BACKGROUND
Holoprosencephaly (HPE) is a structural brain abnormality that results from the failure of the forebrain to divide into the cerebral hemispheres during embryonic development. HPE can present as a spectrum, from the most severe alobar HPE to microform HPE. Diagnoses can be made prenatally if a severe enough structural anomaly or dysmorphisms are present, but often are made during the neonatal period when craniofacial features suggest HPE may be present. Observable phenotypes may range from mild dysmorphisms including hypotelorism, midface retrusion, microcephaly or single central maxillary incisor, to severe malformations including cyclopia, proboscis, anophthalmia/microphthalmia, or bilateral cleft lip/palate. HPE is well documented to have incomplete penetrance and wide clinical variability, even among families. Often familial cases are not identified until a there is a severe presentation of HPE, which then identifies a parentally inherited variant and other more mildly affected relatives. HPE may be isolated or syndromic, and be caused by chromosomal disorders, copy number variants or single nucleotide variants, thus broad-spectrum testing is warranted.
Isolated HPE has been linked to multiple genes; the most commonly mutated ones are SHH, ZIC2, SIX3 and TGIF1. ZIC2 is unique in that relative to other HPE genes in that it has an extremely high penetrance and high rate of de novo variants; thus, familial HPE due to ZIC2 variants is rare. Here, we present a case of familial HPE due to a pathogenic polyalanine expansion in ZIC2. ZIC2 contains a polyalanine tract in exon 3 which natively contains 15 alanines. Expansion to 25 alanines is a recurrent pathogenic allele which interferes with the ability of the ZIC2 transcription factor to bind to its DNA targets, resulting in decreased transcriptional activity.
