RESUMEN
Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty-one subjects (six females) formed the study group with ages between 3.5 months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K-AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1-related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first-tier genomic test rather than CMA in OGID.
Asunto(s)
Estudios de Asociación Genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Gigantismo/diagnóstico , Gigantismo/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Alelos , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 3 , Variaciones en el Número de Copia de ADN , Facies , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Gráficos de Crecimiento , Humanos , India , Lactante , Imagen por Resonancia Magnética , Masculino , Fenotipo , Análisis de Secuencia de ADN , Secuenciación del ExomaRESUMEN
OBJECTIVE: To study the clinical profile and mutation spectrum of Hunter syndrome. METHODS: Evaluation of 18 cases of Hunter syndrome from 17 families was done. Mutation analysis of Iduronate sulfatase (IDS) gene was done in 9 families, and mothers of four affected children with no family history. RESULTS: Joint contracture, hepatomegaly and radiological changes were present in all children. 6 (33%) children had normal cognitive function at presentation. Point mutations were identified in all the 9 families for whom mutation analysis was done. Among 4 mothers tested from families without any family history, 2 (50%) were found to be carriers. CONCLUSION: Accurate etiological diagnosis by mutation analysis of IDS gene is important in Hunter syndrome.