A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Intellectual disability (ID) is a prevalent condition with diverse genetic origins.
• Advancements in next-generation sequencing have significantly increased the identification of monogenic causes for ID.
• The clinical presentation of many genetic disorders causing ID is nonspecific, complicating diagnosis.

Purpose of the Study:

• To identify the genetic etiology of global developmental delay and intellectual disability in a 2-year-old boy.
• To report a novel mutation in the KAT6A gene associated with neurodevelopmental disorder.
• To underscore the diagnostic value of whole exome sequencing in unexplained developmental disorders.

Main Methods:

• Clinical evaluation including neuroimaging (Brain MRI) and genetic testing (banded karyotype, CGH array).
• Whole exome sequencing (WES) was performed to identify the causative genetic mutation.
• Sanger sequencing was used to confirm the identified mutation in the patient and his parents.

Main Results:

• The patient presented with global developmental delay, intellectual disability, feeding difficulties, motor skill delay, and hypotonia.
• Brain MRI showed diffuse white matter loss and corpus callosum thinning.
• WES identified a novel de novo frameshift mutation (c.3390delA) in the KAT6A gene, confirmed by Sanger sequencing.
• The mutation was absent in the patient's parents, confirming its de novo status.

Conclusions:

• The study identified a novel de novo mutation in KAT6A as the cause of intellectual disability and global developmental delay in the patient.
• KAT6A mutations are associated with autosomal dominant mental retardation 32, a disorder with nonspecific clinical features.
• Whole exome sequencing is a powerful tool for rapid and accurate diagnosis of rare genetic neurodevelopmental disorders.