What a negative carrier panel does and does not rule out
Carrier screening tests the parents. A brand new change in the baby is, by definition, not in either parent.
Carrier screening looks at you, and sometimes at your partner, for gene changes that would not affect you but could affect a child if both parents carried the same one. A negative result is often heard as a clean bill of genetic health. It is not that.
First, how much a wide panel adds. A modelling study of 346,790 people screened for up to 94 severe or profound conditions estimated how many hypothetical babies would be affected, per 100,000. For couples of Northern European background the figure was 159.2 with the wide panel, against 55.2 with the shorter guideline-based panels. For Ashkenazi Jewish couples it was 392.2, and for Hispanic couples 94.5. The study defines its terms: Severe conditions were defined as those that if left untreated cause intellectual disability or a substantially shortened lifespan; profound conditions were those causing both.
Two things to hold onto. Even at the very top of that range, 392.2 per 100,000 is about 0.39%, against a background rate of major birth defects of roughly 3%. And this was a modelling exercise about hypothetical pairings, not a count of real affected babies; the authors themselves say prospective studies are needed.
The maximum risk reduction for couples who were not related to each other was up to 5.1%. For related couples it was up to 43.5%.
Read that again. In families who actually had an affected child, screening thousands of genes could in principle have addressed about one twentieth of the risk. Roughly 95% of it was not reachable by carrier screening at all.
Part of the reason is structural. Carrier screening tests parents. A new mutation, one that arises in the egg, the sperm or the early embryo, is by definition not present in either parent. No panel of any size can find it in advance.
How much weight does that category carry? A study of 4,293 families with a child with a developmental disorder estimated: We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences…
And: We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age.
That is the authors' own estimate, with a wide range, extrapolated from a severely affected group of families, and it is UK-led rather than US. It should be read as an estimate, not as a measured population rate.
"If this comes back negative, what is left that it cannot see?"
"Does this test say anything at all about a new change in the baby?"