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

Solomon, Benjamin D.; Lacbawan, Felicitas; Mercier, Sandra; Clegg, Nancy J.; Delgado, Mauricio R.; Rosenbaum, Kenneth N.; Dubourg, Christèle; David, Véronique; Olney, Ann Haskins; Wehner, Lore; Hehr, Ute; Bale, Sherri J.; Paulussen, Aimée D C; Smeets, Hubert; Hardisty, Emily; Tylki‐Szymańska, Anna; Pronicka, Ewa; Clemens, Michelle; McPherson, Elizabeth; Hennekam, Raoul C. M.; Hahn, Jin S.; Stashinko, Elaine; Levey, Eric; Wieczorek, Dagmar; Roeder, Elizabeth; Schell-Apacik, Chayim Can; Booth, Carol W.; Thomas, Ronald; Kenwrick, Sue; Cummings, Derek A. T.; Bous, Sophia M.; Keaton, Amelia A.; Balog, Joan Z.; Hadley, Donald W.; Zhou, Nan; Long, Robert T.; Vélez, Jorge Íván Bonilla; Pineda-Álvarez, Daniel E.; Odent, Sylvie; Roessler, Erich; Muenke, Maximilian

doi:10.1136/jmg.2009.073049

Cited by 77 publications

(139 citation statements)

References 32 publications

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“…This milder facial phenotype with usually no clefts or single nostrils as seen in genes as SIX3 and SHH is consistent with literature. 1,19,22 The specific facial features (bitemporal narrowing, upslanting palpebral fissures, flat nasal bridge, short nose, broad philtrum and large ears) as described recently by Solomon et al 22 could in part be fitted to our patients; specifically patient C, D and I fit several of these features. Distribution of HPE classifications (lobar, semilobar, alobar) were, however, mixed and not different from patients with other mutated genes.…”

Section: Discussionmentioning

confidence: 99%

The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes

et al. 2010

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Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted nonfunctionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P¼0.043) and significantly more in SIX3: 10.5 vs 4.3% (P¼0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance.

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Section: Discussionmentioning

confidence: 99%

The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes

et al. 2010

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“…This difference in the prevalence of structural brain anomalies in the mutation group versus the group with deletions likely reflects ascertainment bias, as there was a greater proportion of probands compared to relatives in the deletion group. Patients with intragenic mutations in TGIF had a lower prevalence of structural brain anomalies compared to patients with intragenic mutations affecting SIX3 or ZIC2 , though the difference was only significant compared to patients with mutations in ZIC2 ( table 2 ) [Lacbawan et al, 2009;Solomon et al, 2009b].…”

Section: Hpe Typementioning

confidence: 90%

“…Two of these studies included liveborn patients and fetuses diagnosed with HPE [Muenke Lab; Lazaro et al, 2004;Ming and Muenke, 2002]. One study focused only on liveborn patients with HPE [Orioli and Castilla, 2007], and the final 2 specifically examined patients with known mutations in either ZIC2 or SIX3 [Lacbawan et al, 2009;Solomon et al, 2009b]. Probands with intragenic TGIF mutations included a greater proportion of patients with microform HPE when compared to the cohort of patients with mutations in ZIC2 .…”

Section: Hpe Typementioning

confidence: 99%

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TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype

et al. 2010

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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-β 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 (χ²₍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.

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“…However, the patient was later found to also have a truncating mutation in ZIC2, and there was stronger evidence that this was the cause of HPE and ADH deficiency in that individual (Solomon et al 2009). …”

Section: Human Mutationsmentioning

confidence: 99%

Role of GLI2 in hypopituitarism phenotype

Arnhold¹,

França²,

Carvalho³

et al. 2015

Journal of Molecular Endocrinology

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GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was R0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.

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

Cited by 77 publications

References 32 publications

The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes

The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes

TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype

Role of GLI2 in hypopituitarism phenotype

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