RESUMO
Due to small numbers of reported patients with pathogenic variants in single genes, the phenotypic spectrum associated with genes causing neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder is expanding. Among these genes is KLF7 (Krüppel-like factor 7), which is located at 2q33.3 and has been implicated in several developmental processes. KLF7 has been proposed to be a candidate gene for the phenotype of autism features seen in patients with a 2q33.3q34 deletion. Herein, we report 4 unrelated individuals with de novo KLF7 missense variants who share similar clinical features of developmental delay/ID, hypotonia, feeding/swallowing issues, psychiatric features and neuromuscular symptoms, and add to the knowledge about the phenotypic spectrum associated with KLF7 haploinsufficiency.
Assuntos
Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Fatores de Transcrição Kruppel-Like/genética , Adolescente , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/psicologia , Feminino , Predisposição Genética para Doença , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/psicologia , Masculino , Mutação de Sentido Incorreto/genética , Sequenciamento do ExomaRESUMO
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
Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, Xlinked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of lossoffunction KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using wholeexome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of Xlinked dominant ID, and broadens the phenotype for KIAA2022 mutations.