are very difficult to diagnose, especially with clinical evaluation alone. The study highlights the need to use broad genetic testing, such as whole-exome or whole-genome sequencing for these patients as the only way to identify the rare diseases that explain such clusters of conditions,” said Lima Jorge.

There are many rare diseases, including growth disorders, so it is naturally difficult to identify many of them, he added. Between 5% and 10% of the world’s population is thought to suffer from a 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. Even so, genetic factors will always be important in development. In healthy children with short or tall stature as a unique manifestation, there will likely be 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 intellectual disability, deafness, autism spectrum disorder, or dysplasia, a change in one or more genes is more likely to account for the complex phenotype involved,” Lima Jorge said.

In light of the results, the researchers support the recognition of multiple genetic diagnoses as a possibility in complex cases of developmental disorder, opening new perspectives for treatment and genetic counseling for these patients, instead of the standard paradigm that requires a single diagnosis to explain all findings.

In the article, the researchers report that the development of next-generation sequencing techniques, such as whole-exome or whole-genome sequencing, has made choosing a single gene as a candidate to explain a case unnecessary. This particular benefit has proven useful in the research setting to promote the discovery of new disease-related genes, to further study conditions with a high degree of genetic heterogeneity, and to care for patients with complex syndromic conditions where diagnosis cannot be made obtained by traditional clinical and genetic methods.

Several challenges highlighted by Lima Jorge include the high cost of genetic testing and the fact that exome sequencing has about a 50% success rate in diagnosing complex cases. In other words, about half of the patients who underwent this type of analysis should continue to seek a definitive diagnosis.