RESUMEN
White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.
Asunto(s)
Envejecimiento Prematuro/genética , Secuencia de Bases , Predisposición Genética a la Enfermedad , Trastornos del Desarrollo del Lenguaje/genética , Leucoencefalopatías/genética , Eliminación de Secuencia , Tetraspaninas/genética , Edad de Inicio , Envejecimiento Prematuro/complicaciones , Envejecimiento Prematuro/etnología , Envejecimiento Prematuro/patología , Pueblo Asiatico , Encéfalo/metabolismo , Encéfalo/patología , Niño , Preescolar , Cromosomas Humanos Par 2 , Exones , Femenino , Humanos , Trastornos del Desarrollo del Lenguaje/complicaciones , Trastornos del Desarrollo del Lenguaje/etnología , Trastornos del Desarrollo del Lenguaje/patología , Leucoencefalopatías/complicaciones , Leucoencefalopatías/etnología , Leucoencefalopatías/patología , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADNRESUMEN
Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype-phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7 Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies.