Trisomy 12 Mosaicism Detected by Genomic Microarray in a Newborn Child

Abstracts and additional minor dysmorphic features; however, the male child was more severely affected and also presented with IUGR, speech problems, and hypothyroidism. The second family was found to carry a 791 Kb tandem duplication from Xq26.1q26.2 that involves 3 genes (IGSF1, OR13H1, FIRRE) and is contained within the duplication found in the first family. This duplication was identified in a mother and her three sons and was associated with a less severe phenotype that included learning disability and speech delay. Patients with overlapping duplications in this region have been found to share common clinical features that include microcephaly, growth retardation, intellectual/learning disability, and additional dysmorphic features. The breakpoints of the few reported patients vary significantly, making it difficult to define a critical region or to establish a genotype-phenotype correlation. Additional cases are needed to identify the specific triplosensitive genes in the Xq25q26 region. The two additional families that we present provide additional information on the phenotypic spectrum associated with duplications in this region, which can range from stillbirth to minor learning disabilities and speech delay.

55 Next Generation Interphase Chromosome Profiling (NextGen ICP): Proof-of-Concept of Novel Technology Ramesh Babu, Ernesto Fuentes, Stephen Papa, Srikanthi Kopuri, Sarah Fuentes

Cytogenetics plays an important role in the diagnosis and prognosis of various genetic conditions. Successful enumeration and characterization of chromosome abnormalities is therefore critical in disease management. Towards this goal, we recently developed and validated a novel methodology called Interphase Chromosome Profiling (ICP) which can produce a 600band resolution to characterize chromosome rearrangements in interphase nuclei. Now, we expanded the concept to further aid in additional areas of genetic diagnostics. We term this enhanced technology NextGen Interphase Chromosome Profiling (NextGen ICP) which comprises several components. Based on the clinical situation/need, one or more components of the technology are utilized. We present here the proof-of-concept. Multiplex ICP: In traditional ICP, each chromosome is studied individually. However, when only a few cells are available in a compromised sample, obtaining whole genome information would be difficult. We solved this problem by designing a multiplex ICP in which six different chromosomes are studied simultaneously in any given cell. By combining four such hybridization results, one can obtain information for the whole genome (24 chromosomes). Rehybe ICP: No methodologies currently exist to obtain an entire karyotype from a single interphase nucleus. By combining the above mentioned Multiplex ICP in several rounds of deprobing and reprobing, i.e. Rehybe ICP, we successfully profiled all 24 chromosomes from a single cell. Rapid ICP: In Pre-Implantation Genetic Screening (PGS) when a fresh embryo transfer is considered, rapid TAT is crucial. By combining all elements of NextGen ICP, we successfully profiled all 24 chromosomes in 24–36 hours so that a 5-day harvest of few cells from the trophectoderm layer could facilitate a next (sixth) day embryo transfer. Clinical utility of NextGen ICP for cell-based non-invasive prenatal diagnosis (NIPD), chromosome profiling of solid tumors from “liquid biopsies” using circulating tumor cells (CTCs) and PGS for IVF patients will be discussed.

247 56 Trisomy 12 Mosaicism Detected by Genomic Microarray in a Newborn Child Bo Hong, Janice Zunich, Amanda Openshaw, Reha Toydemir

Trisomy 12 mosaicism is a rare genetic condition. Most of the trisomy 12 mosaicism cases were reported prenatally, with less than ten cases diagnosed postnatally. The clinical features associated with mosaic trisomy 12 are extremely variable ranging from apparently normal individuals to patients with various dysmorphic features including short stature, scoliosis, cardiac defects, facial dysmorphism, pigmentary dysplasia, and intellectual disability. The phenotypic variation may be associated with the proportion and distribution of the trisomic cells. Here we present a 2-day old girl with mild dysmorphic features, including down slanting palpebral fissures, a scooped and creased nasal bridge, and mild rhizomelic shortening of the limbs, though hands, fingers, and palmar creases appear normal. The pregnancy was conceived by IVF using frozen sperm obtained from the father prior to chemotherapy for chronic myelogenous leukemia (CML) diagnosed at age 19. The prenatal cell free DNA (cff DNA) screening was normal. At two months of age, she has reached developmental milestones. She has had normal echo, normal cranial ultrasound and normal renal ultrasound. The chromosome analysis on peripheral blood showed a normal female karyotype. However, a concurrent genomic microarray analysis suggested mosaic trisomy 12 in about 25% of the sample. Additional 30 metaphases were screened for trisomy 12, and all cells appeared to contain two copies of chromosome 12. FISH analysis with the CEP12 probe was performed on the residual fixed cell pellet prepared for chromosome analysis, to further confirm the genomic microarray findings and detected 6% of cells with trisomy 12. These results suggest that the phenotypical consequences of mosaic trisomy 12 might be very mild. In addition, these results emphasize the clinical utility of microarray analysis in uncultured specimens as the trisomy 12 population might exist at even lower levels in metaphase cells.

57 Characterization of a Complex Derivative Chromosome 18 Andrea Penton, Blair K. Stevens, Peter Papenhausen

We present an unbalanced potential recombinant chromosome 18 [46,XY,der(18)(qter->q22.3::p11.22->qter::?p11.2>pter)] that likely originated from multiple crossing over events during meiosis I from an ancestral balanced pericentric inversion of chromosome 18(p11.22q22.3). Cytogenetic analysis suggests that the distal short arm is retained at the 18q inversion break site along with the duplicated 18q22.2->qter region. The chromosome was detected in a fetus referred for prenatal diagnosis with abnormal ultrasound findings including lower urinary tract obstruction, oligohydramnios, and hypoplastic cerebellum. The derivative 18 chromosome was maternally inherited from a patient with learning disabilities, recurrent hiccups, partial hearing loss and aortic valve insufficiency. Maternal and prenatal microarray analysis detected an 8.64 Mb terminal duplication of 18q22.3 ->qter and an additional presumably unrelated 3.17 Mb microduplication at 22q11.21. The 18q duplication interval includes numerous OMIM genes. Although patients with intellectual