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PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.
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Encefalopatías/genética , Factores de Intercambio de Guanina Nucleótido/genética , Discapacidad Intelectual/genética , Convulsiones/genética , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encefalopatías/epidemiología , Encefalopatías/fisiopatología , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/fisiopatología , Masculino , Mutación , Linaje , Fenotipo , Isoformas de Proteínas/genética , Convulsiones/epidemiología , Convulsiones/fisiopatología , Caracteres SexualesRESUMEN
Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.
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Translocador 2 del Nucleótido Adenina/metabolismo , Deleción Cromosómica , Cromosomas Humanos X/genética , Discapacidad Intelectual/genética , Mitocondrias/metabolismo , Translocador 2 del Nucleótido Adenina/genética , Elementos Alu , Secuencia de Bases , Encéfalo/metabolismo , Encéfalo/patología , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Heterocigoto , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Mitocondrias/genética , Datos de Secuencia Molecular , Linaje , Inactivación del Cromosoma XRESUMEN
We report on a 6-years-old boy with psychomotor retardation, mild dysmorphic features and behavioral disturbances associated with epilepsy. Conventional cytogenetic analysis concluded to an interstitial de novo 6p21.2p22.3 duplication. Molecular cytogenetic analysis, including array-CGH technology, allows characterization of this 7.3Mb interstitial tandem duplication. The phenotype of this small 6p duplication reported to date is compared to other cases in the literature. Presence of epilepsy, although rare in patients with 6p duplication may be linked to genes involved in brain function and synaptic transmission in the 6p21.2p22.1 duplicated region (GABBR1, BRD2 and GRM4).