RESUMO
The authors describe the clinical findings observed in a Brazilian girl that are suggestive of microphthalmia and linear skin defects (MLS) also known as MIDAS syndrome (OMIM #309801). She also presented with short stature, agenesis of corpus callosum, cleft palate, enamel defects, and genitourinary anomalies, which are rarely reported within the clinical spectrum of MLS. The 11,5 Mb deletion in Xp22.3p22.2 observed in the patient includes the entire HCCS gene (responsible for the MLS phenotype) and also encompasses several other genes involved with behavioral phenotypes, craniofacial and central nervous system development such as MID1, NLGN4X, AMELX , ARHGAP6, and TBL1X. The whole clinical features of our proband possibly represents an unusual MLS syndromic phenotype caused by an Xp22.3p22.2 continuous gene deletion.
RESUMO
We describe a girl with a phenotype characterized by frontonasal dysplasia, callosal agenesis, basal encephalocele, and eye anomalies who presents a 46,XX,r(21) karyotype. Array-comparative genomic hybridization using the Afflymetrix 100K DNA oligoarray set showed an interstitial deletion 21q22.3 of approximately 219 kb. Conventional karyotype of both parents was normal, and it was not possible to perform the molecular studies. In this report we raise the hypothesis that the deleted genes located at 21q22.3 could account to the phenotype.
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 21 , Anormalidades Múltiplas/diagnóstico , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/genética , Hibridização Genômica Comparativa , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Anormalidades Craniofaciais , Encefalocele/diagnóstico , Encefalocele/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Face/anormalidades , Fácies , Feminino , Humanos , Lactente , Cariótipo , Imageamento por Ressonância Magnética , Neuroimagem , Polimorfismo de Nucleotídeo Único , SíndromeRESUMO
The authors describe on a Brazilian girl with coronal synostosis, facial asymmetry, ptosis, brachydactyly, significant learning difficulties, recurrent scalp infections with marked hair loss, and elevated serum immunoglobulin E. Standard lymphocyte karyotype showed a small additional segment in 7p21[46,XX,add(7)(p21)]. Deletion of the TWIST1 gene, detected by Multiplex Ligation Probe-dependent Amplification (MPLA) and array-CGH, was consistent with phenotype of Saethre-Chotzen syndrome. Array CGH also showed deletion of four other genes at 7p21.1 (SNX13, PRPS1L1, HD9C9, and FERD3L) and the deletion of six genes (CACNA2D2, C3orf18, HEMK1, CISH, MAPKAPK3, and DOCK3) at 3p21.31. Our case reinforces FERD3L as candidate gene for intellectual disability and suggested that genes located in 3p21.3 can be related to hyper IgE phenotype.
Assuntos
Acrocefalossindactilia/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 7 , Síndrome de Job/genética , Deficiências da Aprendizagem/genética , Acrocefalossindactilia/complicações , Acrocefalossindactilia/diagnóstico , Criança , Pré-Escolar , Bandeamento Cromossômico , Deleção Cromossômica , Hibridização Genômica Comparativa , Fácies , Feminino , Humanos , Lactente , Síndrome de Job/complicações , Síndrome de Job/diagnóstico , Deficiências da Aprendizagem/complicações , Deficiências da Aprendizagem/diagnóstico , FenótipoRESUMO
Conventional karyotyping detects anomalies in 3-15% of patients with multiple congenital anomalies and mental retardation (MCA/MR). Whole-genome array screening (WGAS) has been consistently suggested as the first choice diagnostic test for this group of patients, but it is very costly for large-scale use in developing countries. We evaluated the use of a combination of Multiplex Ligation-dependent Probe Amplification (MLPA) kits to increase the detection rate of chromosomal abnormalities in MCA/MR patients. We screened 261 MCA/MR patients with two subtelomeric and one microdeletion kits. This would theoretically detect up to 70% of all submicroscopic abnormalities. Additionally we scored the de Vries score for 209 patients in an effort to find a suitable cut-off for MLPA screening. Our results reveal that chromosomal abnormalities were present in 87 (33.3%) patients, but only 57 (21.8%) were considered causative. Karyotyping detected 15 abnormalities (6.9%), while MLPA identified 54 (20.7%). Our combined MLPA screening raised the total detection number of pathogenic imbalances more than three times when compared to conventional karyotyping. We also show that using the de Vries score as a cut-off for this screening would only be suitable under financial restrictions. A decision analytic model was constructed with three possible strategies: karyotype, karyotype + MLPA and karyotype + WGAS. Karyotype + MLPA strategy detected anomalies in 19.8% of cases which account for 76.45% of the expected yield for karyotype + WGAS. Incremental Cost Effectiveness Ratio (ICER) of MLPA is three times lower than that of WGAS, which means that, for the same costs, we have three additional diagnoses with MLPA but only one with WGAS. We list all causative alterations found, including rare findings, such as reciprocal duplications of regions deleted in Sotos and Williams-Beuren syndromes. We also describe imbalances that were considered polymorphisms or rare variants, such as the new SNP that confounded the analysis of the 22q13.3 deletion syndrome.
Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Países em Desenvolvimento , Testes Genéticos , Deficiência Intelectual/genética , Kit de Reagentes para Diagnóstico/normas , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Testes Genéticos/economia , Testes Genéticos/métodos , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/diagnóstico , Cariotipagem , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Kit de Reagentes para Diagnóstico/economia , Adulto JovemRESUMO
Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis.
Assuntos
Anormalidades Múltiplas/genética , Mutação , Estabilidade de RNA/genética , Proteínas rab de Ligação ao GTP/genética , Acrocefalossindactilia/genética , Sequência de Bases , Disostose Craniofacial/genética , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Malformações do Sistema Nervoso/genética , Fenótipo , SíndromeRESUMO
We describe a patient with a phenotype characterized by mandibulofacial dysostosis with severe lower eyelid coloboma, cleft palate, abnormal ears, alopecia, delayed eruption and crowded teeth, and sensorioneural hearing loss. The karyotype and the screening for mutations in the coding region of TCOF1 gene were normal. The clinical signs of our case overlap the new mandibulofacial dysostosis described by Stevenson et al. [2007] and the case with Johnson-McMillin syndrome described by Cushman et al. [2005]. The similar clinical signs, mainly, the severe facial involvement observed in these cases suggest that they can represent a new distinct form of mandibulofacial dysostosis or the end of the spectrum of Johnson-McMillin syndrome.
Assuntos
Alopecia/complicações , Fissura Palatina/complicações , Coloboma/complicações , Pálpebras/anormalidades , Disostose Mandibulofacial/complicações , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , SíndromeAssuntos
Fenda Labial/genética , Fissura Palatina/genética , Testes Genéticos , Fatores Reguladores de Interferon/genética , Mutação , Alelos , Brasil , Éxons , Feminino , Frequência do Gene , Humanos , Íntrons , Masculino , Núcleo Familiar , Linhagem , Fatores de TempoRESUMO
Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling.
Assuntos
Craniossinostoses/diagnóstico , Craniossinostoses/genética , Perda Auditiva Neurossensorial/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Audiometria/métodos , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Lactente , Masculino , Mutação , Linhagem , Fenótipo , Fatores Sexuais , Distúrbios da Fala/diagnóstico , Distúrbios da Fala/genética , Síndrome , Tomografia Computadorizada por Raios X/métodosAssuntos
Anormalidades Múltiplas/patologia , Deleção Cromossômica , Cromossomos Humanos Par 22 , Hereditariedade , Anormalidades Urogenitais/patologia , Adolescente , DNA/análise , DNA/genética , Feminino , Marcadores Genéticos , Humanos , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Mapeamento Físico do Cromossomo , Polimorfismo de Nucleotídeo Único , Polimorfismo Conformacional de Fita Simples , Proteínas Proto-Oncogênicas/genética , Radiografia , Receptores do Ácido Retinoico/genética , Receptor X Retinoide alfa/genética , Coluna Vertebral/anormalidades , Coluna Vertebral/diagnóstico por imagem , Síndrome , Ultrassonografia , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/diagnóstico por imagem , Proteínas Wnt/genética , Proteína Wnt4 , Receptor gama de Ácido RetinoicoRESUMO
OBJECTIVE: Screen the known craniosynostotic related gene, FGFR1 (exon 7), and two new identified potential candidates, CER1 and CDON, in patients with syndromic and nonsyndromic metopic craniosynostosis to determine if they might be causative genes. DESIGN: Using single-strand conformational polymorphisms (SSCPs), denaturing high-performance liquid chromatography, and/or direct sequencing, we analyzed a total of 81 patients for FGFR1 (exon 7), 70 for CER1, and 44 for CDON. PATIENTS: Patients were ascertained in the Centro de Estudos do Genoma Humano in São Paulo, Brazil (n = 39), the Craniofacial Unit, Oxford, U.K. (n = 23), and the Johns Hopkins University, Baltimore, Maryland (n = 31). Clinical inclusion criteria included a triangular head and/or forehead, with or without a metopic ridge, and a radiographic documentation of metopic synostosis. Both syndromic and nonsyndromic patients were studied. RESULTS: No sequence alterations were found for FGFR1 (exon 7). Different patterns of SSCP migration for CER1 compatible with the segregation of single nucleotide polymorphisms reported in the region were identified. Seventeen sequence alterations were detected in the coding region of CDON, seven of which are new, but segregation analysis in parents and homology studies did not indicate a pathological role. CONCLUSIONS: FGFR1 (exon 7), CER1, and CDON are not related to trigonocephaly in our sample and should not be considered as causative genes for metopic synostosis. Screening of FGFR1 (exon 7) for diagnostic purposes should not be performed in trigonocephalic patients.
Assuntos
Moléculas de Adesão Celular/genética , Craniossinostoses/genética , Glicoproteínas de Membrana/genética , Proteínas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Supressoras de Tumor/genética , Craniossinostoses/diagnóstico por imagem , Análise Mutacional de DNA/métodos , Éxons/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Polimorfismo Conformacional de Fita Simples , Radiografia , Síndrome , Proteínas de XenopusRESUMO
FG syndrome is an X-linked multiple congenital anomalies (MCA) syndrome. It has been mapped to four distinct loci FGS1-4, through linkage analysis (Xq13, Xp22.3, and Xp11.4-p11.3) and based on the breakpoints of an X chromosome inversion (Xq11:Xq28), but so far no gene has been identified. We describe a boy with FG syndrome who has an inherited duplication at band Xq22.3 detected by comparative genomic hybridization microarray (Array-CGH). These duplication maps outside all four loci described so far for FG syndrome, representing therefore a new locus, which we propose to be called FGS5. MID2, a gene closely related to MID1, which is known to be mutated in Opitz G/BBB syndrome, maps within the duplicated segment of our patient. Since FG and Opitz G/BBB syndromes share many manifestations we considered MID2 a candidate gene for FG syndrome. We also discuss the involvement of other potential genes within the duplicated segment and its relationship with clinical symptoms of our patient, as well as the laboratory abnormalities found in his mother, a carrier of the duplication.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos X/genética , Face/anormalidades , Deficiência Intelectual/genética , Proteínas Associadas aos Microtúbulos/genética , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/patologia , Fatores de Transcrição/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Repetições de Microssatélites/genética , Hibridização de Ácido Nucleico/genética , Linhagem , Transtornos dos Cromossomos Sexuais/genéticaRESUMO
Craniossinostose caracteriza-se pelo fechamento prematuro de uma ou mais suturas cranianas. As craniossinostoses formam um grupo bastante heterogeneo, com incidencia de um para 2000-3000 nascimentos...