RESUMO
The RASopathies are a class of developmental syndromes. Each of them exhibits distinctive phenotypic features, although there are numerous overlapping clinical manifestations that include: dysmorphic craniofacial features, congenital cardiac defects, skin abnormalities, varying degrees of intellectual disability and increased risk of malignancies. These disorders include: Noonan syndrome, Costello syndrome, LEOPARD syndrome, cardio-facio-cutaneous syndrome (CFC), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Legius syndrome and neurofibromatosis type 1 (NF1). The RASopathies are associated with the presence of germline mutation in genes encoding specific proteins of the RAS/mitogen - activated protein kinase (MAPK) pathway that plays a crucial role in embryonic and postnatal development. In this review, we present the clinical and molecular features of selected syndromes from the RASopathies group.
Assuntos
Malformações Arteriovenosas/genética , Capilares/anormalidades , Anormalidades Craniofaciais/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Neurofibromatose 1/genética , Mancha Vinho do Porto/genética , Proteínas ras/genética , Síndrome de Costello , Fácies , Humanos , Síndrome LEOPARD/genética , Sistema de Sinalização das MAP Quinases/genética , Síndrome de Noonan , Transdução de Sinais/genéticaRESUMO
INTRODUCTION: Intellectual disability (ID)/Developmental delay (DD), which occurs in 1-3% of the population, accounts for a large number of cases regularly seen in genetics clinics. Currently, Array Comparative Genomic Hybridization (array CGH) is recommended by the International Standards for Cytogenomic Arrays (ISCA) Consortium as a first line test in the diagnostics of ID/DD, replacing G-banded chromosome analysis. THE AIM: Application of array CGH in clinical diagnostics of developmental delay/ intellectual disability in children. MATERIAL AND METHODS: We present the results of 8x60K oligonucleotide array application that was successfully implemented in a cohort of 112 patients with the clinical diagnosis of intellectual disability and accompanying dysmorphic features and/or congenital malformations. RESULTS: We have identified 37 copy number variants (CNVs) with the size ranging from 40 kb to numerical chromosomal aberrations, including unbalanced translocations and chromosome Y disomy, receiving an overall diagnostic yield of 33%. Known pathogenic changes were identified in 21.4% of the cases. Among patients with pathogenic CNVs identified by array CGH, 41.7% had a previously normal karyotype analysis. CONCLUSIONS: Our studies provide more insights into the benefits derived by using chromosomal microarray analysis and demonstrate the usefulness of array CGH as a first-tier clinical setting test in patients with intellectual disability.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Adolescente , Adulto , Transtornos Dismórficos Corporais/diagnóstico , Transtornos Dismórficos Corporais/genética , Criança , Pré-Escolar , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Adulto JovemRESUMO
Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.
Assuntos
Variações do Número de Cópias de DNA , Exoma , Malformações do Desenvolvimento Cortical/genética , Polimorfismo de Nucleotídeo Único , Caderinas/genética , Feminino , Heterogeneidade Genética , Humanos , Masculino , Malformações do Desenvolvimento Cortical/patologia , Proteínas do Tecido Nervoso/genética , Receptores de Superfície Celular/genéticaRESUMO
We present the phenotype of three unrelated Polish patients with MFD type Guion-Almeida confirmed by EFTUD2 mutations. In all of our patients, dysmorphic craniofacial features, microcephaly, thumb abnormalities, psychomotor and speech delay were described. In addition, among other major defects, esophageal atresia (EA) in one patient and choanal atresia in two of them were present. Three different mutations in EFTUD2 gene were found in presented patients. Our observations confirm the clinical heterogeneity of mandibulofacial dysostosis type Guion-Almeida and its connection with major congenital defects such as esophageal atresia and choanal atresia.
Assuntos
Atresia das Cóanas/genética , Atresia Esofágica/genética , Deficiência Intelectual/genética , Disostose Mandibulofacial/genética , Microcefalia/genética , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Adolescente , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Fenótipo , PolôniaRESUMO
We used whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) in a cohort of 256 patients with developmental delay (DD)/intellectual disability (ID) with or without dysmorphic features, additional neurodevelopmental abnormalities, and/or congenital malformations. In 69 patients, we identified 84 non-polymorphic copy-number variants, among which 41 are known to be clinically relevant, including two recently described deletions, 4q21.21q21.22 and 17q24.2. Chromosomal microarray analysis revealed also 15 potentially pathogenic changes, including three rare deletions, 5q35.3, 10q21.3, and 13q12.11. Additionally, we found 28 copy-number variants of unknown clinical significance. Our results further support the notion that copy-number variants significantly contribute to the genetic etiology of DD/ID and emphasize the efficacy of the detection of novel candidate genes for neurodevelopmental disorders by whole-genome array CGH.