Unknown,Transcriptomics,Genomics,Proteomics

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Investigation of a patient with a partial 16q trisomy

ABSTRACT: A female patient with a partial trisomy 16q was described previously. Her clinical characteristics included obesity, severe anisomastia, moderate to severe mental retardation, dysmorphic facies, and contractions of the small joints. In this paper, we describe a more detailed analysis of the genetic anomaly in this patient. We were particularly interested in the involvement of the fat mass and obesity associated gene (FTO) in her duplication. Single nucleotide polymorphisms in FTO have recently been associated with obesity. We have precisely mapped the breakpoints of the duplication using high resolution oligonucleotide array comparative genome hybridization (CGH). We found that the duplication spans 11.45 Mb on 16q11.2 to 16q13 and it includes FTO. The increased copy number of FTO was confirmed with a qPCR on genomic DNA of the patient and healthy controls. We investigated the influence of the increased FTO copy number on FTO gene expression in immortalized lymphocytes from the using qPCR. We found no evidence of increased FTO expression in the patient. This observation could be explained by maternal imprinting. We found evidence supporting this hypothesis in a database of imprinted genes. In addition, our results generated new candidate genes for the mental retardation, dysmorphic facies, small joints contractions, small teeth, and anisomastia of the patient. We used a high density oligonucleotide microarray to delineate the borders of the duplication with high resolution. This analysis enabled us to confirm the inclusion of FTO in the duplication. This was confirmed with quantitative real-time PCR (qPCR) at the level of genomic DNA. To further investigate the role of FTO in the obese phenotype of the patient, we used qPCR to study the expression of FTO in immortalized lymphocytes of the patient. Remarkably, the increased FTO copy number in the patient’s genomic DNA did not give rise to an increased copy number of FTO mRNA molecules. We think this may be the result of maternal imprinting of the gene. The CGH results also allowed us to generate new hypotheses regarding the etiology of the other clinical problems of the patient. We propose candidate genes for her mental retardation, dysmorphic facies, joint contractures, small teeth, and anisomastia.

ORGANISM(S): Homo sapiens

SUBMITTER: Serge Smeets

PROVIDER: E-GEOD-12741 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:A database of apparently benign copy number variants (bCNVs) detected by a Spectral Genomics Inc./PerkinElmer BAC array platform has been maintained through the University of Utah Comparative Genomic Hybridization laboratory since 2005. The target population for this database represents 1275 patients with abnormal phenotypes, primarily children referred for developmental delay and mental retardation. These bCNVs are independent of any identified copy number abnormality detected. The most common 35 bCNVs observed and their frequencies are reported here, and a subset of ten of the patients studied was evaluated on a new oligonucleotide CNV array set designed by Agilent Technologies. There was a 76% concordance of calls detected by both array platforms in the same patients; the discordant regions may be due to differences in reference DNAs, or false positive/negative results on either array. The higher resolution of the Agilent oligonucleotide array compared to the BAC array allowed for further characterization to determine precise breakpoints of the observed CNVs, in addition to documenting additional CNVs of smaller sizes. As expected, observed CNVs and their frequencies were generally consistent with those of other previously published and available databases, including the Database of Genomic Variants (http://projects.tcag.ca/variation/). The availability of these data should assist other clinical laboratories in the evaluation of CNVs of unknown clinical significance. The Cytogenetics Laboratory at the University of Utah has been using aCGH to evaluate DNA derived from blood of patients with developmental delay, mental retardation and “syndromic” or dysmorphic phenotypes since 2005. From this database, we were able to determine which clones represented sequences which were frequently deleted or duplicated in our patient population. We identified our most common CNV regions and then selected DNAs from ten patients who exhibited copy number changes of those common regions for further study with the Agilent CNV microarray set. Normal male or female DNA from Promega was used as a sex-mismatched control. In addition to the ten clinical specimens, two self-self experiments for two patient samples were analyzed to estimate a false positive rate and to fine tune the parameters used for data analysis. A replicate hybridization was performed on one patient to determine reproducibility.

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Investigation of a patient with a partial 16q trisomy

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