Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination

We report on the prevalence of mutations in the zinc finger transcription f actor gene, ZIC2, in a group of 509 unrelated individuals with isolated hol oprosencephaly (HPE) and normal chromosomes, Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations, Thus, ZIC2 muta tion was the apparent cause of HPE in 3-4% of cases. Seven mutations were f rameshifts that were predicted to result in loss of function, further suppo rting the idea that ZIC2 haploinsufficiency can result in HPE, One mutation , an alanine tract expansion which is caused by the expansion of an imperfe ct trinucleotide repeat, occurred in seven patients from six different fami lies. In three of those families, the father was found to be apparently mos aic for the mutation, We hypothesize that this mutation can arise through e rrors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one muta tion was an in-frame deletion of 12 amino acids, The central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect tone case). Although severe facial anomalies are common in HPE, all of the patients with ZIC2 m utations had relatively normal faces, suggesting that ZIC2 mutations repres ent a large proportion of HPE cases without facial malformation.