False negative fetal cell free DNA screening for microdeletion syndromes in the presence of an unbalanced translocation involving monosomy 4p

Abstract

What's Already Known About This Topic? Aneuploidy screening using cell‐free DNA has recently been expanded to include selected microdeletion syndromes. However, real‐world performance characteristics for the majority of these variants remain unknown. Many primary obstetric providers are unaware of performance limitations and appropriate clinical contexts for ordering these assays. What Does This Study Add? Cell‐free DNA screening using a commercial platform designed to detect chromosomal microdeletions can lead to false negative results, even in the case of a pregnancy at known high risk because of a previous child with 4p‐ syndrome and a paternal translocation carrier. This finding underscores the need for clinician education about the limitations of such testing, the utility of invasive diagnostic testing in similar high‐risk pregnancies, and additional validation of cell‐free DNA assays for microdeletions before further expansion into routine practice.

Genome-wide noninvasive prenatal screening for carriers of balanced reciprocal translocations

“…A previous report noted the failure of NIPS to detect an unbalanced translocation from a known carrier that caused Wolf-Hirschhorn (4p-) syndrome. 38 In this case NIPS was requested with a microdeletion screening panel that included 4p-. The testing laboratory was not informed of the parental translocation and a false negative result for 4p-was returned.…”

Current controversies in prenatal diagnosis 2: Cell‐free DNA prenatal screening should be used to identify all chromosome abnormalities

“…Using the evidence currently available and considering those studies where all cases had CMA, sensitivity ranges from 61% to 97.7% overall for the group of selected microdeletion syndromes tested, but when considering those cases with CNVs <5 Mb, the sensitivity decreases to 14% to 20% (Table ). In 1 case reported recently in a pregnancy at high risk of a large imbalance, cfDNA testing failed to detect this in the fetus . This family had a son with Wolf‐Hirschhorn syndrome, and the father was a known carrier of a balanced 4:8 translocation.…”

“…An 8.9‐Mb deletion of 4pter and a 7‐Mb duplication of 8pter were found with amniocentesis. The cfDNA results were reviewed by the company with knowledge of outcome but found “insufficient evidence of any loss at 4pter,” although this was a relatively large microdeletion that should have been detected as it was included on the panel being used! Thus, the evidence regarding sensitivity for microdeletions is poor and suggests low detection rates, and, as demonstrated above, the largely targeted analyses available will not detect 75% of pathogenic CNVs.…”

“…In 1 case reported recently in a pregnancy at high risk of a large imbalance, cfDNA testing failed to detect this in the fetus. 21 This family had a son with Wolf-Hirschhorn syndrome, and the father was a known carrier of a balanced 4:8 translocation.…”

False Negative Results in Prenatal Aneuploidy Invasive Testing: Two Case Reports

“…While false-negative and false-positive, non-invasive prenatal testing results are the subject of intense interest [4][5][6], false-negative BOBs, CMA, or other quantitative molecular technologies results are rarely reported in the literature. It is important to be aware of the limitations of these assays to provide the most accurate information and the best care to expecting parents.…”