This work describes an approach to characterize the clinical significance of genetic variants detected during the genetic testing of BRCA1 in patients from hereditary breast/ovarian cancer families. Results from transgenic mice and extensive clinical testing support the hypothesis that biallelic BRCA1 mutations result in embryonic lethality. Therefore, it is reasonable to conclude that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer. This approach was applied to a large data set of 55,630 patients who underwent clinical BRCA1 screening by whole gene direct DNA sequencing. Fourteen common single nucleotide polymorphisms (SNPs) were used to assign 10 previously defined common, recurrent, or canonical haplotypes in 99% of these cases. From a total of 1,477 genetic variants detected in these patients, excluding haplotype-tagging SNPs, 877 (59%) could be unambiguously assigned to one or more haplotypes. In 41 instances, variants previously classified as being of uncertain clinical significance, mostly missense variants, were excluded as fully penetrant mutations due to their coincidence in trans with known deleterious mutations. From a total of 1,150 patients that harbored these 41 variants, 956 carried one as the sole variant of uncertain clinical significance reported. This approach could have widespread application to other disease genes where compound heterozygous mutations are incompatible with life or result in obvious phenotypes. This largely computational technique is advantageous because it relies upon existing clinical data and is likely to prove informative for prevalent genetic variants in large data sets.

Background Feed and swaddle is a technique in which an infant is fed and allowed to fall asleep to facilitate diagnostic imaging. This study reviews our experience and diagnostic success in premature and term infants up to 6 months old undergoing brain magnetic resonance imaging (MRI) using a feed and swaddle technique and with comparable patients imaged under anesthesia. Methods We reviewed the charts of all infants ≤6 months who underwent brain MRI at our institution between 1 January 2013 and 31 March 2016. We recorded and analyzed demographic information, scan indication, scan length, prematurity status, anesthetic technique if used, complications, and diagnostic success or failure. Results One hundred and sixty‐four term infants underwent brain MRI using a feed and swaddle technique. The success rate in term infants <90 days was 91.1% (113/124) versus 95.0% (38/40) in infants ≥90 days and ≤181 days old. Fifty‐three premature infants underwent feed and swaddle for brain MRI with a diagnostic success rate of 92.5% (49/53). No complications were noted in any feed and swaddle patients. Those who received anesthesia had a diagnostic success rate of 100% (70/70) but experienced complications including hypoxemia, 14.3% (10/70); hypothermia, 18.9% (10/53); bradycardia, 10.1% (7/69); and hypotension, 4.2% (3/70). Conclusion Given the high rate of success and absence of complications with feed and swaddle in children ≤6 months for brain MRI and the presence of anesthesia‐related complications, most infants should undergo a trial of feed and swaddle prior to undergoing brain MRI with anesthesia.

Victim identification initiatives undertaken in the wake of Mass Fatality Incidents (MFIs) where high-body fragmentation has been sustained are often dependent on DNA typing technologies to complete their mandate. The success of these endeavors is linked to the choice of DNA typing methods and the bioinformatic tools required to make the necessary associations. Several bioinformatic tools were developed to assist with the identification of the victims of the World Trade Center attacks, one of the most complex incidents to date. This report describes one of these tools, the Mass Disaster Kinship Analysis Program (MDKAP), a pair-wise comparison software designed to handle large numbers of complete or partial Short Tandem Repeats (STR) genotypes, and infer identity of, or biological relationships between tested samples. The software performs all functions required to take full advantage of the information content of processed genotypic data sets from large-scale MFIs, including the collapse of victims data sets, remains re-association, virtual genotype generation through gap-filling, parentage trio searching, and a consistency check of reported/inferred biological relationships within families. Although very few WTC victims were genetically related, the software can detect parentage trios from within a victim's genotype data set through a nontriangulated approach that screens all possible parentage trios. All software-inferred relationships from WTC data were confirmed by independent statistical analysis. With a 13 STR loci complement, a fortuitous parentage trio (FPT) involving nonrelated individuals was detected. Additional STR loci would be required to reduce the risk of an FPT going undetected in large-scale MFIs involving related individuals among the victims. Kinship analysis has proven successful in this incident but its continued success in larger scale MFIs is contingent on the use of a sufficient number of STR loci to reduce the risk of undetected FPTs, the use of mtDNA and Y-STRs to confirm parentage and of bioinformatics that can support large-scale comparative genotyping schemes capable of detecting parentage trios from within a group of related victims.

No abstract