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Cody J.D.,University of Texas Health Science Center at San Antonio | Cody J.D.,The Chromosome 18 Registry and Research Society | Hale D.E.,University of Texas Health Science Center at San Antonio
American Journal of Medical Genetics, Part A | Year: 2011

Nine out of 10 people has a chromosome copy number variation (CNV) of >1,000bp of DNA. In some cases they are inconsequential, in other cases the variations cause disease or disability, and in most cases the relevance has not been elucidated. Several studies describe CNVs as "normal" biological variants while other studies suggest that CNVs may be associated with developmental disability. A concerted effort is needed to classify genes according to their dosage sensitivity, or to their lack of sensitivity. Over time, this effort will lead to the establishment of principles that permit the prediction of the consequence of any one genomic copy number change. © 2011 Wiley-Liss, Inc. Source


Hermetz K.E.,Emory University | Newman S.,Emory University | Conneely K.N.,Emory University | Martin C.L.,Emory University | And 7 more authors.
PLoS Genetics | Year: 2014

Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes. © 2014 Hermetz et al. Source


Tragus R.,University of Texas Health Science Center at San Antonio | Cody J.D.,University of Texas Health Science Center at San Antonio | Cody J.D.,The Chromosome 18 Registry and Research Society
Clinical and Translational Science | Year: 2013

There is a need for metrics that describe the full range of services provided by a clinical research unit; given that services have expanded to include such things as investigator training, regulatory compliance monitoring, and budget negotiations. We developed a tool and methodology that allows tracking of these expanded services. This not only allowed us to more accurately describe the work of the research unit staff, but to monitor the status of a study across the entire study lifespan from the idea to the publication. In addition to measuring work, it allows us to anticipate future needs in clinical staff and expertise because we are involved very early in study planning. We also expect that by analyzing these data from many studies over time, we will identify process barriers that will direct future program improvement. © 2013 Wiley Periodicals, Inc. Source


Sebold C.,University of Texas Health Science Center at San Antonio | Soileau B.,University of Texas Health Science Center at San Antonio | Heard P.,University of Texas Health Science Center at San Antonio | Carter E.,University of Texas Health Science Center at San Antonio | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Deletions of the short arm of chromosome 18 have been well-described in case reports. However, the utility of these descriptions in clinical practice is limited by varied and imprecise breakpoints. As we work to establish genotype-phenotype correlations for 18p-, it is critical to have accurate and complete clinical descriptions of individuals with differing breakpoints. In addition, the developmental profile of 18p- has not been well-delineated. We undertook a thorough review of the medical histories of 31 individuals with 18p- and a breakpoint in the centromeric region. We collected developmental data using mailed surveys and questionnaires. The most common findings included neonatal complications; cardiac anomalies; hypotonia; MRI abnormalities; endocrine dysfunction; strabismus; ptosis; and refractive errors. Less common features included holoprosencephaly and its microforms; hearing loss; and orthopedic anomalies. The developmental effects of the deletion appear to be less severe than reported in the literature, as average IQ scores were in the range of borderline intellectual functioning. Based on responses to standardized questionnaires, it appears this population has marked difficulty with activities of daily living, though several young adults were able to live independent of their parents. This manuscript represents the most comprehensive description of a cohort of 18p- individuals with identical breakpoints. Despite identical breakpoints, a great deal of phenotype variability remained among this population, suggesting that many of the genes on 18p- cause low-penetrance phenotypes when present in a hemizygous state. Future efforts will focus on the clinical description of individuals with more distal breakpoints and the identification of critical regions and candidate genes. © 2015 Wiley Periodicals, Inc. Source


O'Donnell L.,University of Texas Health Science Center at San Antonio | Soileau B.T.,University of Texas Health Science Center at San Antonio | Sebold C.,University of Texas Health Science Center at San Antonio | Gelfond J.,University of Texas Health Science Center at San Antonio | And 3 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Our purpose was to describe intellectual and behavioral characteristics of persons with tetrasomy 18p. This is a more detailed investigation into the cognitive and behavioral characteristics of our previously reported tetrasomy 18p cohort of 43 plus six additional participants. We evaluated the intellectual functioning using standard measures of cognitive ability, measures of executive functioning, adaptive and maladaptive behaviors. Intellectual abilities ranged from mild impairment/borderline normal to severe/profound impairment calling into question the assumption that severe cognitive limitation is always a feature of tetrasomy 18p. For persons with tetrasomy 18p with mild cognitive deficits, the main barriers to successful functioning stems from limited social and metacognitive skill development and behavior regulation problems rather than being solely determined by cognitive deficits alone. © 2015 Wiley Periodicals, Inc. Source

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