Recurrent Pregnancy Loss: The Genetic Workup Beyond a Karyotype

One of the hardest parts of recurrent pregnancy loss is the phrase "everything came back normal." You have done the bloodwork, the imaging, maybe a karyotype, and you still have no answer. No cause, no plan, just the suggestion to try again.

That experience is common, and it does not mean the testing failed you. It often means the standard workup looked carefully in the places it is designed to look — and a genetic cause, if there is one, can sit outside those places.

What "recurrent" means, and how often a cause is found

Professional groups generally define recurrent pregnancy loss as two or more pregnancy losses. The hard truth from that same guidance is that even after a thorough evaluation, roughly half of couples never receive a clear explanation (ACOG). "Unexplained" is one of the most common findings in this field, not a sign that something was overlooked.

What the standard workup checks

A typical recurrent-loss evaluation looks across several systems, one at a time. Each part answers a different, specific question.

Where a karyotype stops

Start with the karyotype, because it is offered for a concrete reason. In roughly 2 to 5% of couples with recurrent loss, one partner carries a balanced structural rearrangement — most often a translocation, where pieces of two chromosomes have swapped places (ASRM, 2026). That parent is healthy and usually has no idea, but embryos can inherit an unbalanced amount of chromosome material, which often ends in loss. A karyotype is built to catch exactly this, which is why it is worth doing.

Two things are easy to miss about that, though. First, it is an uncommon cause — those few percent leave most couples without an answer. Second, a karyotype reads the large-scale structure of chromosomes; it does not read the individual genes inside them. Standard carrier screening has its own blind spot: it checks whether you carry well-known recessive conditions like cystic fibrosis, aimed at conditions in a future child, not at the genes that govern whether a pregnancy continues in the first place.

Between "the chromosomes look structurally fine" and "you are not a carrier for these recessive conditions" sits a layer of single-gene factors tied directly to early development and pregnancy maintenance. The standard workup steps right over that gap. The newer finding is how much may be hiding there, beyond the few percent a karyotype was built to catch.

The newer finding: one in four in unexplained euploid loss

In a 2025 genome-sequencing study of 118 families with unexplained recurrent euploid loss, researchers found a single-gene cause in about one in four — 25.4%, or 30 of 118 families (Aminbeidokhti et al., medRxiv, 2025; preprint). About 83% of those causes were inherited from one or both parents — the kind of variant parental screening is positioned to find.

Researchers have also studied "maternal-effect" genes such as TUBB8, NLRP7, and PADI6 that act in the earliest steps of development. Variants in genes like these have been linked to developmental arrest and pregnancy loss.

Putting the two numbers together: why they don't simply subtract

It is tempting to line up "2 to 5%" against "one in four" and conclude that genetics suddenly explains far more loss than anyone thought. But that math does not work, because the two numbers are measured over different groups of couples.

So the point is not that the karyotype was wrong. It answered its question well and ruled itself out for most couples. In doing so, it pointed at a different layer — single-gene factors in unexplained euploid loss — where newer research suggests more may be hiding.

Where Reticular fits

If this describes your situation — a workup that came back unexplained, with the karyotype and carrier screening both clear — the layer it points at is exactly what reproductive-gene screening looks at. Reticular's screening reviews both partners for variants in a panel of genes tied to embryo viability and pregnancy loss, a different question from a karyotype or standard carrier screening. It does not require embryo data, so it can be used while trying to conceive or alongside IVF, and counseling is included so a finding is explained before you have to act on it.

Two honest limits keep this in proportion. It will not explain every loss — no genetic test can — and a finding is not a diagnosis. It is one more place to look, aimed at the gap the standard workup steps over. Here is what is worth raising with your own clinic: which parts of the workup are still open, what the karyotype and carrier screening did and did not cover, whether screening both partners is reasonable given your history and what a result would actually change, and whether a genetic counselor should help you weigh it. If your losses involved chromosomally normal embryos specifically, the companion piece When a Euploid Embryo Doesn't Make It goes deeper on that situation.

Where this leaves you

Taken together, this does not give you a final answer — it gives you a better question to ask. The standard workup is thorough within its scope, the karyotype rules out a structural cause for most couples, and the newer data suggests single-gene factors may sit in the gap it leaves. The two numbers describe different groups, so they do not cancel out.

"Unexplained" is an honest answer, not a closed door. Looking into that gap will not give every couple a cause. For some, it offers one more avenue when the usual tests have run out — and a clearer basis for the next decision, made with a clinician rather than in the dark.