Genetic sequencing crucial for diagnosing growth disorders, study finds

In an article published in the Journal of Pediatrics, researchers have described the case of a nine-year-old boy admitted to hospital with multiple symptoms and overlapping conditions that made diagnosis difficult, such as short stature, thin tooth enamel (dental enamel hypoplasia), moderate mental deficiency, speech delay, asthma, mildly altered blood sugar, and a history of recurring infections in infancy.

The team used exome sequencing, in which only the protein-coding portion of the genome 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. Identification of the exact cause of the problem and the discovery of a blood sugar alteration significantly influenced their choice of treatment.

For the study, researchers sequenced the exomes of 115 patients with syndromic growth disorders that had hitherto unknown causes, diagnosing 63 on the basis of the genetic analysis; 9.5% of these had a multiple diagnosis, far more than in previous studies.

“The cases involved two or more rare monogenic conditions in the same patient. Such cases are very hard to diagnose, especially by clinical assessment alone. The study highlights the need to use broad genetic tests 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 Alexander Augusto de Lima Jorge, author of the article.

There are numerous 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 believed to have a rare disease.

The study's findings highlight the importance of considering multiple genetic diagnoses in complex cases of growth disorder. This approach offers new treatment and genetic counselling avenues, diverging from the traditional single-diagnosis paradigm. The researchers also state that the development of next-generation sequencing techniques such as whole exome or whole genome sequencing has made selecting a single gene as the candidate to explain a case unnecessary.

Reference: DOI:10.1016/j.jpeds.2023.113841