To determine whether abnormal first trimester serum analytes (low PAPP-A and/or beta-hCG) are associated with pathologic copy number variants (CNV) on chromosomal microarray (CMA). This retrospective cohort included all CMA studies (n = 2880) that were performed via chorionic villus sampling (CVS) or amniocentesis at a single institution in a single laboratory from 2011 to 2017. We excluded cases in which an abnormal karyotype was detected, as well as multiple gestations or those who had no prior nuchal translucency screening. The prevalence of abnormal serum analytes was compared between patients with pathologic CNVs (abnormal CMA, VOUS likely abnormal, and mosaics) i.e. study group (n = 56) and those with normal CMAs i.e. controls (n = 884). Odds ratios were calculated and statistical significance was determined as p < 0.05. Low serum free beta-hCG (<= 0.45 MoM) was associated with an increased risk for pathologic CNV (OR 3.53, p < 0.01), as well as for abnormal CNV (OR 4.7, p < 0.01) (Table 1). The association of pathologic CNV with low serum PAPP-A (<= 0.4 MoM) was not statistically significant (OR 1.26, p = 0.6) (Table 1). Low first trimester serum beta-hCG is associated with an increased risk of pathologic, as well as, abnormal CNVs on CMA testing. This strong association should be taken into consideration when counseling patients regarding abnormal serum beta-hCG levels.

Objective To determine whether abnormal levels of first-trimester maternal serum free beta-hCG and PAPP-A are associated with significant copy number variants (CNVs) on chromosomal microarray analysis (CMA). Methods Results Retrospective cohort of singleton prenatal CMA studies (n = 2880). Cases with an abnormal karyotype, benign familial or de novo variants, and absence of heterozygosity were excluded. The prevalence of abnormal serum analytes was compared between patients with significant CNVs (n = 56) and those with normal CMA (n = 884). Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using Fisher's exact test. Mantel-Haenszel method was utilized to adjust ORs for prenatal diagnostic procedure type and indications for testing. Statistical significance was determined as P value Abnormally low serum free beta-hCG (<= 0.45 MoM) was associated with an increased risk of significant CNVs (OR 3.53, 95% CI, 1.25-8.66, P < 0.01). This association remained significant after adjusting for abnormal nuchal translucency and advanced maternal age (AMA) (adjusted OR 3.04, 95% CI, 1.05-7.48, P < 0.05) or procedure type and AMA (adjusted OR 3.21, 95% CI 1.13-8.16, P < 0.05). The associations of abnormally high serum free beta-hCG, low PAPP-A, and high PAPP-A with significant CNVs were not statistically significant. Conclusion Low first-trimester serum beta-hCG is associated with an increased risk of significant CNVs on CMA.

Objective To assess the additive value of prenatal chromosomal microarray analysis (CMA) for all indications and the likelihood of detecting pathologic copy number variations (CNVs) based on specific indications.Methods A retrospective analysis was performed on amniocentesis and chorionic villi sampling results obtained between 2010 and 2014 in a single institution. A total of 3,314 consecutive patients undergoing invasive genetic testing for different indications were offered CMA in addition to standard karyotype. The prevalence of pathologic CNVs was compared between patients with low-risk indications and those with high-risk indications. Likewise, the prevalence of pathologic CNVs among patients with different sonographic abnormalities was calculated and compared with the low-risk group. Chi-square and Fisher exact tests were used for statistical analysis.Results The prevalence of pathologic CNVs was significantly higher in patients with high-risk indications and specifically those with sonographic abnormalities, compared with the low-risk group (2.8 and 5.9% vs. 0.4%, respectively; all p < 0.05).Conclusion Prenatal CMA detected clinically relevant CNVs in fetuses with a normal karyotype. Major structural malformations and nuchal translucency (NT) >= 3.0 mm are associated with the highest risk for a CMA abnormality. Nevertheless, the prevalence of pathologic CNVs in the low-risk population was high enough (1:250) to consider genetic counseling in this group.

To assess the likelihood of pathologic CNVs based on the specific indication for chromosomal microarray analysis (CMA). We performed a retrospective analysis of amniocentesis and CVS results obtained during a 4-year period in a single center. 3314 consecutive patients undergoing invasive genetic testing were offered CMA in addition to standard karyotype. 2026 (61%) elected to also pursue CMA. The prevalence of pathologic CNVs [abnormal CNV or variants of unknown significance (VOUS) – likely abnormal] was compared between patients with low-risk indications (AMA or parental desire) and those with high-risk indications (sonographic abnormalities, abnormal aneuploidy screen, personal or familial history of genetic conditions). Likewise, the prevalence of pathologic CNVs in patients with different sonographic abnormalities was calculated and compared to the low-risk group. Chi-square and Fisher's exact tests were used for statistical analysis. Summary of the results is presented in table 1. The prevalence of pathologic CNVs was significantly higher in patients with high-risk indications and specifically sonographic abnormalities, relative to the low-risk group (all p < 0.05). Prenatal CMA detected clinically relevant CNVs in a substantial number of fetuses with a normal karyotype. Major structural malformations and NT ≥ 3.0mm are associated with the highest risk for a CMA abnormality. Additionally, the prevalence of pathologic CNVs in the low-risk population is high enough (1:250) to suggest genetic counselling even in this group.

A 34 year old healthy G2P1, was seen in our MFM unit for a routine anatomical survey at 21 post menstrual weeks. The pregnancy was uncomplicated thus far and the mother reported no medical conditions or known teratogenic exposure. Detailed sonographic evaluation revealed complete agenesis of the corpus callosum with no additional intra/extra cranial malformations. Subsequent workup included amniocentesis detecting a normal male karyotype. To our surprise, a 17p12 micro-duplication (1.323 Mb) was noted on the CMA. This is a mutation in the critical region of the Charcot-Marie-Tooth type 1A (CMT 1A) gene. It is an autosomal-dominant (AD) condition that is characterised by progressive distal muscle weakness and atrophy, peripheral neuropathy and subsequent incurable debilitation. The mother was found to have the same mutation and her neurological evaluation was significant for mild weakness of the lower extremities, minimal muscular atrophy, but no significant limitation in motor performance. A multidisciplinary team of specialists in MFM, genetics, neurology and fertility collaborated in consultation. The couple elected to terminate the pregnancy. Subsequently, 3 additional pregnancies were terminated following detection of CMT 1A affected fetuses on CVS. With recent advances in laboratory availability, performing pre-implantation genetic diagnosis (PGD) for CMT 1A, an unaffected embryo was selected resulting in a healthy infant. This case illustrates several clinical and ethical challenges that are byproducts of introducing new genetic technology such as CMA into the prenatal arena. These include incidental detection of maternal conditions on prenatal testing, detection of genetic conditions with late onset clinical manifestations, the risk of recurrence with future pregnancies (AD inheritance) and the option for PGD in such cases. In addition, whether and when evaluation of other siblings may be considered (2 year old daughter in our case) presents an ethical dilemma to the family.

Journal of Ultrasound in MedicineVolume 33, Issue 7 p. 1305-1307 Clinical Letters Isolated Fetal Macrodactyly: Phenotypic and Genetic Disparities in Mosaic Overgrowth Syndrome Eran Bornstein MD, Eran Bornstein MD Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, New York, New York USASearch for more papers by this authorCarlos A. Bacino MD, Carlos A. Bacino MD Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas USASearch for more papers by this authorKristen Maliszewski MS, CGC, Kristen Maliszewski MS, CGC Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas USASearch for more papers by this authorKim Delaney RDMS, Kim Delaney RDMS Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, New York, New York USASearch for more papers by this authorReut Moyal MD, Reut Moyal MD Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, New York, New York USASearch for more papers by this authorMichael Y. Divon MD, Michael Y. Divon MD Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, New York, New York USASearch for more papers by this author Eran Bornstein MD, Eran Bornstein MD Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, New York, New York USASearch for more papers by this authorCarlos A. Bacino MD, Carlos A. Bacino MD Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas USASearch for more papers by this authorKristen Maliszewski MS, CGC, Kristen Maliszewski MS, CGC Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas USASearch for more papers by this authorKim Delaney RDMS, Kim Delaney RDMS Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, New York, New York USASearch for more papers by this authorReut Moyal MD, Reut Moyal MD Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, New York, New York USASearch for more papers by this authorMichael Y. Divon MD, Michael Y. Divon MD Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, New York, New York USASearch for more papers by this author First published: 01 July 2014 https://doi.org/10.7863/ultra.33.7.1305Citations: 5Read the full textAboutPDF 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 No abstract is available for this article. References 1Lindhurst MJ, Parker VE, Payne F. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet 2012; 44: 928–933. 10.1038/ng.2332 CASPubMedWeb of Science®Google Scholar 2Lindhurst MJ, Sapp JC, Teer JK. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011; 365: 611–619. 10.1056/NEJMoa1104017 CASPubMedWeb of Science®Google Scholar 3Kurek KC, Luks VL, Ayturk UM. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. 2012; 90: 1108–15. 10.1016/j.ajhg.2012.05.006 CASPubMedWeb of Science®Google Scholar 4Yüksel A, Yagmur H, Kural BS. Prenatal diagnosis of isolated macrodactyly. Ultrasound Obstet Gynecol 2009; 33: 360–362. 10.1002/uog.6326 PubMedWeb of Science®Google Scholar 5Hussain K, Challis B, Rocha N. An activating mutation of AKT2 and human hypoglycemia. Science 2011; 334: 474. 10.1126/science.1210878 CASPubMedWeb of Science®Google Scholar 6Poduri A, Evrony GD, Cai X. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 2012; 74: 41–48. 10.1016/j.neuron.2012.03.010 CASPubMedWeb of Science®Google Scholar 7Jamis-Dow CA, Turner J, Biesecker LG, Chovke PL. Radiologic manifestations of Proteus syndrome. Radiographics 2004; 24: 1051–1068. 10.1148/rg.244035726 PubMedWeb of Science®Google Scholar 8Lacombe D, Battin J. Isolated macrodactyly and Proteus syndrome. Clin Dysmorphol 1996; 5: 255–257. 10.1097/00019605-199607000-00010 PubMedWeb of Science®Google Scholar Citing Literature Volume33, Issue7July 2014Pages 1305-1307 ReferencesRelatedInformation

To evaluate the clinical value of prenatal chromosomal microarray analysis (CMA) in patients with a normal karyotype and to determine the risk factors most likely to yield informative CMA results. We conducted a retrospective analysis of all amniocentesis (n=1180) and CVS (n=424) samples obtained during a 20 month period in a single center. All patients were offered CMA in addition to standard testing. 533 patients (33%) elected to pursue CMA studies, which were performed in a single laboratory primarily using uncultured samples. 500 cases were tested with a BCM V7 (105K) array containing oligos corresponding to over 270 known genomic disorders, as well as 41 unique subtelomeric regions and all 43 unique pericentromeric regions. The other 34 cases were tested with a V8 (180K) array with exon coverage for 1700 genes. CMA results were stratified based on indications for testing, and the additive detection rate of CMA was compared among these indications using Fisher's exact test. 523 women who elected to have CMA performed had a normal karyotype. Stratification of CMA results based on the indication for testing is presented in the table. In our cohort, abnormal CMA results were detected in 1.9% of the patients regardless of the indication for testing. CMA abnormalities were detected in 5.5% of patients with abnormal 1st or 2nd trimester sonographic findings, whereas none were detected among patients who were tested due to AMA or parental concern alone (p<0.001).Tabled 1 Prenatal CMA detected clinically relevant genetic abnormalities that were not detected by traditional karyotype analysis. The additive value of CMA in the prenatal population varies significantly based on the patient's risk factors, with abnormal ultrasound findings comprising the highest risk group.