RESUMO
BACKGROUND: High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). METHODS: This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). RESULTS: A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations. CONCLUSION: Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.
Assuntos
Proteínas Argonautas , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Aminoácidos/genética , Heterozigoto , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , RNA Mensageiro , Proteínas Argonautas/genéticaRESUMO
We report a 6-month-old boy with diffuse hypertonia and developmental delay who had unilateral separated-lip schizencephaly and contralateral polymicrogyria. The contralateral polymicrogyria was associated with an incomplete clefting in that hemisphere. An umbilical cord hamartoma is presumed to have caused hypoperfusion to the early developing brain, resulting in bilateral lesions.
Assuntos
Encefalopatias/etiologia , Córtex Cerebral/patologia , Hamartoma/patologia , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/embriologia , Cordão Umbilical/patologia , Encefalopatias/patologia , Deficiências do Desenvolvimento/etiologia , Lateralidade Funcional , Hamartoma/complicações , Humanos , Lactente , Imageamento por Ressonância Magnética , MasculinoRESUMO
We report a newborn girl with hydranencephaly. In the setting of a monochorionic twin pregnancy, one twin's demise was detected by ultrasonography at 18 weeks of gestation, apparently the result of a twin-twin transfusion. In the surviving twin, the evolution of ventriculomegaly, first noted at 18 weeks, to hydranencephaly at 27 weeks is documented by serial sonograms. These findings were confirmed with fetal and postnatal magnetic resonance imaging.
Assuntos
Morte Fetal , Transfusão Feto-Fetal , Hidranencefalia/etiologia , Hidranencefalia/patologia , Ultrassonografia Pré-Natal , Adulto , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido , Imageamento por Ressonância Magnética , Gravidez , GêmeosRESUMO
Neonatal-onset epilepsies are rare conditions, mostly genetically determined, that can have a benign or severe phenotype.(1,2) There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.(3,4) This is a rare condition and all patients reported so far were diagnosed well after the neonatal period.(3,4) We report on 3 new cases of KCNQ2 encephalopathy diagnosed in the neonatal period and studied with continuous video-EEG recording. We describe a distinct electroclinical phenotype and report on efficacy of antiepileptic drug (AED) therapies.