P623: Prenatal diagnosis of a RNU4ATAC-related disorder detected by whole genome sequencing not seen by exome sequencing on the initial proband

Background: Noninvasive prenatal screening (NIPS) for detection of fetal aneuploidy has seen rapid implementation since commercial availability in 2011.More recently, it has expanded to encompass genome-wide aneuploidies, select copy number variants, and single-gene disorders.A variety of NIPS approaches exist with aim to identify and analyze placental cell-free fetal DNA (cfDNA) in maternal blood.Namely, single nucleotide polymorphism (SNP) based approaches determine fetal fraction and copy number variation by amplifying, sequencing, and comparing thousands of SNPs with high levels of heterozygosity between parental and cfDNA.In situations of suspected or known consanguinity, a result may not be yielded, due to the inability to distinguish if an abnormal SNP count is due to copy number variation in the fetus or homozygosity between mother and fetus.We report on atypical sex chromosome results in a consanguineous couple with SNP-based NIPS who elected amniocentesis for clarification.Whole-genome chromosomal microarray (CMA) revealed 46, XX with multiple regions of homozygosity (ROH).Our case highlights that certain NIPS results may not have a definitive explanation, even after diagnostic testing, provoking novel considerations in test selection and pre-and post-test counseling.Case presentation: In the present case, Panorama™ NIPS (Natera™) predicted female sex with "no result for sex chromosome abnormalities due to atypical finding of suspected fetal (placental) origin".Analysis for routine aneuploidies, triploidy, 22q11.2deletion were low risk.Sixteen week ultrasound showed normal fetal anatomy with female genitalia.ClariSure® Oligo-SNP chromosomal microarray with Quest Diagnostics™ on amniotic fluid revealed 46, XX with no copy number variants, but multiple ROHs (combined length ~24.5 Mb) encompassing chromosomes 5, 6, and 14.Although our patient reported she and her partner are from a small Hmong community and had no known consanguinity, the 0.9% ROH on CMA suggested fifth degree relatedness.The laboratory performing CMA did not report on ROH on chromosome X because of naturally high sequence homology.Some potential causes for the atypical SNP-based NIPS result include fetal or placental mosaicism, sex chromosome anomaly, parental consanguinity.One retrospective cohort study by Ayyash et al, reviewing Panorama™ NIPS results of 5,886 women found 49 atypical results (chromosomes unspecified), and all atypical results had normal second trimester ultrasound.Fourteen of these atypical results were among a subset of Arab American women, eight of whom reported consanguinity.The authors concluded that consanguinity may inflate the rate of atypical SNP-NIPS results.Our case highlights the need for clinicians to practice careful judgement in test selection and counseling when parental consanguinity is a possible contributor to an atypical SNP-NIPS result.For families who wish to avoid diagnostic testing, massive parallel shotgun sequencing NIPS, can be considered, while accounting for case-specific theoretic advantages of SNP-based NIPS (eg, detection of triploidy, twin chorionicity, maternal mosaicism).For families who consider diagnostic testing, clinicians can facilitate decision-making by generating a risk assessment for the fetus which accounts for clinical findings (eg, ultrasound anomalies), family history, and literature review examining consanguinity in less-studied geographic regions (in the present case, Hmong).Further, a laboratory that can assess ROH on the X chromosome should be considered with understanding that not all reported ROH definitively extrapolate a specific familial relationship (due to influence by random meiotic recombination, generational inbreeding, adoption, etc). Conclusion:The clinical utility and continued technologic and analytic expansion of NIPS and CMA have been invaluable for the field of prenatal genetics.However, unconventional nuances inevitably arise, and patients must be adequately informed about test benefits and limitations.Here, we highlight that certain "atypical" NIPS results may not be definitively explained even after diagnostic testing and thus may alter considerations for test selection and pre-and post-test counseling.