Biallelic mutations in human DCC cause developmental split-brain syndrome.

Area of Science:

• Neuroscience
• Human Genetics
• Developmental Biology

Background:

• Brain development relies on midline-bridging neuronal commissures for coordinated motor, sensory, and integrative functions.
• Mutations in the deleted in colorectal carcinoma (DCC) gene are linked to congenital mirror movements in heterozygotes.
• The human phenotype of biallelic DCC loss-of-function has not been previously reported.

Purpose of the Study:

• To identify the genetic cause and characterize the human phenotype of a novel syndrome involving disrupted brain commissures.
• To elucidate the role of the DCC gene in the development of white matter tracts in the human central nervous system (CNS).

Main Methods:

• Clinical evaluation of affected individuals presenting with horizontal gaze palsy, scoliosis, and intellectual disability.
• Genetic analysis to identify mutations in the DCC gene.
• Structural Magnetic Resonance Imaging (MRI) and diffusion tractography to assess white matter organization in the CNS.

Main Results:

• Affected individuals exhibited biallelic loss-of-function mutations in the DCC gene.
• Broad disorganization of CNS white matter tracts, including the absence of commissural tracts at multiple levels, was observed.
• These findings indicate DCC is essential for midline crossing and white matter development.

Conclusions:

• DCC is a critical regulator of midline crossing and the development of white matter projections throughout the human CNS.
• Biallelic loss-of-function mutations in DCC result in a distinct human syndrome with severe neurological and developmental consequences.
• This study expands the known phenotypic spectrum of DCC mutations and underscores its importance in neurodevelopment.