CNVs type in patients with clinically significant CNVs and patients with CNVs of unknown clinical significance.

<p>CNVs type in patients with clinically significant CNVs and patients with CNVs of unknown clinical significance.</p

Management recommendations for clinically significant CNVs and recommendation according to the level of evidence.

<p>Abbreviations: MCA = Multiple Congenital Anomalies; DD = Developmental Delay; ASD = Autism Spectrum Disorders; Dys = Dysmorphism; UCS = Uncertain Clinical Significance.</p><p>Abbreviations: S = Surveillance; R =  specialist Referral/assessment; D = Diagnostic testing; P = medical/surgical Procedure; M = Medication administration; L = Lifestyle recommendation; O = Other interventions.</p><p>* = pathogenic CNVs, ∧ = likely pathogenic CNVs.</p><p>N = not tested; Mat  =  maternal inheritance; Pat  =  paternal inheritance.</p><p>Management recommendations for clinically significant CNVs and recommendation according to the level of evidence.</p

Diagnostic sensitivity for the detection of a 3 Mb microdeletion/microduplication.

<p>The diagnostic sensitivity for detecting the aberration is plotted against the fetal DNA percentage. The computer simulation analysis was performed assuming that a total of 150 million plasma DNA molecules were analyzed.</p

The fetal DNA percentage estimated by the alterations of the genomic representation of the regions affected by microdeletion/microduplication, and the proportions of chromosome Y sequences in the maternal plasma.

a<p>The chr Y approach is only applicable for those cases with a male fetus.</p>b<p>For case 05, as the mother also carried the aberration, the genomic representation of the affected region in the maternal plasma could not be used to determine the fetal DNA percentage.</p>c<p>The former and latter figures represent the fetal DNA percentage estimated from the microduplication on chromosome 3 and the microdeletion on chromosome 4, respectively.</p

Sample information.

<p>Sample information.</p

Copy number aberrations detected in maternal plasma.

<p>The chromosome(s) showing copy number aberrations for each case is shown. (A) Cases 01 to 04; (B) case 05; and (C) case 06. The genomic position is shown on the x-axis and the z-score is plotted on the y-axis. Each vertical bar represents a 1-Mb bin. Regions with three or more consecutive 1-Mb bins of increased or reduced representation in plasma are indicated by green and red bars, respectively.</p

Number of molecules required to be sequenced and aligned to achieve different diagnostic resolutions and diagnostic sensitivities assuming that the fetal DNA percentage is 5%^a.

a<p>In this theoretical analysis, the diagnostic specificity is >99.9% for all cases based on the criteria that three consecutive bins having genomic representations >3SD (for either over- or underrepresentation) from the mean of the references in the same direction.</p

Circos plot of the detected copy number aberrations across the genome in maternal plasma.

<p>From inside to outside: cases 01 to 06. Chromosome ideograms (outermost ring) are oriented pter to qter in a clockwise direction. Each bar represents a 1-Mb window. Regions with three or more consecutive 1-Mb bins of increased or reduced representation in plasma are indicated by green and red bars, respectively. Red arrows highlight the approximate chromosomal locations on these aberrant regions.</p

Clinically significant CNVs other than common aneuploidies detected in the first-tier test study which were not detected by karyotyping.

<p>AF: amniotic fluid; ASD: atrial septal defect; CV: chorionic villi; DCDA: dichorionic diamniotic; DS: Down syndrome screening; FB: fetal blood; Gest: Gestation; IUGR: intrauterine growth restriction; PPROM: preterm premature rupture of membranes; TOP: termination of pregnancy; USS: ultrasound scan findings; w: weeks; +ve: positive.</p

Proposed workflow for replacing karyotyping with aCGH in prenatal testing in Hong Kong.

<p>Pregnancies with Down syndrome screening positive without ultrasound abnormalities can be subjected to non-invasive prenatal testing; while pregnancies with Down syndrome screening positive in the presence of ultrasound abnormalities can be subjected to invasive test by QF-PCR to exclude common aneuploidy and maternal contamination, followed by aCGH as shown. aCGH, array CGH; DS+ve, Down syndrome screening positive; FISH, fluorescent in-situ hybridization; NIPT, non-invasive prenatal testing; QF-PCR, quantitative fluorescent-polymerase chain reaction for common aneuploidy detection.</p