Pitfalls of clinical exome and gene panel testing: alternative transcripts

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Clinical exome and gene panel testing are crucial for diagnosing rare Mendelian disorders.
• A significant number of patients remain undiagnosed despite current genetic testing methods.

Purpose of the Study:

• To investigate if alternative transcripts in known disease genes can yield molecular diagnoses for additional patients.
• To identify brain-expressed coding regions missed by standard neonatal epilepsy gene panels and exome tests.

Main Methods:

• Integration of alternative transcripts for known neonatal epilepsy genes with RNA-Seq data.
• Identification of brain-expressed coding regions not covered by current clinical gene panel and exome tests.

Main Results:

• Brain-expressed alternative coding regions were found in 30% of 292 neonatal epilepsy genes.
• These regions include 15,713 bases that are noncoding in primary transcripts.
• Pathogenic variants were identified in alternative coding regions of at least 5 genes.
• Three candidate variants were found in public exome data from 337 epilepsy patients.
• Analysis of 44 patient genomes identified the pathogenic variant in one epilepsy case and two variants of uncertain significance in controls.

Conclusions:

• Assessing alternative transcripts in clinical genetic tests can improve diagnostic yield for unexplained rare genetic disorders.
• This approach may provide diagnoses for patients with non-explanatory standard testing without significantly increasing variants of uncertain significance.