Single Nucleotide Polymorphism Microarray Testing Research Articles

Single-nucleotide polymorphism microarray detects molar pregnancies in 3% of miscarriages

To determine the frequency of molar pregnancy in miscarriage cases based on single-nucleotide polymorphism (SNP) microarray testing on products of conception (POC) tissue and to estimate the sensitivity of ultrasound and histopathologic evaluation for cases identified to be at risk for gestational trophoblastic disease. Retrospective cohort analysis. Reference laboratory. POC specimens from 26,101 consecutive miscarriages. POC samples were sent to a single laboratory for analysis. Maternal age, gestational age, egg donor use, indication for testing, and additional clinical information were obtained from the requisition form and a survey sent to ordering providers. Rates of full paternal uniparental disomy (UPD), indicative of complete molar pregnancy, and triploidy of paternal origin, indicative of partial molar pregnancy, in POC samples. Paternal triploidy was detected in 638 cases (2.8%) and full paternal UPD in 72 cases (0.3%). Of the cases with complete clinical information (224/710; 31.5%), histopathology and/or ultrasound did not detect 71% of partial molar pregnancies and 30% of complete molar pregnancies. Molar pregnancy, detected in 3.1% of all miscarriages in this study with the use of 24-chromosome SNP microarray testing, occurred significantly more frequently than previously estimated with the use of ultrasound and/or histopathology.

Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls

Endolymphatic sac tumor (ELST) is a rare neoplasm arising in the temporal petrous region thought to originate from endolymphatic sac epithelium. It may arise sporadically or in association with Von-Hippel-Lindau syndrome (VHL). The ELST prevalence in VHL ranges from 3 to 16% and may be the initial presentation of the disease. Onset is usually in the 3rd to 5th decade with hearing loss and an indolent course. ELSTs present as locally destructive lesions with characteristic computed tomography imaging features. Histologically, they show papillary, cystic or glandular architectures. Immunohistochemically, they express keratin, EMA, and variably S100 and GFAP. Currently it is recommended that, given its rarity, ELST needs to be differentiated from other entities with similar morphologic patterns, particularly other VHL-associated neoplasms such as metastatic clear cell renal cell carcinoma (ccRCC). Nineteen ELST cases were studied. Immunohistochemistry (18/19) and single nucleotide polymorphism microarray testing was performed (12/19). Comparison with the immunophenotype and copy number profile in RCC is discussed. Patients presented with characteristic bone destructive lesions in the petrous temporal bones. Pathology of tumors showed characteristic ELST morphology with immunoexpression of CK7, GFAP, S100, PAX-8, PAX-2, CA-9 in the tumor cells. Immunostaines for RCC, CD10, CK20, chromogranin A, synaptophysin, TTF-1, thyroglobulin, and transthyretin were negative in the tumor cells. Molecular testing showed loss of 3p and 9q in 66% (8/12) and 58% (7/12) cases, respectively. Immunoreactivity for renal markers in ELST is an important diagnostic caveat and has not been previously reported. In fact, renal markers are currently recommended in order to rule out metastatic RCC although PAX gene complex and CA-9 have been implicated in the development of the inner ear. Importantly copy number assessment of ELST has not been previously reported. Loss of 3p (including the VHL locus) in ELST suggests similar mechanistic origins as ccRCC.

Novel ALOX12B Mutation Identified in Parents following Single Nucleotide Polymorphism Microarray Testing of Banked DNA from a Fatal Case of Congenital Ichthyosis.

In genetically and phenotypically heterogeneous conditions like ichthyosis, it is clinically not possible to predict mutation in a specific gene. Sequential testing of all the causative genes is time consuming and expensive. In consanguineous families with autosomal recessive genetically heterogeneous disorders, it is possible to narrow down the candidate gene/genes by recognizing the regions of homozygosity by a single nucleotide polymorphism (SNP) array. Here, we present a fatal case of autosomal recessive severe congenital ichthyosis born to a consanguineous couple. Two candidate genes were recognized by SNP array on banked DNA of the subject. Sequencing of these candidate genes in parents found them to be carriers of the same variation, a novel heterozygous deletion of single nucleotide in exon 8 (c. 1067delT) of ALOX12B gene. The present case illustrates the utility of DNA banking, SNP array and testing of parents to arrive at a definitive molecular diagnosis, essential for genetic counseling, and prenatal testing.

Prenatal Diagnosis of Abnormal Sternum Development and Dilated Aortic Root in a Fetus with a Novel 204 kb Microdeletion of the TGFRB2 Gene

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is associated with vascular abnormalities, including aggressive aortic aneurysms, as well as skeletal and craniofacial malformations. The molecular mechanism of this syndrome remains to be fully elucidated. In this case, we describe a 29-year-old woman, gravida 2 para 1, who was referred for consultation after urinary tract malformations were observed during her mid-gestation anatomic survey. Following referral to our unit, ultrasound examination of the 21-week fetus was repeated. The fetus was observed to have a dilated aortic root and a poorly ossified sternum with mild pectus deformity. After elective termination, single nucleotide polymorphism microarray testing identified a novel 204 kb microdeletion involving the short arm of chromosome 3. The deleted genetic material included 4 exons of the TGFBR2 gene. Although the phenotype of LDS may be caused by haploinsufficiency of the TGFBR1 or TGFBR2 gene, our experience suggests a more complex picture of LDS. The study of such cases might further elucidate its pathogenesis.

Single-nucleotide polymorphism microarray testing (SNP) of paraffin-embedded products of conception (PPOC) as first-line assessment for recurrent pregnancy loss (RPL)

Previous studies recommend cytogenetic analysis of fresh POC at the time of a second pregnancy loss. When it is not performed or fails to yield a result, ASRM recommends a RPL workup (parental karyotypes, antiphospholipid antibodies (APA), TSH, Prolactin and uterine cavity evaluation). New SNP technology can determine karyotype from PPOC, with the added ability to exclude maternal cell contamination (MCC). This study investigated whether PPOC testing is a suitable alternative to the ASRM RPL workup for the initial evaluation of RPL without prior cytogenetic data.

Utilization of Magnetic-Activated Cell Sorting and High-Density Single Nucleotide Polymorphism Microarrays Improves Diagnostic Yield and Prognostic Value in Clinical Testing for Patients with Multiple Myeloma and Normal Routine Chromosome Study

Utilization of Magnetic-Activated Cell Sorting and High-Density Single Nucleotide Polymorphism Microarrays Improves Diagnostic Yield and Prognostic Value in Clinical Testing for Patients with Multiple Myeloma and Normal Routine Chromosome Study

The Perils of SNP Microarray Testing: Uncovering Unexpected Consanguinity

Although single nucleotide polymorphism chromosomal microarrays identify areas of small genetic deletions or duplications, they can also reveal regions of homozygosity indicative of consanguinity. As more nongeneticists order single nucleotide polymorphism microarrays, they must prepare for the potential ethical, legal, and social issues that result from revelation of unanticipated consanguinity. We describe an infant with multiple congenital anomalies who underwent single nucleotide polymorphism microarray testing. The results of the single nucleotide polymorphism microarray revealed several large regions of homozygosity that indicated identity by descent most consistent with a second-degree or third-degree relative mating (e.g., uncle/niece, half-brother/sister, first cousins). The mother was not aware of the test's potential to reveal consanguinity. When informed of the test results, she reluctantly admitted to being raped by her half-brother around the time of conception. During the pretesting consent process, providers should inform parents that single nucleotide polymorphism microarray testing could reveal consanguinity. Providers must also understand the psychological implications, as well as the legal and moral obligations, that accompany single nucleotide polymorphism microarray results that indicate consanguinity.

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Changing culture conditions. blastocyst ploidy following standard incubation and uninterrupted culture in the embryoscope (ES)

To determine the effect of uninterrupted culture with minimal light exposure, versus standard incubation of embryos in a 5.5% CO2, 5% O2 environment, on the euploid:aneuploid ratio of blastocysts, determined by trophectoderm biopsy. Patients attended for preimplantation aneuploidy screening of their blastocysts. Between November 2009 and April 2011 embryos were cultured in low O2 incubators (Galaxy, SLS, UK) and observed daily. Between April 2011 and April 2012, embryos were cultured uninterrupted in the ES (Unisense, Denmark) and observed using time-lapse images. This study aimed to compare the euploid:aneuploid ratio of embryos developed in these contrasting incubators. Trophectoderm biopsy was performed on 126 blastocysts at CARE Fertility in Manchester, England. Blastocyst chromosome constitution was determined by array comparative genomic hybridisation for 15 patients and single nucleotide polymorphism microarray testing for 18 patients. The euploid:aneuploid ratio from each incubation condition and the proportion of embryos suitable for biopsy were compared using Fisher's Exact Test. 304 embryos were cultured for 33 patients. 41.9% and 41.1% of embryos cultured in the standard and ES incubators respectively underwent biopsy and obtained a screening result. No significant difference in the proportion of euploid and aneuploid blastocysts was observed following standard or ES incubation (P=0.5884,n=52 standard,n=74 ES). Average patient age was 37.1±3.98 and 37.5±4.24 respectively for standard and ES culture. The change from single observation standard incubation to uninterrupted culture has not significantly altered the euploid:aneuploid ratio or the proportion of blastocysts suitable for biopsy. Therefore, the uninterrupted culture, enhanced air quality and decreased temperature fluctuations of the ES appear not to affect chromosome segregation within blastocysts. As patient numbers increase, the analysis will be updated.

Variability in laboratory reporting practices for regions of homozygosity indicating parental relatedness as identified by SNP microarray testing

Single-nucleotide polymorphism (SNP) microarrays are capable of detecting regions of homozygosity (ROH) that can suggest parental consanguinity or incest. This study was designed to describe the variable reporting practices of clinical laboratories in the United States regarding ROH found on SNP microarray tests, to discuss the follow-up practices of laboratory personnel when findings of ROH indicate consanguinity or incest, and to highlight the legal and ethical dilemmas faced by workers who have discovered these incidental findings. A 20-question survey was administered to microarray experts at 18 laboratories offering clinical SNP microarray tests. The results are presented using descriptive statistics. There was variability in laboratory SNP microarray reporting practices with respect to information and interpretation of ROH findings. All the laboratories agreed that they have a duty to inform the ordering physician about results suggesting consanguinity or incest, but the follow-through practices varied among laboratories. This study discovered variability in reporting practices and follow-up procedures for microarray results that suggest parental consanguinity or incest. Our findings highlight the need for laboratory guidelines to standardize reporting practices for SNP microarray and other tests that are capable of detecting ROH.