P700: Clinical exome sequencing efficacy and phenotypic expansions involving congenital anomalies of kidney and urinary tract (CAKUT)

referred for SNV microarray testing.The presence of one major abnormality was associated with an increased detection of ~4.9% cytogenetic anomalies by array (conventional cytogenetics normal) and ~5.3% increased detection of cytogenetic abnormalities by array when there were two or more major US abnormalities.This study demonstrates an increased diagnostic yield by microarray and refines our estimates of cytogenomic anomalies (combined array and conventional cytogenetics) for four specific US defects (cystic hygroma, diaphragmatic hernia, omphalocele and holoprosencephaly).Methods: In this study standard cytogenetic and SNV microarray analyses were performed on patients ascertained with four specific types of US abnormality detected prenatally: cystic hygroma (10,222 patients); diaphragmatic hernia (1395); omphalocele (2759) & holoprosencephaly (1097).Results: We report: (1) The frequency of chromosome anomalies detected by karyotype for various US abnormalities ranged from 12% (Diaphragmatic Hernia) to 45.1% (Cystic Hygroma); (2) Rates of chromosome anomalies were higher when there were additional US abnormalities -ranging from 31.6% (Diaphragmatic Hernia) to 60.2% (Cystic Hygroma); (3) Rates of additional findings from microarray detected varied between 2.7% (Omphalocele) and 8.0% (Holoprosencephaly); (4) Rates of additional findings from microarray analysis were increased when there were additional US anomalies between 7.2% (Omphalocele) to 12.8% (Cystic Hygroma); (5) For three of these US abnormalities (Diaphragmatic Hernia, Omphalocele and Holoprosencephaly), the addition of a major heart defect resulted in the highest frequency of chromosome anomalies; (6) Patients ascertained with Diaphragmatic Hernia, Omphalocele and Holoprosencephaly occurred mostly after 20 weeks.In contrast, we observed more cystic hygroma in the 1st trimester (2 times greater) with differing rates of chromosome anomalies (48.5% -1st trimester vs 38.4% -2nd trimester).However, the additional findings from the array analysis were higher in 2nd trimester cases (+6.7%) vs +5.1% in 1st; (7) The highest percent of structural chromosome/array anomalies were detected in patients with holoprosencephaly.Overall, 77.7% of the structural abnormalities involved genes specifically associated with holoprosencephaly; 22.1% of these aberrations could only be detected by array; (8) Additionally, 91.6% of all the chromosome and array anomalies detected in patients with holoprosencephaly could be related to the phenotypic findings; (9) Specific chromosome findings were associated with the different US findings (GATA4 deletions and iso(12p) in diaphragmatic hernias; trisomy 21 in cystic hygroma; trisomy 18 in omphalocele; and the deletion of multiple different genes (SIX2, ZIC2, SHH, TGIF and DLL1) and trisomy 13 in holoprosencephaly); (10) Examination of 499 cases with US abnormalities that also had cfDNA study showed an overall positive predictive value (PPV) of 98.8%; and in 230 cases with cfDNA indicating an abnormality for trisomy 13 or 18, PPV was 98.7%.Conclusion: This is the most comprehensive study to date utilizing chromosome and microarray analysis with specific congenital defects.It affirms that microarray provides added value over conventional cytogenetics and our findings carry significant implications for accurate genetic counseling for these families.The results show that: (1) An increased yield of abnormalities can be detected by microarray study, but more patients are still referred for chromosome studies than array analysis resulting in a lower yield of abnormalities; (2) There is a wide difference in the frequency of abnormalities based on a number of factors including type of defects, complexity of defects, and gestational age.