RESUMEN
Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses.
Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos Par 3 , Variaciones en el Número de Copia de ADN , Fenotipo , Humanos , Femenino , Masculino , Cromosomas Humanos Par 3/genética , Duplicación Cromosómica/genética , Niño , Variaciones en el Número de Copia de ADN/genética , Preescolar , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Adolescente , Estudios de Cohortes , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Adulto , LactanteRESUMEN
The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira+/- mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira+/- mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.
Asunto(s)
Proteínas de Ciclo Celular/genética , Síndrome de DiGeorge/genética , Haploinsuficiencia , Chaperonas de Histonas/genética , Trastornos del Neurodesarrollo/genética , Plasticidad Neuronal/genética , Neuronas/metabolismo , Factores de Transcripción/genética , Animales , Secuencia de Bases , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/deficiencia , Proteínas de Ciclo Celular/metabolismo , Niño , Preescolar , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Síndrome de DiGeorge/metabolismo , Síndrome de DiGeorge/patología , Femenino , Fórnix/metabolismo , Fórnix/patología , Expresión Génica , Heterocigoto , Hipocampo/metabolismo , Hipocampo/patología , Chaperonas de Histonas/antagonistas & inhibidores , Chaperonas de Histonas/deficiencia , Chaperonas de Histonas/metabolismo , Humanos , Ratones , Trastornos del Neurodesarrollo/metabolismo , Trastornos del Neurodesarrollo/patología , Neurogénesis/genética , Neuronas/patología , Cultivo Primario de Células , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/deficiencia , Factores de Transcripción/metabolismoRESUMEN
Polymicrogyria is a brain malformation due to abnormal cortical organization. Two histological types, unlayered or four-layered can be distinguished. Polymicrogyria is a rare manifestation of chromosome 22q11 deletion syndrome. We report two boys with chromosome 22q11 deletion syndrome and polymicrogyria, and describe the neuropathological features of the malformation in one of them. Clinical examinations, EEG, brain MRI, chromosomal analysis with FISH, and neuropathological studies of surgically resected cortical tissue were performed. Both patients showed severe developmental delay with cardiovascular malformations and one of them had drug resistant epilepsy. Polymicrogyria was found in the frontal, parietal, and temporal areas, unilaterally in one patient and bilaterally in the other. Histology revealed four-layered polymicrogyria. The pathogenesis of polymicrogyria in 22q11 deletion syndrome is discussed.
