Rings and things- Noninvasive prenatal testing¹s unique view of the biology and embryology behind chromosomal ring formation and segregation

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cases Image 1. NIPT genomic traces for chromosome 18 NIPT genomic traces for chromosome 18 show a 0.75 Mb deletion at 18q22.1. The DNA fraction and trace data suggest a maternal origin. No evidence of the ring chromosome with distal loss on either arm is present, suggesting ring formation may have occurred in later embryogenesis. (Theory outlined in Image 2.) Image 2. Proposed theory behind origin of fetal ring 18 chromsome Fetal inheritance of the maternal deleted 18 lead to post zygotic instability at the deleted locus. Subsequent breakage at that locus, followed by fusion with the 18p subtelomere region, took place in select embryologic tissues. Chromosome 18 Loci Loss Gain Image 1. NIPT genomic traces for chromosome 18 show an 11.6 Mb terminal deletion at 18p11.21. Chromosome 18 Loci Loss Gain Image 1. Sex chromosome data plot shows a reduction in X chromosome representation with minimal Y material Chromosome X representation Chromosome Y representation X case 2 Distribution of sex chromosome X and Y representations: The colored zones demarcate different representation levels. The green and magenta regions have very low or no Y chromosome representation and an under or over representation of chromosome X respectively. Purple and turquoise regions represent normal female and male respectively. Blue and yellow regions show male and females with overrepresentation of chromosome Y respectively. case 1 case 2 case 3 case 4 Gestational age 19 weeks 13 weeks 14 weeks 20 weeks MaterniT21 Plus® result Trisomy 13, Female Negative, Inconclusive Sex Determination* Negative, Male Non-Reportable* Z Score Z13 = 12.10 ZX = -7.81 Z18 = 0.90 Z18 = -7.17 High risk indication Positive biochemical screen Abnormal ultrasound Abnormal ultrasound Positive biochemical screen Amniocentesis diagnostic testing results (FISH, Karyotype, Microarray) N/A 45,X,-Y[8]/46,X,r(Y)[7] 46,XY,r(18) Normal FISH Results 45,XX,-18[8]/46,XX,r(18)[4]/46,XX[8] 11.9 Mb loss at 18p11.32p11.21 Postnatal blood results 47,XX,+r(13) N/A N/A N/A Parental studies Both mother and father's chromosomes were normal N/A Maternal aCGH confirmed a 773Kb interstitial deletion at 18q22.1 N/A Rings and things: Noninvasive prenatal testing's unique view of the biology and embryology behind chromosomal ring formation and segregation 31-41505R1.0_0315 BacKGROUND Noninvasive prenatal testing (NIPT) relies on the presence of circulating cell-free DNA believed to be largely placental trophoblast in origin. The early embryologic origin of this tissue allows a unique glimpse into the timing of post- zygotic, de novo chromosomal events. Here we review four cases involving de novo fetal ring chromosomes and relate their unique NIPT findings to a variety of clinical outcomes. DiscUssiON & cONclUsiONs Chromosomal rings are uncommon karyotypic anomalies that are both technically and clinically complex. Ring structures are typically de novo in origin and often accompanied by mosaicism, which makes for challenging interpretation of prenatal testing and prognoses. Rings greatly disrupt the mechanics of cell division. The consequence of entangled, broken, doubled, or otherwise disrupted rings following sister chromatid exchange lends to complex, mosaic karyotypes. These cases describe four pregnancies initially screened with NIPT and later confirmed to have a variety of ring chromosomes. The impact on NIPT results was highly variable, presumably due to each case's unique timing and 'location' of ring formation during embryogenesis. Early ring formation is postulated in cases 1, 2, and 4, as NIPT traces show clear evidence of genomic imbalance. Mosaicism due to ring loss or possible rescue event was clearly evident in Case 2. Alternatively, Case 3 is presumed to have been a relatively later mitotic event, given the lack of NIPT trace evidence and presence of a corresponding maternal deletion proposed to have led to chromosome fragility during mitosis. This case only came to our attention after the provider alerted us to the amniocentesis findings. The emerging contribution of NIPT genomic data offers a unique view into the earliest forming layer of placenta (trophoblast). Providing a snapshot in an embryology timeline, NIPT can assist with deciphering the timing and origin of complex de novo events such as ring chromosomes. This invaluable insight can help explain chromosomal inconsistencies that result among tissue types, screening tests, and diagnostic technologies. Clinicians need to be mindful of the biological strengths and limitations of NIPT, especially in regard to chromosomal mosaicism and complex structural rearrangements. Such awareness is invaluable when presented with seemingly discrepant prenatal results and promotes accurate clinical assessment, counseling, and overall case interpretation. Furthermore, clinicians should also be aware of NIPT's ability to identify maternal subchromosomal abnormalities. Accurate clinical information provided to the laboratory may aid in additional interpretation. Theresa Boomer 1 , Judy Fisher Newell 2 , Patricia Santiago-Munoz 2 , Christina Settler 1 , Michelle N Strecker 3 , Jenna Wardrop 1 , Julie Jesiolowski 4 , Ron McCullough 1 , Juan-Sebastian Saldivar 1 , William B Paxton 1 , Thomas Monroe 4 , Nilesh Dharajiya 1 1 Sequenom Laboratories™, San Diego, CA ; 2 University of Texas Southwestern Medical Center, Department of Obstetrics and Gynecology, Dallas, TX; 3 Combimatrix, Irvine, CA; 4 Sequenom Laboratories™, Morrisville, NC RefeReNces 1. Editors McKinley Gardner RJ, Sutherland GR. Chromosome abnormalities and genetic counseling. Oxford: Oxford University Press (3rd edn.) 2003:25, 392-432. ISBN 0 195 14960 2 (hardback). Table 1. *Laboratory Director call accompanied release of result due to complex findings. CASE 3 CASE 2 CASE 4

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