Meeting the challenge of interpreting high‐resolution single nucleotide polymorphism array data in prenatal diagnosis: does increased diagnostic power outweigh the dilemma of rare variants?

Abstract

Objective Several studies have already shown the superiority of chromosomal microarray analysis (CMA) compared with conventional karyotyping for prenatal investigation of fetal ultrasound abnormality. This study used very high‐resolution single nucleotide polymorphism (SNP) arrays to determine the impact on detection rates of all clinical categories of copy number variations (CNVs), and address the issue of interpreting and communicating findings of uncertain or unknown clinical significance, which are to be expected at higher frequency when using very high‐resolution CMA. Design Prospective validation study. Setting Tertiary clinical genetics centre. Population Women referred for further investigation of fetal ultrasound anomaly. Methods We prospectively tested 104 prenatal samples using both conventional karyotyping and high‐resolution arrays. Main outcome measures The detection rates for each clinical category of CNV. Results Unequivocal pathogenic CNVs were found in six cases, including one with uniparental disomy (paternal UPD 14). A further four cases had a ‘likely pathogenic’ finding. Overall, CMA improved the detection of ‘pathogenic’ and ‘likely pathogenic’ abnormalities from 2.9% (3/104) to 9.6% (10/104). CNVs of ‘unknown’ clinical significance that presented interpretational difficulties beyond results from parental investigations were detected in 6.7% (7/104) of samples. Conclusions Increased detection sensitivity appears to be the main benefit of high‐resolution CMA. Despite this, in this cohort there was no significant benefit in terms of improving detection of small pathogenic CNVs. A potential disadvantage is the high detection rate of CNVs of ‘unknown’ clinical significance. These findings emphasise the importance of establishing an evidence‐based policy for the interpretation and reporting of CNVs, and the need to provide appropriate pre‐ and post‐test counselling.

Genomic Alterations Are Enhanced in Placentas from Pregnancies with Fetal Growth Restriction and Preeclampsia: Preliminary Results

“…CMA analyses enable focusing on gene alterations that are below the detectable levels of known genetic abnormalities [Kearney et al, 2011;Ganesamoorthy et al, 2013]. CMA analysis in the current study revealed heterogenic genetic changes.…”

“…Advances in microarray technology allow high-resolution, genome-wide evaluation of DNA copy number variations (CNVs) -both deletions and duplicationsand opens new directions for research connecting genetics to abnormal placentation [Founds et al, 2009;Ganesamoorthy et al, 2013;Madeleneau et al, 2015;Rabaglino et al, 2015]. It is a significant tool for identifying genomic alterations leading to diseases.…”

Dilemmas in Prenatal Chromosomal Diagnosis Revealed Through a Single Center's 30 Years' Experience and 90,000 Cases

“…Indeed, we also observed CNV's representing known and well-documented polymorphisms or inherited benign/low risk variants for which counseling is relatively straightforward, while in our series we did not come across any (un-interpretable) variants of unknown clinical significance. This is in contrast, however, with the multitude of VOUS detected by higher resolution aCGH platforms, with figures ranging from 1-4% [48,50,51], necessitating parental follow-up studies and complicated genetic counseling and perhaps these drawbacks cannot be offset by the slightly higher detection rate.…”

Chromosomal Microarrays in Prenatal Diagnosis: Time for a Change of Policy?

“…A positive correlation between array resolution and the detection rate of pathogenic CNVs as well as of VOUS is likely and not unexpected [39,40]. Srebniak et al [41] have demonstrated this by retrospectively reassessing high resolution genome-wide array data of 456 fetuses at different resolution levels.…”