Abstract
BackgroundKaryotyping is the gold standard cytogenetic method for detection of ring chromosomes. In this study we report the molecular characterization of a novel ring 6 (r6) chromosome in a six-year-old girl with severe mental retardation, congenital heart disease and craniofacial abnormalities.MethodsCytogenetic analysis was performed by conventional karyotyping. Molecular genetic analyses were performed using high-resolution chromosome microarray analysis (CMA) and next generation sequencing (NGS). OMIM, UCSC and PubMed were used as reference databases to determine potential genotype to phenotype associations.ResultsPeripheral blood and skin fibroblast karyotyping revealed the presence of a dominant cell line, 46,XX,(r6)(p25.3;q27) and a minor cell line 45,XX,-6. Molecular karyotyping using NGS identified 6p25.3 and 6q27 subtelomeric deletions of 1.78 Mb and a 0.56 Mb, respectively. Based on the known genes located within the r6 deletion interval 6q25.3-pter, genotype to phenotype association studies found compelling evidence to suggest that hemizygous expression of disease genes FOXC1, FOXF2, IRF4 and GMDS was the main underlying cause of the patient’s phenotype. We further speculate that the severity of the patient’s symptoms may have been exacerbated by low-level instability of the r6 chromosome.ConclusionThis is the first report of a novel r6 chromosome characterized at the molecular level using NGS.
Highlights
Karyotyping is the gold standard cytogenetic method for detection of ring chromosomes
In this study, using both array comparative genomic hybridization (CGH) and copy number variation sequencing (CNV-Seq), we report a comprehensive molecular characterization of a novel r6 chromosome in a six-yearold girl with severe intellectual disability, congenital heart disease and dysmorphic craniofacial features
This study presents detailed cytogenetic and molecular analyses to characterize a novel r6 chromosome originally detected by conventional karyotyping in a six-year-old girl
Summary
Karyotyping is the gold standard cytogenetic method for detection of ring chromosomes. In this study we report the molecular characterization of a novel ring 6 (r6) chromosome in a six-year-old girl with severe mental retardation, congenital heart disease and craniofacial abnormalities. Ring chromosomes can involve any of the 24 chromosomes and are recognized in approximately 1 in 25,000 conceptions by karyotyping [2]. In a review of selected r6 cases [7], phenotypes were highly variable, with the most consistent clinical features involving mental and developmental retardation, in association with facial dysmorphic features including microcephaly, microgathia, short neck, flat or broad nasal bridge, epicanthus bilateral and malformations of the ocular and auditory systems
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