TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype

Area of Science:

• Genetics
• Developmental Biology
• Neuroscience

Background:

• Holoprosencephaly (HPE) is the most common forebrain malformation, resulting from incomplete midline forebrain division.
• The etiology of HPE is complex, with at least 12 associated genes identified, including TGIF.
• TGIF mutations are found in 1-2% of non-syndromic, non-chromosomal HPE cases.

Purpose of the Study:

• To establish the genotypic and phenotypic range of HPE associated with TGIF gene alterations.
• To compare intragenic TGIF mutations with TGIF deletions in HPE patients.
• To identify differences in inheritance patterns and clinical manifestations between mutation types.

Main Methods:

• Combined data from comprehensive HPE studies with a literature search for individuals with HPE and TGIF mutations.
• Analyzed 34 patients with intragenic TGIF mutations and 21 with TGIF deletions.
• Performed statistical analysis to compare inheritance and phenotypic features between the two groups.

Main Results:

• The majority of intragenic TGIF mutations affect the homeodomain region.
• Patients with TGIF alterations exhibit the full phenotypic spectrum of non-chromosomal, non-syndromic HPE.
• TGIF deletions were more likely to be de novo and associated with extra-craniofacial manifestations compared to intragenic mutations.

Conclusions:

• TGIF intragenic mutations and deletions present distinct inheritance patterns and clinical features in HPE.
• The TGIF homeodomain region is critical for HPE development.
• Findings can inform genetic counseling for patients with HPE and TGIF alterations.