New SHH and Known SIX3 Variants in a Series of Latin American Patients with Holoprosencephaly

Abstract

Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the <i>SHH</i>, <i>SIX3</i>, <i>ZIC2</i>, and <i>TGIF1</i> genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new <i>SHH</i> variants and a third known <i>SIX3</i> likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with <i>SHH</i> pathogenic variants, presented benign variants of the <i>SHH</i>, <i>SIX3</i>, <i>ZIC2</i>, and <i>TGIF1</i> genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same <i>SIX3</i> variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.