RESUMO
De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of 15 individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe 2 nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of 2 aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioral problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in 2 individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype-phenotype correlation, although 2 individuals harboring a stop codons at the end of the kinase domain might have a milder phenotype. Overall, there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an à vue diagnosis of this syndrome and therefore genome-wide or gene-panel driven genetic testing is needed. Based on this overview, we provide suggestions for clinical work-up and management of this recently described ID syndrome.
Assuntos
Proteína Quinase CDC2/genética , Deficiências do Desenvolvimento/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Códon sem Sentido , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Cardiopatias Congênitas/fisiopatologia , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Sítios de Splice de RNA/genética , Adulto JovemRESUMO
Human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2) has been previously associated with intellectual disability and developmental delay in three patients. Here, we describe six patients with developmental delay, intellectual disability, and dysmorphic features with de novo likely gene-damaging variants in HIVEP2 identified by whole-exome sequencing (WES). HIVEP2 encodes a large transcription factor that regulates various neurodevelopmental pathways. Our findings provide further evidence that pathogenic variants in HIVEP2 lead to intellectual disabilities and developmental delay.
Assuntos
Transtornos Dismórficos Corporais/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Adolescente , Transtornos Dismórficos Corporais/complicações , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Feminino , Humanos , Deficiência Intelectual/complicações , Masculino , Mutação , Sequenciamento do ExomaRESUMO
Three girls with Rett syndrome are presented. Patients A and B had initially exhibited normal development, patient C showed severe developmental delay from birth on. In all three stereotypical hand movements arose which led to Rett syndrome being suspected. For patients A and B the clinical diagnosis was further supported by the identification of mutations in the MECP2-gene. In patient C, the mutation found turned out to be a neutral variant. Rett syndrome is a X-linked developmental disorder, which is particularly prevalent in girls. In 70-90% of clinically diagnosed RS patients a mutation is detected. MECP2-mutations result in a far wider range of phenotypes than classic RS. Mutations of this gene also occur in boys, with or without Rett-syndrome type phenotypes.