According to a new research published in American Journal of Hematology, exome sequencing (ES) has the potential to molecularly diagnose causes of inherited platelet disorders (IPD) and to identify candidate genes for functional evaluation.

Molecular diagnosis of IPDs in pediatric patients remains a challenge affecting patients, families, and clinicians worldwide due to incomplete current knowledge of all disease-causing variants; however, genome and exome sequencing represent powerful techniques to help overcome this challenge. The results here demonstrate the utility and limitations of ES as a molecular diagnostic tool in a single-center, pediatric clinic for individuals with suspected IPDs.

Inherited platelet disorders (IPD) are a heterogeneous group of rare disorders that affect platelet number and function and often predispose to other significant medical complications. In spite of the identification of over 50 IPD disease-associated genes, a molecular diagnosis is only identified in a minority (10%) of affected patients without a clinically suspected etiology.

The research team studied a cohort of 21 pediatric patients with suspected IPDs by exome sequencing (ES) to examine the performance of the exome test for IPD genes, determine if this exome-wide diagnostic test provided a higher diagnostic yield than has been previously reported, to evaluate the frequency of variants of uncertain significance identified, and to identify candidate variants for functional evaluation in patients with an uncertain or negative diagnosis.

The researchers established a high priority gene list of 53 genes, evaluated exome capture kit performance, and determined the coverage for these genes and disease-related variants. We identified likely disease-causing variants in 5 of the 21 probands (23.8%) and variants of uncertain significance in 52% of patients studied. This is the first report of an exclusively pediatric platelet disorder cohort evaluated by ES.

In conclusion, ES has the potential to molecularly diagnose causes of IPD and to identify candidate genes for functional evaluation. Robust exome sequencing also requires that coverage of genes known to be associated with clinical findings of interest need to be carefully examined and supplemented if necessary. Clinicians who undertake ES should understand the limitations of the test and the full significance of results that may be returned. The team is optimistic about the potential for new and developing technologies such as whole genome sequencing and functional experiments to improve diagnosis in the patients.