Description

Carrier screening core panel analyses 19 genes associated with genetic diseases of high incidence and severity in individuals with unknown carrier status.

Genes tested

ACADM, ASPA, BLM, CFTR, DHCR7, DMD, ELP1, FANCC, GALT,  GBA, GJB2, GJB6, HBA1, HBA2, HBB, HEXA, MCOLN1, PAH, SMPD1

Technical specifications

• DMD: Deletion/Duplication analysis at single exon resolution is not offered for NM_004006.3 (DMD): exon 1, exon 2, exon 23, exon 25, exon 26, exon 27, exon 28, exon 31, exon 33, exon 34, exon 35, exon 36, exon 38, exon 39, exon 40, exon 41, exon 42, exon 54, exon 58, exon 60, exon 67, exon 69, exon 71, exon 72, exon 73, exon 75, exon 77, exon 78.
• HBA1/2: the assay is designed to detect deletions and duplications of HBA1 and HBA2. All positive copy number variations (CNVs) are confirmed using an orthogonal method. The test does not distinguish among the different HBA types of deletions/duplications, and any variant identified will be called as HBA loss/gain.
• Genomic regions not covered by this test:
  • NM_020533.3 (MCOLN1): exon 1
  • NM_004006.3 (DMD): exon 23

Technical limitations

The test aims to detect all variants relevant to the genes listed above by targeting all coding exons of MANE and/or canonical transcripts, and 12 bp of adjacent intronic sequence. Variants that fall outside the targeted regions are not intended to be detected by this assay. Unless otherwise noted, sequence changes (SNVs and INDELs) in promoter and other non-coding regions are not covered by this assay. Certain sequence changes (SNVs and INDELs) in non-coding regions of selected genes that are of clinical significance are also included in the analysis. In cases where two variants are identified in a gene, the test does not distinguish whether these are on one chromosome (in cis) or on different chromosomes (in trans). Certain types of genetic abnormalities, such as inversions, rearrangements, polyploidy and epigenetic effects, are not covered by this test. Certain sequence changes (SNVs and INDELs) in targeted regions containing repeats, sequences of high homology such as segmental duplications and pseudogenes, as well as regions of high or low GC content, may not be detected.

Copy number variants (CNVs) are identified using high-quality, de-duplicated and uniquely aligned sequencing reads. CNVs are detected in a subset of the targeted regions using a depth-of-coverage approach, with GC-content normalisation applied. Genomic regions are called as variants if their normalised depth of coverage deviates significantly from the expected normalised coverage, which is estimated from a set of reference clinical samples. The test can detect CNVs down to a resolution of a few exons. The test cannot detect CNVs in genomic regions with either low mappability or repeats, pseudogenes, and high or low GC content. Detection of CNVs using NGS has lower sensitivity and specificity than orthogonal quantification methods; therefore, the absence of reported CNVs does not guarantee their absence.

The absence of disease-causing variants in the targeted genes reduces, but does not exclude, the possibility of an associated genetic syndrome. Although the test is highly accurate, there remains a possibility of false-positive or false-negative results.