RESUMEN
The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous â¼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.
Asunto(s)
Arritmias Cardíacas/genética , Debilidad Muscular/genética , Rabdomiólisis/genética , Alelos , Árabes/genética , Arritmias Cardíacas/diagnóstico , Secuencia de Bases , Niño , Preescolar , Estrés del Retículo Endoplásmico/genética , Exoma , Exones , Femenino , Eliminación de Gen , Aparato de Golgi/genética , Aparato de Golgi/metabolismo , Hispánicos o Latinos/genética , Homocigoto , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Debilidad Muscular/diagnóstico , Linaje , Rabdomiólisis/diagnóstico , Población Blanca/genéticaRESUMEN
GNB5 encodes the G protein ß subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.
Asunto(s)
Bradicardia/genética , Bradicardia/fisiopatología , Discapacidades del Desarrollo/genética , Subunidades beta de la Proteína de Unión al GTP/genética , Genes Recesivos/genética , Mutación/genética , Nodo Sinoatrial/fisiopatología , Adolescente , Animales , Niño , Discapacidades del Desarrollo/fisiopatología , Femenino , Subunidades beta de la Proteína de Unión al GTP/deficiencia , Reflujo Gastroesofágico/genética , Reflujo Gastroesofágico/fisiopatología , Eliminación de Gen , Frecuencia Cardíaca/genética , Heterocigoto , Humanos , Masculino , Hipotonía Muscular/genética , Mutación Missense/genética , Linaje , Fenotipo , Enfermedades de la Retina/genética , Enfermedades de la Retina/fisiopatología , Convulsiones/genética , Síndrome , Adulto Joven , Pez Cebra/genética , Pez Cebra/fisiología , Proteínas de Pez CebraRESUMEN
Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.