Interaction of the cockayne syndrome B (CSB) protein with the genome

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Non-invasive prenatal testing : Clinical utility and ethical concerns about recent advances

The combined first trimester screening test for Down syndrome, involving a nuchal translucency scan and biochemistry at 11–13 weeks, improved detection rates to 90% when compared with the sensitivity of screening by age-related a priori risk of around 30% for a false positive rate of 5%. The advent of non-invasive prenatal testing (NIPT) in 2010 as a screening test for the common trisomies was revolutionary, with sensitivity, specificity and detection rates unmatched by the combined first trimester screening programs. NIPT was found to achieve a detection rate for Down syndrome of 99.7%, with a false positive rate of 0.04%. However, some NIPT providers now additionally offer extended panels and low resolution whole genome sequencing (WGS) including sex chromosome aneuploidies, rare autosomal aneuploidies, and subchromosomal deletions, duplications and recurrent microdeletions. This comes at a cost of a higher false positive rate and lower positive predictive value. Moreover, the expanded panels and WGS NIPT raise issues of clinical utility and ethical concerns

Mosaic 22q11.2 deletion and tetralogy of Fallot with absent pulmonary valve: an unreported association

Chromosome 22q11.2 microdeletion is the most common microdeletion syndrome. Mosaic 22q11.2 deletions are very rare and only a few have been reported. We describe a case of a neonate with tetralogy of Fallot with absent pulmonary valve with mosaic 22q11.2 deletion. Fluorescent in situ hybridization analysis of lymphocytes showed a hemizygous 22q11.2 microdeletion in 66% of interphase nuclei. Microarray testing confirmed a 1.66 Mb deletion at 22q11.2. The child did not have any clinical manifestations of 22q11.2 deletion other than the cardiac malformation

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy

We present a patient with a behavioral disorder, epilepsy, and autism spectrum disorder who has a 520 kb chromosomal deletion at 15q26.1 encompassing three genes: <i>ST8SIA2</i>, <i>C15orf32</i>, and <i>FAM174B</i>. Alpha-2,8-Sialyltransferase 2 (ST8SIA2) is expressed in the developing brain and appears to play an important role in neuronal migration, axon guidance and synaptic plasticity. It has recently been implicated in a genome wide association study as a potential factor underlying autism, and has also been implicated in the pathogenesis of bipolar disorder and schizophrenia. This case provides supportive evidence that ST8SIA2 haploinsufficiency may play a role in neurobehavioral phenotypes

Ovarian microcystic stromal tumor: a rare clinical manifestation of familial adenomatous polyposis

Microcystic stromal tumor (MST) is a rare tumor of presumed sex-cord stromal differentiation. We present a case of MST arising within a patient with constitutional 5q deletion syndrome, whose deletion encompassed the APC gene. Genomic analysis of the MST revealed a point mutation in the remaining APC allele, predicted to result in abnormal splicing of Exon 7. Subsequent clinical investigation revealed multiple gastrointestinal polyps qualifying for a diagnosis of familial adenomatous polyposis. This case emphasizes the importance of an aberrant Wnt/β-catenin pathway in the development of MST and adds credence to the inclusion of MST as a rare phenotype of familial adenomatous polyposis. In a search for additional genetic aberrations which may contribute to the development of this rare tumor, genomic analysis revealed a frameshift mutation in FANCD2, a protein which plays a key role in DNA repair. This protein is expressed in human ovarian stromal cells and FANCD2-knockout mice are known to develop sex cord-stromal tumors, factors which further support a possible role of aberrant FANCD2 in the development of MST

DNA extraction from placental, fetal and neonatal tissue at autopsy: what organ to sample for DNA in the genomic era?

Incorporation of genome and exome sequencing into fetal and neonatal autopsy investigations has been shown to improve diagnostic yield. This requires deoxyribonucleic acid (DNA) to be extracted from either the placenta or autopsy tissue for molecular testing. However, the sources and quality of DNA obtained are highly variable and there are no adequate published data on what tissue is most ideal to sample for DNA extraction in this setting. Here we compare the quality of DNA extracted from sampling the placenta and various solid organs at fetal and neonatal autopsy, thereby determining the optimal tissue from which to source DNA for ancillary testing as part of the modern perinatal autopsy. A total of 898 tissue samples were obtained at autopsy from 176 fetuses (gestational ages 17-40 weeks) and 44 neonates (age range 0-28 days) at our tertiary institution. Fetal tissue was processed using the QIAsymphony DSP DNA Mini kit and placental tissue was extracted using the New iGENatal Kit. DNA concentration was quantified using the Qubit dsDNA BR Assay Kit. DNA integrity, as stratified by gel electrophoresis was classified as high (≥5 kb) or low quality

Upper Atmosphere Re-Entry Study High Altitude Burnup. Volume 2

Methods of determining the fate of radioactive fuels in space power units burned up on re-entry into the earth's atmosphere are reviewed. Particulate characteristics experiments were derived from an analytical study on the ablation of Dlutonium fuel. This study revealed that the particulate size distribution resulting on re-entry burnup is a function of: the fuel form in use and the material velocity and atmospheric density at the time the fuel is exposed. The particulate fate experiments were derived essentially from studies of the effects of thermal and turbulent diffusion, and wind and gravity dispersion on the particulate cloud. The experiments recommended are described. (M.C.G.

KRAS mutation testing of metastatic colorectal cancer in Australia: where are we at?

Aim: To carry out a nationwide study of KRAS testing in metastatic colorectal cancer as reported by nine major molecular pathology service providers in Australia, including mutation frequencies and turnaround times that might impact on patient care. Methods: Participating laboratories contributed information on KRAS mutation frequencies, including the G13D mutation type, as well as turnaround times for tumor block retrieval and testing. Results: The KRAS mutation frequency observed by nine different test sites for a total of 3688 metastatic colorectal cancers ranged from 34.4% to 40.7%, with an average across all sites of 38.8%. The average frequency of the G13D mutation type among all cases was 8.0%. The median turnaround time was 17 days (range 0-191), with 20% of cases requiring more than 4 weeks for a KRAS test result. The major contributor to long turnaround times was the time taken to retrieve archived blocks of primary tumor, particularly from sources external to the test site. Conclusion: The frequency of KRAS mutations in metastatic colorectal cancer reported by the major Australian test sites is very similar to that reported by other large overseas studies. More widespread introduction of routine testing at the time of initial diagnosis should eliminate the long turnaround times currently being experienced in a significant proportion of cases. Future expansion of testing to include other KRAS and NRAS mutation hotspots may spur the introduction of next-generation sequencing platforms

Isolated ventricular noncompaction cardiomyopathy presenting as fetal hydrops at 24 weeks gestation: a genomic analysis

Ventricular noncompaction cardiomyopathy is a rare form of congenital cardiomyopathy with increasing evidence of genetic etiology, especially when presenting in childhood. Fetal presentation is rare. We describe a case of fetal hydrops, presenting at 24 weeks gestation and leading to intrapartum death at 26 weeks gestation. Autopsy examination revealed characteristic features of left ventricular noncompaction. A genetic analysis identified a constellation of variants of unknown significance in MYH6, TNNC1, and MYBPC3, genes known to be important in sarcomeric function. Additionally, the variant in MYBPC3 was homozygous. While this case did not demonstrate a conventional single-gene mutation as the cause of the ventricular noncompaction, a broader genomic investigation revealed several variants in sarcomeric genes which may act synergistically to impact cardiac function