Table 1.
Evidence from recent EQAs by GenQA of fading competence of laboratories for clinical genetics in recognizing and interpreting cytogenetic abnormalities.
| EQA, year | Referral reason | Expected resulta as validated by multiple, independent assessors | Recurrent error | Number of-participants and % who made the recurrent error | Base line % of poor performanceb | Clinical consequences of error |
|---|---|---|---|---|---|---|
| Postnatal bloods, 2016 | Infertile male, hypogonadism | 46,X,idic(Y)(q11.?12)[17]/45,X[13].ish idic(Y)(SRY++) | Interpretation of idic(Y) as a structurally normal Y chromosome | 48 out of 164 (29.3%) | 1.7% | Whereas the absence of the AZF genes on Yq would have been detected by DNA studies, the clinical management of a patient with 45,X/46,XY mosaicism is different to that of a 46,X,idic(Y)/45,X male patient |
| Molecular Rapid Aneuploidy in CVS, 2018 | Combined screening risk of 1 in 150 for tri-13 or tri-18; no ultrasound abnormalities | ~60% trisomy 13 mosaicism | Failure to recognize that the sample was mosaic for trisomy 13 | 21 out of 110 (19.1%) | 1.7% | Failure to instigate appropriate follow-up by amniocentesis to assess the foetal karyotype |
| Failure to recognize that the trisomy could be confined to the placenta | 19 out of 110 (17.3%) | 0.3% | Potential termination of a pregnancy with a chromosomally normal foetus | |||
| Postnatal bloods, 2019 | Microarray shows 3q29 gain in proband; mother has the corresponding balanced translocation t(3;15)(q29;q11.1) | 47,XY,+der(15)t(3;15)(q29;q11.1) | Not recognizing the supernumerary chromosome as +der(15)t(3;15) or mislabelling it as +der(3) or +rec(3) | 6 out of 169 (3.5%) | 1.7% | Failure to recognize that +der(15)t(3;15) results from a 3:1 maternal segregation, thereby providing an erroneous basis for future pregnancies with respect to the recurrence risk and the need for studying other family members at risk |
| Myeloid (AML/MDS/CML), 2019 | Acute myeloid leukemia | 48,XX,+8,t(9;11)(p21;q23),+14[15].nuc ish(KMT2Ax2)(5´KMT2A sep 3´KMT2Ax1)[150] | Missing the translocation t(9;11)(p21;q23) that was visible in G-banded metaphases | 12 out of 111 (10.8%) | 3.7% | failure to provide the right information for patient management to clinician |
| Identifying an 11q abnormality by KMT2A FISH but not relating this to the translocation t(9;11)(p21;q23) | 7 out of 111 (6.3%) | 2.5% | failure to provide the right information for patient management to clinician |
aThe SRY and KMT2A probes used for FISH in these examples were from a commercial supplier and only approximate genomic coordinates for these probes can be given. Whereas this may represent an undesired situation with respect to the inclusion of HGVS nomenclature (Human Genome Variation Society, see varnomen.hgvs.org) in the expected results of these EQAs, these probes have been validated for specific diagnostic applications and can, therefore, be reliably used in the clinical setting for detecting whether SRY is present, and whether there is a break in KMT2A, respectively. Commercially available tests for Rapid Molecular Aneuploidy testing are based on specified, highly polymorphic short tandem repeat loci, each with a defined and unique position that is known to the users. Although the positions of the PCR primers may be known only to the manufacturer, these tests have also been validated for this specific diagnostic purpose.
bFor comparison, base line percentages of poor performance are shown for 2015–2019, as determined by excluding the recurrent errors mentioned in this table; also poor performance as a result of non-submission of results was excluded.