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1.
Genet Med ; 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30197418

RESUMO

PURPOSE: De novo variants (DNVs) represent an important fraction of the pathogenic variant burden in holoprosencephaly (HPE). However, unexpected recurrences can occur, as evidenced by multiple affected children harboring the same apparently DNV. This study was performed to estimate the rate of parental mosaicism in a cohort of patients with HPE. METHODS: We developed a targeted capture next-generation sequencing (NGS) panel of 153 genes with potential implication in HPE. Sequencing data from a cohort of 136 HPE family trios were analyzed to identify probands with apparently DNVs. DNVs were examined in the proband and their parents to detect any deviations from the expected ~50/50 allele ratio of true heterozygosity. Selected variants were confirmed by Droplet Digital™ polymerase chain reaction (ddPCR). RESULTS: We identified 28 high-confidence DNVs, 20 of which occurred in known HPE genes. Nineteen of the 20 variants (95%) were pathogenic or likely pathogenic. Sequence data analysis showed evidence of parental mosaicism in five cases, for an overall mosaicism rate of 26%. In addition, we found evidence for likely postzygotic events in four cases (50%). CONCLUSIONS: High sensitivity methods, such as high-depth NGS and ddPCR, are essential to providing an accurate assessment of recurrence risk in HPE families with apparently DNVs.

2.
Hum Mutat ; 39(10): 1416-1427, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29992659

RESUMO

Here, we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). We now show that comparisons of variant transmission versus nontransmission among 136 HPE Trios indicates some reported genes now lack confirmation, while novel genes are implicated. Furthermore, we demonstrate that variation of modest intrinsic effect can synergize with these driver mutations as gene modifiers.

3.
Am J Med Genet C Semin Med Genet ; 178(2): 165-174, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29770992

RESUMO

Holoprosencephaly (HPE) is the direct consequence of specific genetic and/or environmental insults interrupting the midline specification of the nascent forebrain. Such disturbances can lead to a broad range of phenotypic consequences for the brain and face in humans. This malformation sequence is remarkably common in utero (1 in 250 human fetuses), but 97% typically do not survive to birth. The precise molecular pathogenesis of HPE in these early human embryos remains largely unknown. Here, we outline our current understanding of the principal driving factors leading to HPE pathologies and elaborate our multifactorial integrated genomics approach. Overall, our understanding of the pathogenesis continues to become simpler, rather than more complicated. Genomic technologies now provide unprecedented insight into disease-associated variation, including the overall extent of genetic interactions (coding and noncoding) predicted to explain divergent phenotypes.

4.
Anat Rec (Hoboken) ; 301(6): 973-986, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29663664

RESUMO

Holoprosencephaly (HPE) is a genetically and phenotypically heterogeneous disorder involving developmental defects. HPE is a rare condition (1/10,000-20,000 newborns) but can be found as frequently as 1/250 among conceptions, suggesting that most HPE embryos are incompatible with postnatal life and result in spontaneous abortions during the first trimester of gestation. Beginning in 1961, the Kyoto University in Japan collected over 44,000 human conceptuses in collaboration with several hundred domestic obstetricians. Over 200 cases of HPE have been identified in the Kyoto collection, which represents the largest single cohort of HPE early stage embryo specimens. In this study, we present a comprehensive clinical and demographic evaluation of this HPE cohort prior to genomic analysis. The total percentage of the threatened abortion among HPE embryos in the Kyoto collection was 67%. Almost 20% of the women with embryos affected by HPE had experienced spontaneous miscarriage. In addition, there was a significant tendency that the mothers with HPE cases had fewer live births than the control. Moreover, in 70% of cases, the mother reported bleeding during pregnancy, a higher percentage than expected, indicating that most of the conceptions with HPE embryos tend to be terminated spontaneously. There were no differences in smoking between mothers with HPE affected and unaffected pregnancies; however, alcohol use was higher in women with pregnancies affected by HPE. In this study, we precisely characterize the phenotype and environmental influences of embryos affected by HPE allowing the future leveraging of genomic technologies to further understand the genetics of forebrain development. Anat Rec, 301:973-986, 2018. © 2018 Wiley Periodicals, Inc.

5.
Hum Mol Genet ; 27(11): 1989-1998, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29584859

RESUMO

The utilization of next generation sequencing has been shown to accelerate gene discovery in human disease. However, our confidence in the correct disease-associations of rare variants continues to depend on functional analysis. Here, we employ a sensitive assay of human FGF8 variants in zebrafish to demonstrate that the spectrum of isoforms of FGF8 produced by alternative splicing can provide key insights into the genetic susceptibility to human malformations. In addition, we describe novel mutations in the FGF core structure that have both subtle and profound effects on ligand posttranslational processing and biological activity. Finally, we solve a case of apparent digenic inheritance of novel variants in SHH and FGF8, two genes known to functionally coregulate each other in the developing forebrain, as a simpler case of FGF8 diminished function.

6.
Genet Med ; 20(1): 14-23, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28640243

RESUMO

PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Holoprosencefalia/diagnóstico , Holoprosencefalia/genética , Adolescente , Adulto , Facies , Feminino , Testes Genéticos , Humanos , Imagem por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Fenótipo , Sistema de Registros , Adulto Jovem
7.
Congenit Anom (Kyoto) ; 58(1): 29-32, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28670735

RESUMO

Holoprosencephaly (HPE) is failure of the forebrain to divide completely during embryogenesis. Incomplete penetrance has not been reported previously in SIX3 whole gene deletions, which are known to cause HPE. Both chromosomal microarray and whole exome sequencing (WES) were used to evaluate families with inherited HPE. Two families showed inherited deletions that contain SIX3 and were incompletely penetrant for HPE. Using WES, we ruled out parental mosaicism, a SIX3 hypomorph, and clinically significant variants in genes that are known to interact with SIX3 as causes of incomplete penetrance. We demonstrate the importance of molecular cascade testing in families with HPE and we answer important questions about incomplete penetrance.


Assuntos
Proteínas do Olho/genética , Deleção de Genes , Holoprosencefalia/genética , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Prosencéfalo/anormalidades , Adulto , Pré-Escolar , Expressão Gênica , Holoprosencefalia/diagnóstico , Holoprosencefalia/metabolismo , Holoprosencefalia/patologia , Humanos , Lactente , Recém-Nascido , Análise em Microsséries , Proteínas do Tecido Nervoso/deficiência , Penetrância , Prosencéfalo/metabolismo , Sequenciamento Completo do Exoma
8.
Hum Mutat ; 38(11): 1464-1470, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28677295

RESUMO

Holoprosencephaly (HPE), a common developmental defect of the forebrain and midface, has a complex etiology. Heterozygous, loss-of-function mutations in the sonic hedgehog (SHH) pathway are associated with HPE. However, mutation carriers display highly variable clinical presentation, leading to an "autosomal dominant with modifier" model, in which the penetrance and expressivity of a predisposing mutation is graded by genetic or environmental modifiers. Such modifiers have not been identified. Boc encodes a SHH coreceptor and is a silent HPE modifier gene in mice. Here, we report the identification of missense BOC variants in HPE patients. Consistent with these alleles functioning as HPE modifiers, individual variant BOC proteins had either loss- or gain-of-function properties in cell-based SHH signaling assays. Therefore, in addition to heterozygous loss-of-function mutations in specific SHH pathway genes and an ill-defined environmental component, our findings identify a third variable in HPE: low-frequency modifier genes, BOC being the first identified.


Assuntos
Genes Modificadores , Holoprosencefalia/genética , Imunoglobulina G/genética , Receptores de Superfície Celular/genética , Animais , Expressão Gênica , Variação Genética , Holoprosencefalia/metabolismo , Humanos , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Camundongos , Modelos Moleculares , Mutação , Conformação Proteica , Domínios Proteicos , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo
9.
Hum Mol Genet ; 25(10): 1912-1922, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26931467

RESUMO

Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generation sequencing, only five distinct mutations in the kinase domain behave as dominant-negative mutations in zebrafish over-expression assays. Three FGFR1 mutations seen in HPE probands behave identical to wild-type FGFR1 in rescue assays, including one apparent de novo variation. Interestingly, in one HPE family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of-function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of gene:gene synergistic interactions causing HPE in humans.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Dedos/anormalidades , Predisposição Genética para Doença , Deformidades Congênitas da Mão/genética , Holoprosencefalia/genética , Hipogonadismo/genética , Deficiência Intelectual/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Alelos , Animais , Criança , Pré-Escolar , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Modelos Animais de Doenças , Feminino , Dedos/fisiopatologia , Regulação da Expressão Gênica , Genótipo , Deformidades Congênitas da Mão/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Holoprosencefalia/fisiopatologia , Humanos , Hipogonadismo/patologia , Lactente , Deficiência Intelectual/fisiopatologia , Síndrome de Kallmann/genética , Síndrome de Kallmann/patologia , Masculino , Mutação , Linhagem , Índice de Gravidade de Doença , Peixe-Zebra/genética
10.
J Med Genet ; 51(6): 413-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24744436

RESUMO

BACKGROUND: Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. OBJECTIVE: To characterise the genotypic and phenotypic findings in individuals with GLI2 variants and clarify clinical findings in individuals with loss-of-function mutations. METHODS: Through the National Institutes of Health and collaborating centres, ∼400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies were screened for GLI2 mutations. Results were combined with all published cases. We compared the clinical and molecular features of individuals with truncating mutations to individuals with variants of unknown significance (defined as not resulting in protein truncation, reported in normal controls and/or deemed unlikely to be pathogenic by functional prediction software). RESULTS: 112 individuals with variants in GLI2 were identified, with 43 having truncating mutations. Individuals with truncating mutations were more likely to have both pituitary anomalies and polydactyly versus those with variants of unknown significance (p<0.0001 by Fisher's exact test); only 1 of 43 had frank HPE. These individuals were more likely to have recognised penetrance (polydactyly or pituitary anomalies or both) than those without truncating mutations (p=0.0036 by Fisher's exact test). A common facial phenotype was seen in individuals (with midface hypoplasia, cleft lip/palate and hypotelorism) with truncating mutations. CONCLUSIONS: Individuals with truncating mutations in GLI2 typically present with pituitary anomalies, polydactyly and subtle facial features rather than HPE. This will be helpful in screening populations for GLI2 mutations and for counselling affected patients. TRIAL REGISTRATION: 98-HG-0249/04-HG-0093.


Assuntos
Anormalidades Múltiplas/genética , Fatores de Transcrição Kruppel-Like/genética , Mutação/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/patologia , Face/patologia , Dedos/patologia , Holoprosencefalia , Humanos , Lactente , Fenótipo , Dedos do Pé/patologia , Proteína Gli2 com Dedos de Zinco
11.
PLoS One ; 7(7): e39026, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22859937

RESUMO

Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp element in the 3' untranslated region (3'UTR) is highly conserved across the evolutionary history of vertebrates from fish to humans. Furthermore, we show that while genetic variation of this element is unexpectedly common among holoprosencephaly subjects (6/528 or >1%), it is not present in control individuals. Two of six proband-unique variants are de novo, supporting their pathogenic involvement in HPE outcomes. These findings support a general recommendation that the identification and analysis of key ultraconserved elements should be incorporated into the genetic risk assessment of holoprosencephaly cases.


Assuntos
Regiões 3' não Traduzidas , Holoprosencefalia/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Sequência de Bases , Padronização Corporal , Sequência Conservada , Análise Mutacional de DNA , Redes Reguladoras de Genes , Estudos de Associação Genética , Humanos , Dados de Sequência Molecular , Prosencéfalo/crescimento & desenvolvimento , Alinhamento de Sequência , Peixe-Zebra
12.
Birth Defects Res A Clin Mol Teratol ; 94(11): 912-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22847929

RESUMO

BACKGROUND: Holoprosencephaly is the most frequent congenital malformation of the forebrain in humans. It is anatomically classified by the relative degree of abnormal formation and separation of the developing central nervous system. Mutations of ZIC2 are the second most common heterozygous variations detected in holoprosencephaly (HPE) patients. Mutations in most known HPE genes typically result in variable phenotypes that rage from classic alobar HPE to microforms represented by hypotelorism, solitary central maxillary incisor (SCMI), and cleft lip/palate, among others. Patients with HPE owing to ZIC2 mutations have recently been described by a distinct phenotype compared with mutations in other HPE causative genes. METHODS: We report the comparison of ZIC2 molecular findings by Sanger bidirectional DNA sequencing and ad hoc genotyping in a cohort of 105 Brazilian patients within the clinical spectrum of HPE, including classic and microform groups. RESULTS: We detected a total of five variants in the ZIC2 gene: a common histidine tract expansion c.716_718dup (p.His239dup), a rare c.1377_1391del_homozygous (p.Ala466_470del, or Ala 15 to 10 contraction), a novel intronic c.1239+18G>A variant, a novel frameshift c.1215dupC (p.Ser406Glnfs*11), and a c.1401_1406dup (p.Ala469_470dup, or alanine tract expansion to 17 residues). CONCLUSIONS: From these patients, only the latter two mutations found in classic HPE are likely to be medically significant. In contrast, variants detected in the microform group are not likely to be pathogenic. We show conclusively that the histidine tract expansion is a polymorphic alteration that demonstrates considerable differences in allele frequencies across different ethnic groups. Therefore, careful population studies of rare variants can improve genotype-phenotype correlations. Birth Defects Research (Part A) 2012.


Assuntos
Estudos de Associação Genética , Holoprosencefalia/genética , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adulto , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Grupos de Populações Continentais , Feminino , Frequência do Gene , Genótipo , Heterozigoto , Histidina/genética , Holoprosencefalia/classificação , Holoprosencefalia/etnologia , Humanos , Masculino , Tipagem Molecular , Fenótipo , Análise de Sequência de DNA
13.
Eur J Med Genet ; 55(10): 510-4, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22750566

RESUMO

We have applied a GWAS to 40 consanguineous families segregating cases of non-syndromic cleft lip with or without cleft palate (NS CL/P) (a total of 160 affected and unaffected individuals) in order to trace potential recessive loci that confer susceptibility to this common facial malformation. Pedigree-based association test (PBAT) analyses reported nominal evidence of association and linkage over SNP markers located at 11q25 (rs4937877, P = 2.7 × 10(-6)), 19p12 (rs4324267, P = 1.6 × 10(-5)), 5q14.1 (rs4588572, P-value = 3.36 × 10(-5)), and 15q21.1 (rs4774497, P = 1.08 × 10(-4)). Using the Versatile Gene-Based Association Study to complement the PBAT results, we found clusters of markers located at chromosomes 19p12, 11q25, and 8p23.2 overcome the threshold for GWAS significance (P < 1 × 10(-7)). From this study, new recessive loci implicated in NS CL/P include: B3GAT1, GLB1L2, ZNF431, ZNF714, and CSMD1, even though the functional association with the genesis of NS CL/P remains to be elucidated. These results emphasize the importance of using homogeneous populations, phenotypes, and family structures for GWAS combined with gene-based association analyses, and should encourage. other researchers to evaluate these genes on independent patient samples affected by NS CL/P.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Genes Recessivos , Encéfalo/anormalidades , Estudos de Casos e Controles , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Proteínas de Ligação a DNA/genética , Feminino , Marcadores Genéticos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Glucuronosiltransferase/genética , Glicosídeo Hidrolases/genética , Humanos , Masculino , Proteínas de Membrana/genética , Linhagem , Fatores de Transcrição/genética
14.
J Med Genet ; 49(7): 473-9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22791840

RESUMO

BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. OBJECTIVE: To characterise genetic and clinical findings in individuals with SHH mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. RESULTS: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. CONCLUSIONS: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.


Assuntos
Estudos de Associação Genética/métodos , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Mutação , Feminino , Genótipo , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Prosencéfalo/patologia
16.
Mol Genet Metab ; 106(2): 241-3, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22503063

RESUMO

Holoprosencephaly (HPE) is the most common structural anomaly of the human forebrain. Various genetic and teratogenic causes have been implicated in its pathogenesis. A recent report in mice described Noggin (NOG) as a candidate gene involved in the etiogenesis of microform HPE. Here, we present for the first time genetic analysis of a large HPE cohort for sequence variations in NOG. On the basis of our study, we conclude that mutations in the coding region of NOG are rare, and play at most an uncommon role in human HPE.


Assuntos
Proteínas de Transporte/genética , Holoprosencefalia/genética , Substituição de Aminoácidos , Humanos , Mutação , Polimorfismo de Nucleotídeo Único
18.
Mol Genet Metab ; 105(4): 658-64, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22310223

RESUMO

Clinical molecular diagnostic centers routinely screen SHH, ZIC2, SIX3 and TGIF for mutations that can help to explain holoprosencephaly and related brain malformations. Here we report a prospective Sanger sequence analysis of 189 unrelated probands referred to our diagnostic lab for genetic testing. We identified 28 novel unique mutations in this group (15%) and no instances of deleterious mutations in two genes in the same subject. Our result extends that of other diagnostic centers and suggests that among the aggregate 475 prospectively sequenced holoprosencephaly probands there is negligible evidence for direct gene-gene interactions among these tested genes. We model the predictions of the observed mutation frequency in the context of the hypothesis that gene×gene interactions are a prerequisite for forebrain malformations, i.e. the "multiple-hit" hypothesis. We conclude that such a direct interaction would be expected to be rare and that more subtle genetic and environmental interactions are a better explanation for the clinically observed inter- and intra-familial variability.


Assuntos
Proteínas do Olho/genética , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de Homeodomínio/genética , Modelos Estatísticos , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Proteínas do Olho/metabolismo , Proteínas Hedgehog/metabolismo , Holoprosencefalia/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Taxa de Mutação , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/metabolismo , Análise de Sequência , Fatores de Transcrição/metabolismo
19.
Hum Genet ; 131(2): 301-10, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21842183

RESUMO

Holprosencephaly (HPE) is the most common disorder of the developing forebrain in humans, and is characterized by varying degrees of abnormal union of the cerebral hemispheres. These defects are typically co-associated with midline craniofacial anomalies. The combination of forebrain and craniofacial defects that comprise HPE can present along a broad and variable phenotypic spectrum. Both the SHH and NODAL signaling pathways play important roles in the pathogenesis of this disorder. Disruption of these pathways by chromosomal rearrangements, mutations in pathway-related genes and/or biochemical alterations are proposed to contribute to HPE in a large number of patients. Additional factors that are not yet fully delineated are also very likely to be involved in the pathogenesis and phenotypic heterogeneity of the disorder. Genetic loss of GAS1, a cell membrane receptor and positive regulator of SHH, has been demonstrated to contribute to the HPE phenotypic spectrum in animal models. We have evaluated the coding and flanking sequence of GAS1 in 394 patients who have clinical findings within the HPE phenotypic spectrum, and now report five novel missense sequence variants among five unrelated HPE probands. Finally, we tested the effect of these variants (as well as previously reported GAS1 variants) on the ability of GAS1 to bind to SHH. Here, we demonstrate that sequence variants in GAS1 can impair its physical interaction with SHH, suggesting a decrease in the SHH downstream signaling cascade as a pathogenic mechanism of disease.


Assuntos
Proteínas de Ciclo Celular/genética , Holoprosencefalia/genética , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Proteínas de Ciclo Celular/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Ligantes , Dados de Sequência Molecular , Análise de Sequência de DNA
20.
Am J Med Genet A ; 155A(11): 2713-20, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21976454

RESUMO

Holoprosencephaly (HPE) is the most common disorder of the developing forebrain in humans, and is characterized by failed or incomplete cleavage of the cerebral hemispheres and deep brain structures. HPE includes wide phenotypic variability, with a continuum of both brain and craniofacial anomalies. While "classic" eye findings, including the spectrum of midline anomalies ranging from cyclopia to hypotelorism, as well as chorioretinal coloboma and microphthalmia, have been frequently described in patients with HPE, other subtle eye anomalies may also occur. In our study we prospectively analyzed a small cohort of 10 patients in whom we identified mutations in SHH, SIX3, ZIC2, or FGF8, the latter of which is a very recently described HPE-associated gene. We found that 9 of 10 patients had at least two ophthalmologic anomalies, including refractive errors, microcornea, microphthalmia, blepharoptosis, exotropia, and uveal coloboma. These findings contribute to the understanding of the phenotypic variability of the HPE spectrum, and highlight findings in one medically important but often incompletely investigated system.


Assuntos
Anormalidades Craniofaciais/patologia , Oftalmopatias/patologia , Holoprosencefalia/patologia , Adulto , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Oftalmopatias/diagnóstico , Oftalmopatias/genética , Proteínas do Olho/genética , Feminino , Testes Genéticos , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Exame Físico , Estudos Prospectivos
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