Objectives The objective of this study was to examine the concordance of results between mosaic pre-implantation genetic testing for aneuploidy (PGT-A) and diagnostic testing in resulting pregnancies conceived by IVF with PGT-A.Methods This study retrospectively provides analysis of 328 patients ascertained due to a mosaic PGT-A finding and 25 with a discordant reported sex, studied prenatally, utilizing standard karyotype and/or SNP microarray analysis.Results None of the 328 mosaic PGT-A findings were confirmed by the diagnostic prenatal studies with karyotype and/or microarray analysis. Additionally, of the 298 prenatal microarray studies performed, five demonstrated pathogenic abnormalities (1.7%) that were unrelated to PGT-A referral. Thirty-four of these cases were also studied to determine if UPD occurred; all were biparental.Conclusions This work emphasizes the importance of PGT-A follow-up and demonstrates that the vast majority will have normal diagnostic results and only a small number will be confirmed using prenatal diagnostic analysis. This work also suggests the most efficient way to proceed with diagnostic follow-up studies. Additionally, it shows the importance of fetal sex confirmation in all normal PGT-A studies.

Objectives: The overall objective of this study is to examine prenatal patients ascertained without an abnormal ultrasound (US) or an abnormal cell-free DNA (cfDNA) finding to provide a unique understanding of pathogenic copy number variants, identity by descent (IBD) and variants of uncertain significance (VUSs) in a normal population. Methods: This study retrospectively provides an analysis of over 28,362 prenatal specimens ascertained without an abnormal US or abnormal cfDNA finding utilizing an SNP microarray. These specimens include at least 10 different ascertainment groups, including advanced maternal age (AMA), anxiety, abnormal maternal serum screen (MSS) with/without AMA, and a previous or familial child/pregnancy with a chromosome abnormality or a genetic disorder. Results: This study provides a basic understanding of pathogenic copy number variants (CNVs), homozygosity and VUSs in an essentially normal population. This low-risk population has a frequency of pathogenic CNVs of ~1.26%; however, ~52% were associated with neurodevelopmental microdeletions/microduplications and ~13% were associated with incidental findings. Overall, ~1.32% of these patients showed an increase in homozygosity, the majority due to consanguinity. Lastly, VUSs were seen in 1.41% of this group, of which ~90% were familial. Conclusions: Overall, these findings provide a better estimate of the baseline frequencies and types of pathogenic CNVs and homozygosity in a low-risk population. It provides insight into the distribution of stretches of homozygosity associated with identity by descent in this population and gives a better understanding of the extent of variants of uncertain significance in phenotypically unaffected individuals.

This study investigates the frequency, ascertainment, and clinical implications of whole chromosomal isodisomy using a database of over 415,000 chromosomal microarray (CMA) tests conducted since 2008 across prenatal, postnatal, and products of conception specimens. In this cohort, 0.04% of cases exhibited the rare chromosomal phenomenon of isodisomy. Analysis of these cases revealed distinct patterns in frequency, chromosome involvement, and parent of origin related to specimen type. Isodisomy 14 was most frequent in prenatal samples, while chromosomes 6, 7, and 15 were more common in postnatal cases. The involvement of imprinted and non-imprinted chromosomes was equivalent for prenatal cases, while imprinted chromosomes consisted of two-thirds of postnatal cases, with paternal uniparental isodisomy more prevalent than maternal across all specimen types. Several cases demonstrated unmasking of pathogenic variants in recessive genes, and findings support prior studies of associations between isodisomy 11 and prenatal or neonatal lethality. These results underscore the diagnostic value of CMA and contribute to an extended understanding of isodisomy's clinical relevance.

Uniparental Disomy (UPD) occurs when both copies of a chromosome or chromosomal segment originate from only one parent. Mosaic genome-wide UPD (mos gwUPD) is typically identified in cases of fetal demise and placental dysplasia or in prenatal cases, where imprinting effects are associated with abnormal ultrasound findings. Children with mos gwUPD and clinical features due to UPD-associated imprinting effects (especially Beckwith-Wiedemann syndrome) have been reported; however, reports of adults with mos gwUPD are rare. Here we describe mos gwUPD in two apparently healthy pregnant adult women. Carrier testing noted variants with skewed allelic ratios outside of the normal heterozygous range, prompting further testing. Single nucleotide polymorphism (SNP) microarray identified mosaicism for gwUPD in both individuals, present at 85% and 90%, respectively, in blood, with varying percentages in other tissues. Neither woman displayed clinical features that would be expected with gwUPD at the time of testing, although retrospective careful personal history was consistent. Both women had uneventful pregnancies and delivered full-term healthy infants. These two cases demonstrate that mos gwUPD can be an incidental finding identified in apparently healthy adult women. Clinical follow-up is important for tumor monitoring, genetic counseling, and monitoring of future pregnancies due to mos gwUPD in the maternal endometrial tissue.

Trisomy rescue derived uniparental disomy (UPD) is inferred by the loss of a haplotype visualized as an extended region of homozygosity (ROH) that localizes to a single diploid chromosome detected by SNP microarray testing. We present data from 13 patients in which SNP array analysis shows an extra haplotype at a single chromosome. This rare allele dosage pattern is consistent with the rescue of meiotic trisomy by two events each involving a different homologue rather than the more commonly observed rescue of post-zygotic trisomy by one homologue, a unique phenomenon we call double rescue.

PURPOSE:To examine the utility of single-nucleotide polymorphisms (SNP) microarray analysis to detect uniparental disomy (UPD) by utilizing trios and duos (for which only 1 parent is available). METHODS:We established Mendelian Inheritance Error (MIE) values associated with either UPD or biparental inheritance in a cohort of 124 patients. In duos, the percentage of proband heterozygous (AB) SNPs contributed from the parent submitted was also used to detect UPD. RESULTS:Examination of 25 trios revealed UPD with a MIE = 0.02 +/- 0.02 and a range of 0.01 to 0.23 for the contributing parent and a MIE = 8.76 +/- 1.68 with a range of 5.96 to 11.14 for the noncontributing parent. Detailed examination of 13 duos (involving 16 chromosomes) showed an AB% = 52.0% +/- 4.85% consistent with biparental origin of the chromosome of interest. In 6 duos (6 chromosomes), the AB% = 97.2% +/- 2.6% and a range of 92.9% to 99.4% were consistent with UPD. CONCLUSION:Our results demonstrate utility of a SNP microarray to detect UPD. Distinct MIE ranges were observed that defined UPD or biparental inheritance. In duos, the AB% calculation effectively detected UPD. The diagnostic yield for UPD testing is significantly decreased when large regions of homozygosity are not detected by routine microarray analysis, which has implications for UPD test ordering practices.

Congenital heart defect (CHD) is a common abnormality seen in approximately 9 of every 1,000 babies born. It comprises several different subtypes and can be classified from simple to complex. While most can be diagnosed prenatally and some cytogenetic testing has been reported, most studies evaluating chromosome and microarray analysis for CHD lack sufficient numbers to make satisfactory correlations. During the past 12 years, over 11,000 prenatal patients referred because of prenatal ultrasound findings indicating a concern for heart defects were studied with a SNP microarray and/or chromosome analysis.

ObjectivesTo investigate the prenatal detection rate of mosaicism by SNP microarray analysis, in which an individual has not one, but two, complete genomes (sets of DNA) in their body, a normal biparental line with a Genome Wide Uniparental Disomy (GWUPD) cell line was used.MethodsThis study retrospectively examines the prenatal detection of GWUPD in a cohort of similar to 90,000 prenatal specimens and similar to 20,000 products of conceptions (POCs) that were studied by SNP microarray.ResultsIn total, 25 cases of GWUPD were detected; 16 cases were detected prenatally with GWUPD (similar to 0.018%) and 9 POCs revealed GWUPD (0.045%). The nine POC specimens presented with placental abnormalities. The 12 amniotic fluid specimens were ascertained because of abnormal ultrasound findings. Nine of 12 pregnancies had findings consistent with Beckwith-Wiedemann syndrome or because of abnormal placentas. However, three pregnancies were detected with GWUPD of maternal origin, with less common findings and demonstrated maternal origin. Four other pregnancies showed GWUPD in a chorionic villus sample, but normal findings in amniotic fluid and apparently normal fetal development.ConclusionsThis cohort with GWUPD mosaicism expands our understanding of GWUPD and has implications for prenatal care and counseling. Additional studies are necessary to understand the rarer maternal GWUPD. What's already known about this topic?An unusual type of mosaicism, GWUPD, has been previously reported in a limited number of cases. Most ascertained postnatally involve a paternal origin with findings consistent with Beckwith-Wiedemann syndrome (BWS).What does this study add?This is the largest cohort of patients ascertained both prenatally and in products of conceptions (POCs) with GWUPD and both paternal and maternal origins of the mosaic genome have been detected. We discuss the implications of GWUPD detected prenatally.

Supplementary Figure 5 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Supplementary Table 3 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

American Journal of Medical Genetics Part AVolume 191, Issue 7 p. 1681-1686 ISSUE INFORMATIONFree Access Table of Contents, Volume 191A, Number 7, July 2023 First published: 07 June 2023 https://doi.org/10.1002/ajmg.a.62813AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Volume191, Issue7July 2023Pages 1681-1686 RelatedInformation

Supplementary Figure 1 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Background Noninvasive prenatal testing (NIPT) allows for screening of fetal aneuploidy and copy number variants (CNVs) from cell-free DNA (cfDNA) in maternal plasma. Professional societies have not yet embraced NIPT for fetal CNVs, citing a need for additional performance data. A clinically available genome-wide cfDNA test screens for fetal aneuploidy and CNVs larger than 7 megabases (Mb). Results This study reviews 701 pregnancies with “high risk” indications for fetal aneuploidy which underwent both genome-wide cfDNA and prenatal microarray. For aneuploidies and CNVs considered ‘in-scope’ for the cfDNA test (CNVs ≥ 7 Mb and select microdeletions), sensitivity and specificity was 93.8% and 97.3% respectively, with positive and negative predictive values of 63.8% and 99.7% as compared to microarray. When including ‘out-of-scope’ CNVs on array as false negatives, the sensitivity of cfDNA falls to 48.3%. If only pathogenic out-of-scope CNVs are treated as false negatives, the sensitivity is 63.8%. Of the out-of-scope CNVs identified by array smaller than 7 Mb, 50% were classified as variants of uncertain significance (VUS), with an overall VUS rate in the study of 2.29%. Conclusions While microarray provides the most robust assessment of fetal CNVs, this study suggests that genome-wide cfDNA can reliably screen for large CNVs in a high-risk cohort. Informed consent and adequate pretest counseling are essential to ensuring patients understand the benefits and limitations of all prenatal testing and screening options.

Supplementary Table 4 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion