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Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals.

ABSTRACT: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE.To characterise genetic and clinical findings in patients with ZIC2 mutations.Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE spectrum disorders was analysed for sequence variations in ZIC2. Clinical details were examined and all other known cases of mutations in ZIC2 were included through a literature search.By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, ZIC2 mutations were found in 8.4% (49/582) of probands. A total of 157 individuals from 119 unrelated kindreds are described, including 141 patients with intragenic sequence determined mutations in ZIC2. Only 39/157 patients have previously been clinically described. Unlike HPE due to mutations in other genes, most mutations occur de novo and the distribution of HPE types differs significantly from that of non-ZIC2 related HPE. Evidence is presented for the presence of a novel facial phenotype which includes bitemporal narrowing, upslanting palpebral fissures, a short nose with anteverted nares, a broad and well demarcated philtrum, and large ears.HPE due to ZIC2 mutations is distinct from that due to mutations in other genes. This may shed light on the mechanisms involved in formation of the forebrain and face and will help direct genetic counselling and diagnostic strategies.

SUBMITTER: Solomon BD

PROVIDER: S-EPMC3208626 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals.

Solomon Benjamin D BD Lacbawan Felicitas F Mercier Sandra S Clegg Nancy J NJ Delgado Mauricio R MR Rosenbaum Kenneth K Dubourg Christèle C David Veronique V Olney Ann Haskins AH Wehner Lars-Erik LE Hehr Ute U Bale Sherri S Paulussen Aimee A Smeets Hubert J HJ Hardisty Emily E Tylki-Szymanska Anna A Pronicka Ewa E Clemens Michelle M McPherson Elizabeth E Hennekam Raoul C M RC Hahn Jin J Stashinko Elaine E Levey Eric E Wieczorek Dagmar D Roeder Elizabeth E Schell-Apacik Chayim Can CC Booth Carol W CW Thomas Ronald L RL Kenwrick Sue S Cummings Derek A T DA Bous Sophia M SM Keaton Amelia A Balog Joan Z JZ Hadley Donald D Zhou Nan N Long Robert R Vélez Jorge I JI Pineda-Alvarez Daniel E DE Odent Sylvie S Roessler Erich E Muenke Maximilian M

Journal of medical genetics 20091202 8

<h4>Background</h4>Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE.<h4>Objective</h4>To characterise genetic and clinical findings in patients with ZIC2 mutations.<h4>Methods</h4>Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE ...[more]

PMID: 19955556

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Project description:Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-? signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE. We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (?(2) ((2)) = 6.97, p(permutated) = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.

Dataset Information

Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals.

Publications

Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals.

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