Novel pathogenic variants and multiple molecular diagnoses in neurodevelopmental disorders

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Rare de novo variants are a significant cause of neurodevelopmental delay and intellectual disability (ID).
• Previous exome sequencing provided diagnoses for 1336 of 4351 patients with various neurodevelopmental phenotypes.
• Novel neurodevelopmental disorder (NDD) genes are continually being identified.

Purpose of the Study:

• To investigate the role of variants in 14 recently implicated novel NDD genes.
• To increase the diagnostic yield for patients with unexplained neurodevelopmental disorders.

Main Methods:

• Exome sequencing data from 4351 patients with neurodevelopmental phenotypes were re-analyzed.
• Focus was placed on identifying rare, protein-changing variants in 14 novel NDD candidate genes.
• Variants were classified as pathogenic or likely pathogenic based on established criteria.

Main Results:

• Sixty-five rare, protein-changing variants were identified in 11 of the 14 novel candidate genes.
• Fourteen variants in CDK13, CHD4, KCNQ3, KMT5B, TCF20, and ZBTB18 were confirmed as pathogenic or likely pathogenic.
• Multiple molecular diagnoses were established in two patients, indicating co-occurring genetic conditions.

Conclusions:

• Searching for pathogenic variants in newly identified NDD genes successfully provided molecular diagnoses for 14 patients.
• Regular re-evaluation of existing exome data is crucial for improving diagnostic yield in rare diseases.
• This approach enhances the ability to serve patients and their families by uncovering the genetic basis of their conditions.