Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. Among several important HPE mutational target genes, the transcription factor SIX3 encodes an early regulator of Shh, Wnt, Bmp and Nodal signaling expressed in the developing forebrain and eyes of all vertebrates.
Objective: To characterize genetic and clinical findings in patients with SIX3 mutations.
Methods: We test individuals with HPE and their family members for mutations in HPE-associated genes and analyze genetic and clinical findings, including additional cases found in the literature. We correlate results with a mutation-specific functional assay in zebrafish.
Results: In a cohort of patients (n≈800) with HPE, we detect SIX3 mutations in 4.7% of probands; we identify additional individuals through testing of relatives. We present data on 138 individuals, 59 of whom have not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. We find an over-representation of severe HPE among individuals whose mutations confer greater loss-of-function as measured through the functional zebrafish assay. The F:M ratio in this combined set of patients is 1.5:1 and maternal inheritance is almost twice as common as paternal. 14% of SIX3 mutations in probands occur de novo. There is a wide intra-familial clinical range of features and classical penetrance is estimated to be at least 62%.
Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE, and that there is a genotype-phenotype correlation revealed by functional studies using animal models.