News About Reproductive and General Genetics: Germline Variant Identification, the Ongoing PGT-A Saga, and PGT-P
Today’s posting addresses news topics regarding reproductive and general genetics. From the questionable marketing of polygenic risk screening of embryos to the potential use of germline variant identification when flagging cancer risk in pediatric patients, these updates will keep you in the loop on some of the most pressing issues in the reproductive medicine — and general medicine — fields today. As always, we welcome comments from our readers.
The CHR’s Editorial Staff
Identifying Increased Elevated Cancer Risk in Pediatric Patients Through Germline Variant Identification
Chinese investigators now in an article in Nature Medicine confirmed that cancer risk and tumor characteristics could be identified in children with pathogenic germline variants, - thus providing information for genetic counseling and early preventative measures.1 The study was performed using 2016-2025 data from a large genomic analysis of 75,602 children, assessing variations across 139 pediatric cancer-predisposition genes in relation to their tumor outcomes, - among those 203 tumors that were already present at the time of initial genetic testing, 97 malignant. Such preexisting tumors included Wilms tumors, retinoblastoma, neuroblastoma, and hepatoblastomas, as well as 106 benign tumors, mostly teratomas, hamartomas, and neurofibromas. In a follow-up cohort of 75,399 children initially tumor-free, P/LP germline variants were detected in 1.9%. Longitudinal follow-up of these children showed that in 85.15% of these children (n=64,187), 208 new tumor diagnoses were made.
These findings support the notion that pathological germline variants found in children are not innocent incidental findings, but can and should be used for subsequent genetic counseling, risk advice, and fitting clinical surveillance for these children. The paper was also accompanied by a Research Briefing that summarized these findings.2
REFERENCES
Dong X, Zhang K. Nat Med 2026;32:2238-2244:
Wang et al., Nat Med 2026;32:1991
And the Continuing Saga of Preimplantation Genetic Testing for Aneuploidy (PGT-A)
MOSAICISM IN PGT-A -- And in another study by Chinese investigators, the discussion continues, - though, unfortunately, under continuing incorrect ground rules, starting with the use of the term “mosaicism” for the “diagnosis” being made based on the presence of more than one DNA cell lineage being detected in an on-average 5-6-cell trophectoderm biopsy, while the correct definition of the term “mosaicism” is detection of more than one cell lineage in a complete organism derived from a single cell. In the case of PGT-A, this, therefore, should mean detection of a second cell lineage in any of the cells of a blastocyst-stage embryo.
With this basic definition of “mosaicism” not followed, the here-presented retrospective data analysis is already defined as incorrect and, consequently, we are again presented with data defining a medical diagnosis (“mosaicism”) in an incorrectly selected patient population that renders the study basically worthless because the study population is to an unknown degree contaminated by embryos that in reality are not “mosaic.”
The results of the study, described by the authors as “segmental and chromosomal monosomy mosaic embryos having pregnancy outcomes comparable with euploid embryos, whereas chromosomal trisomy mosaic embryos are associated with significantly poorer outcomes,” are, therefore, biased and incorrect.
IMPACT OF NUMBER OF BIOPSIED CELLS -- And a third study from Chinese investigators – this time in Reproductive Medicine Online – in a row investigated the impact of the number of biopsied trophectoderm cells on the “quality” of PGT-A.2
Once again, we see here a paper that made it into the press with authors, reviewers, and editors missing an essential design flaw, - in this case, a power analysis between range in the number of biopsied trophectoderm cells in relationship to total number of cells a biopsied embryo has at the moment of biopsy. And this failure does not even consider the fact that it is technically impossible to know the exact number of cells biopsied. In other words: a study design that biologically and statistically has no chance of offering a valid result. No wonder they were unable to demonstrate an outcome difference based on alleged cell numbers biopsied!
REPORT ON THE PGDIS TASK GROUP ON THE STATUS OF PGT-A -- And one more disappointing paper in Reproductive Biomedicine Online, this time by several prominent PGT-A proponents associated with the Preimplantation Genetic Diagnosis International Society (PGDIS), which for too long has been “poisoning” IVF practice with misleading published guidelines, which IVF practice, unfortunately, has been mostly following.3
The CHR’s investigators and some other members of the International Do No Harm Group in IVF (DNHG-IVF) submitted a detailed rebuttal article to the journal, which is currently under peer review. We, therefore, cannot go into further detail here but strongly encourage our readers to look for this article and consider it critically.
REFERENCES
Jin et al., Fertil Steril 2026;125(5):786-795
Kung et al., Reprod Biomed Online 2026;52(5):105407.
Leigh et al., Reprod Biomed Online 2026; 52(6): 105498
And That Also Applies to Polygenic Risk Screening of Embryos (PGT-P)
If the almost universal utilization of PGT-A in IVF by many IVF clinics is already an unprecedented shame for IVF practice, - the marketing of PGT-P by several genetic testing laboratories and IVF clinics goes even beyond that. Two colleagues from the University of Pennsylvania are, therefore, to be congratulated for an Inkling article in Fertility and Sterility (F&S) – yes, an Inkling article. While we dislike most Inkling articles, some are exceptions, and this is one of those – because the article describes the marketing “hype” surrounding PGT-P well.1
The authors correctly argue that enthusiasm for PGT-P is moving faster than the scientific evidence supporting it. They caution fertility clinics against offering the technology routinely before its clinical value, accuracy, and ethical implications are properly established. They correctly point out the following concerns: (i) Limited predictive accuracy: Polygenic scores are imperfect and often do not translate reliably from population studies to individual embryos. Small differences between embryos may not be clinically meaningful. (ii) Lack of validated clinical benefit: There is currently insufficient evidence showing that selecting embryos using PGT-P leads to healthier children or better long-term outcomes. (iii) Risk of misleading patients: The marketing may create unrealistic expectations that embryos can be optimized or that disease risk can be substantially eliminated, when in reality genetics is only one contributor to complex disease, and, indeed, contributes only a relative minority of predisposition. (iv) Ethical and social concerns: The authors warn about possible expansion toward non-medical trait selection and broader societal concerns around “designer babies,” inequity, and discrimination. (v) Need for oversight and research: They advocate for cautious use only within research settings until safety, effectiveness, and ethical standards are better established.
We totally agree with points (i) through (iv), but must disagree with point (v), probably - we assume - just added out of courtesy (which we, of course, don’t possess) because they do point out in their point (iii) that genetics contributes only a minority of every phenotype, with a majority determined by environmental factors in utero and after birth. Biology, therefore, completely contradicts the concept of PGT-P, - even more so than for PGT-A.
Congratulations to the authors, reviewers, and editors of F&S for publishing this Inkling article!
REFERENCE
Dokras P, Gracia C. Fertil Steril 2026; 125(5):784-785