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-ZebraRESUMO
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 , Feminino , Frequência do Gene , Genótipo , Heterozigoto , Histidina/genética , Holoprosencefalia/classificação , Holoprosencefalia/etnologia , Humanos , Masculino , Tipagem Molecular , Fenótipo , Grupos Raciais , Análise de Sequência de DNARESUMO
This study evaluated audiological and electrophysiological profiles in 13 patients with holoprosencephaly. All patients had imaging evaluation by magnetic resonance imaging and molecular screening for the genes SHH, GLI2, and SIX3. Each patient underwent clinical (otological and vestibular antecedents, otoscopy) and instrumental (tympanometry, auditory brainstem response--ABR) evaluation to compare hearing and the electrophysiological profile possibly occurring in patients with these mutations. To our knowledge there are no systematic studies correlating molecular/imaging and evoked potentials in patients with HPE. Here, we discuss the audiological and electrophysiological profiles of patients and the possible role of the genes studied on the overall findings.
Assuntos
Holoprosencefalia/fisiopatologia , Testes de Impedância Acústica , Adolescente , Audiometria , Criança , Pré-Escolar , Potenciais Evocados Auditivos do Tronco Encefálico , Proteínas do Olho/genética , Feminino , Proteínas Hedgehog/genética , Holoprosencefalia/diagnóstico , Holoprosencefalia/genética , Proteínas de Homeodomínio/genética , Humanos , Lactente , Fatores de Transcrição Kruppel-Like/genética , Imageamento por Ressonância Magnética , Masculino , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Reflexo Acústico , Proteína Gli2 com Dedos de Zinco , Proteína Homeobox SIX3RESUMO
Congenital malformations involving the face, oral cavity, and digits are the main findings in the oro-facio-digital (OFD) syndromes. Various eye anomalies and central nervous system involvement have also been reported in this condition. Here we report on a Brazilian boy with features belonging to the clinical spectrum of the OFD syndromes. He also had additional findings of periventricular nodular heterotopia (PVNH), asymmetric limb involvement, and microphthalmia. This unusual pattern of anomalies has not been reported previously and appears to be unique.