The full spectrum of holoprosencephaly-associated mutations within the<i>ZIC2</i>gene in humans predicts loss-of-function as the predominant disease mechanism

Roessler, Erich; Lacbawan, Felicitas; Dubourg, Christèle; Paulussen, Aimée D C; Herbergs, Jos; Hehr, Ute; Bendavid, Claude; Zhou, Nan; Ouspenskaia, Maia V.; Bale, Sherri J.; Odent, Sylvie; David, Véronique; Muenke, Maximilian

doi:10.1002/humu.20982

Cited by 57 publications

(58 citation statements)

References 29 publications

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“…Missense mutation p.L382P is located in the SRR region, in which several HPE mutations have been detected and which functions to bind cholesterol. 15 We detected 9 of 86 mutations in ZIC2 (10.5%), a percentage comparable with a recent summarizing study from Roessler et al 16 Consistent with previous studies 9, 16,21 we found: (1) a high frequency (455%) of frame shifts, nonsense mutations and gene deletions (Table 1), (2) 450% de novo mutations, (3) several frame shift mutations in the C-terminal end of the ZIC2 protein, leaving the zinc-finger domains theoretically intact, (4) the poly-alanine tract expansion as a prevalent mutation type. Inconsistencies with previous studies were also found: in two of three patients the alanine tract expansion was de novo, in the third patient maternally inherited, therefore not predominantly from the father as previously described.…”

Section: Discussionsupporting

confidence: 71%

“…No other information such as sex, clinical characteristics, inheritance, familial history, etc was included in these studies. [14][15][16] The distribution of the 21 mutations over the genes was three in SHH (14%), nine in ZIC2 (43%), nine in SIX3 (43%) and 0 in TGIF (0%). Eleven (52%) mutations occurred de novo and non-paternity was excluded in all of them.…”

Section: Resultsmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 71%

Section: Resultsmentioning

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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“…ZIC2 mutations have been thought to be the second most common identified cause of non-chromosomal non-syndromic HPE (after mutations in SHH ). In recent estimates, at least 3% of probands with HPE have mutations in ZIC2 , though a more accurate estimate is likely to be at least double that 6 18…”

Section: Introductionmentioning

confidence: 99%

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

Solomon

Lacbawan

Mercier

et al. 2009

Journal of Medical Genetics

122

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Holoprosencephaly (HPE) is the most common malformation of the human forebrain, and may be due to cytogenetic anomalies, teratogens, occur in the context of a syndrome, or be due to mutations in single genes associated with non-syndromic HPE. Mutations in ZIC2, a transcription factor located on chromosome 13q32, are the second-most common cause of non-syndromic, non-chromosomal HPE. Blood samples from over 1000 individuals with HPE-spectrum disorders and their relatives were analyzed for sequence variations in ZIC2. We examined clinical details and included all other known previously published and unpublished cases of mutations in ZIC2 through a literature search and collaboration with other centers. We find mutations in ZIC2 in 8% of probands with HPE, and describe 153 individuals from 116 unrelated kindreds, including 137 patients with molecularly-determined mutations in ZIC2 and 16 patients with deletions of the ZIC2 locus. Unlike HPE due to mutations in other genes, the vast majority of cases are sporadic and the proportional distribution of HPE types differs significantly from previously published analyses of non-chromosomal non-syndromic HPE. Furthermore, we describe a novel facial phenotype in patients with mutations in ZIC2 which includes bitemporal narrowing, upsplanting palpebral fissures, a short nose with anteverted nares, and a broad and well-demarcated philtrum, and large ears. This phenotype is distinct from the standard facial dysmorphisms associated with non-chromosomal, non-syndromic HPE. Our findings show that HPE due to mutations in ZIC2 is distinct from that due to mutations in other genes. This may shed light on the mechanisms that contribute to the formation of the face and the forebrain and may help direct genetic counseling and diagnostic strategies.

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“…dispatched homolog 1 (DISP1) (13)(14)(15)(16)(26)(27)(28). Only about 28% of HPE cases are caused by mutations of these genes; thus, other genetic and/or environmental factors probably contribute to this malformation (15).…”

mentioning

confidence: 99%

Pathogenesis of holoprosencephaly

Geng¹,

Oliver²

2009

J. Clin. Invest.

101

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The full spectrum of holoprosencephaly-associated mutations within theZIC2gene in humans predicts loss-of-function as the predominant disease mechanism

Cited by 57 publications

References 29 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

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

Pathogenesis of holoprosencephaly

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