title: Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination.
abstract: We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes. Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations. Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation. We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation 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 (one case). Although severe facial anomalies are common in HPE, all of the patients with ZIC2 mutations had relatively normal faces, suggesting that ZIC2 mutations represent a large proportion of HPE cases without facial malformation.
authors: Department of Obstetrics and Gynecology, PH16 Columbia University, New York, NY 10032, USA.
authors: L Y
authors: LY
authors: Brown
authors: S
authors: S
authors: Odent
authors: V
authors: V
authors: David
authors: M
authors: M
authors: Blayau
authors: C
authors: C
authors: Dubourg
authors: C
authors: C
authors: Apacik
authors: M A
authors: MA
authors: Delgado
authors: B D
authors: BD
authors: Hall
authors: J F
authors: JF
authors: Reynolds
authors: A
authors: A
authors: Sommer
authors: D
authors: D
authors: Wieczorek
authors: S A
authors: SA
authors: Brown
authors: M
authors: M
authors: Muenke
mesh_terms: D000409:Alanine; D000595:Amino Acid Sequence; D005260:Female; D018392:Genomic Imprinting; D016142:Holoprosencephaly / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D010375:Pedigree; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D014157:Transcription Factors / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human; D000409:Alanine