Mutation in an alternative transcript of CDKL5 in a boy with early-onset seizures

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Infantile-onset epilepsies are severe, heterogeneous genetic disorders.
• Current clinical genetic testing identifies causative mutations in only 20-50% of affected individuals.
• Diagnostic challenges persist due to genetic complexity and limitations of standard testing methods.

Purpose of the Study:

• To report a novel de novo mutation in the CDKL5 gene.
• To highlight the diagnostic utility of whole-genome sequencing over gene panel testing.
• To emphasize the importance of considering alternative gene transcripts in genetic diagnostics.

Main Methods:

• Case report of a male infant with intractable seizures.
• Clinical genetic testing using a gene panel.
• Research-based whole-genome sequencing of the proband and family members.
• Bioinformatic analysis to identify mutations and assess transcript variants.

Main Results:

• Gene panel testing was unrevealing.
• Whole-genome sequencing identified a de novo mutation (c.2828_2829delGA) in CDKL5.
• The mutation was located in an alternative, brain-expressed transcript of CDKL5.
• The mutation was missed by standard gene panel testing due to its intronic location in the commonly used transcript (NM_003159).

Conclusions:

• This is the first reported case of a patient with a CDKL5 mutation in an alternative transcript.
• Clinical genetic testing, including gene panels and exome sequencing, may miss pathogenic variants in alternative transcripts.
• Incorporating alternative transcripts into test design and variant interpretation can enhance diagnostic yield for infantile epilepsies and other genetic disorders.