Decision Tree for Genetic Diagnoses in Neurodevelopmental Cases

In a recent study published in Genetics in Medicine, a group of researchers identified clinical factors associated with genetic diagnoses in patients with neurodevelopmental disorder (NDD), which affects brain development and causes cognitive or motor delays, and created a decision tool to guide genetic testing decisions.

Background:

Neurodevelopmental disorders (NDDs), including global developmental delay, autism spectrum disorder (ASD), and intellectual disability, are highly heritable.

Advances in genetic testing, such as chromosomal microarray (CMA) and exome sequencing (ES), have increased diagnostic accuracy. Genetic variations are found in 10% to 20% of CMA cases, but in more than 40% of ES cases.

According to studies, those with genetic diagnosis are more likely to have medical comorbidities. More research is needed to validate decision tools and find additional phenotypic characteristics that would increase genetic diagnosis accuracy in various clinical populations.

About the study
In this investigation, 110 patients and their legal guardians gave informed consent for prospective clinical data collecting. Additionally, 206 patients’ charts were retrospectively evaluated under an Institutional Review Board (IRB)-approved waiver.

All patients’ data were manually collected from the University of California, Los Angeles (UCLA) electronic health record and entered into an encrypted database. Seventy patients were rejected due to insufficient genetic testing or a lack of insurance permission.

Patients were eligible if they had a known or suspected neurogenetic condition and had undergone at least one genetic test, such as CMA, fragile X, mitochondrial Deoxyribonucleic Acid (DNA), single-gene sequencing, or ES.

The study divided the participants into three groups depending on their genetic test results: pathogenic or likely pathogenic (P/LP), negative, and ES-negative subgroup. Clinical data, such as age at milestones, history of motor and language deficits, congenital heart disease, and other variables, were collected and categorized for analysis.

Statistical analysis used χ2 and two-sample Wilcoxon tests to investigate correlations between clinical factors and genetic diagnosis. Following that, logistic regression, classification, and regression tree (CART) analyses were done to determine which clinical features were most strongly related with a genetic diagnosis.

Conclusions
To summarize, this study found that motor delay, female sex, and hypotonia were highly related with a higher risk of receiving a genetic diagnosis. Each one-month delay in walking increased the probability of a pathogenic or possibly pathogenic variation by 5% to 11%.

Congenital heart disease was also connected to genetic diagnoses, but not epilepsy, which could be due to sample characteristics. Finally, the CART analysis identified motor delay and hypotonia as useful screening criteria for genetic testing.

For more information: Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic, Genetics in Medicine.  doi:https://doi.org/10.1016/j.gim.2024.101252