High Intellectual Function in Individuals with Mutation-Positive Microform Holoprosencephaly.

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Holoprosencephaly (HPE) is a common forebrain malformation associated with severe neurodevelopmental and facial abnormalities.
• HPE exhibits genetic and environmental heterogeneity, involving chromosomal aberrations, syndromes, or mutations in over 10 genes.
• The HPE spectrum ranges from lethal brain malformations to subtle midline facial differences, with microform HPE often associated with intellectual disability.

Purpose of the Study:

• To investigate the phenotypic spectrum of microform holoprosencephaly.
• To identify the molecular genetic causes of HPE in individuals with microform presentation and above-average intellect.
• To enhance genetic counseling for families affected by HPE.

Main Methods:

• Clinical phenotyping of 5 patients with microform holoprosencephaly.
• Molecular genetic analysis to identify causative mutations.
• Review of existing literature on HPE genetics and phenotypes.

Main Results:

• Five patients with phenotypic signs of microform holoprosencephaly were identified, all demonstrating above-average intellectual function.
• Causative mutations in SHH, SIX3, GLI2, and FGF8 genes were identified in 4 of the 5 patients.
• The findings expand the known phenotypic range of holoprosencephaly.

Conclusions:

• Microform holoprosencephaly can occur in individuals with superior intellectual function.
• Genetic mutations in key developmental pathway genes (SHH, SIX3, GLI2, FGF8) are implicated in microform HPE.
• This study refines the understanding of HPE's phenotypic variability and aids in genetic counseling.