With as rare as the specific mutation Indi had is, would that have been able to be diagnosed prenatally? I know genetic screening has gotten a lot cheaper and easier in the past decade, but would such a rare condition be able to be screened for before birth?
It's possible, but not likely, especially for a first pregnancy with no relevant family history. People think of genetic testing as a monolith, but there are multiple methods for identifying mutations. This is an excellent
explanation from the United States National Institutes of Health, but in short, it's extremely costly and onerous to screen a person's entire genome for a mutation, and most of the genetic testing conducted is not comprehensive.
The most common initial strategy is testing for mutations in a single gene or group of genes of interest. Of course, this requires that the clinician have some idea of what the problem is. For example, a child with drug-resistant seizures might be tested for a mutation in several genes known to be associated with childhood-onset intractable epilepsy, or a newborn with multiple congenital anomalies suggestive of a particular syndrome might be tested for a mutation only in the causative gene. Without actual evidence to point the way, it's tantamount to a wild goose chase, especially considering how exceedingly rare a disorder such as
combined D2/L2 hydroxyglutaric aciduria is, with fewer than 150 cases
ever reported in the world. I would wager that the vast majority of family physicians or even pediatricians have likely never heard of it, and it would almost certainly not have been on their radar even once the seizures manifested. Even if there were concerns prior to Indi's birth, it would be quite extraordinary for anyone to initiate the kind of testing needed to identify such an incredibly rare disorder. Medical students are taught to think horses instead of zebras for a reason.
If single gene or panel testing results are negative, more comprehensive testing may be done, which I assume is how Indi was diagnosed. The available evidence suggests that D2/L2AD is inherited in an autosomal recessive manner, which just means that a proband must inherit two mutated copies of the
SLC25A1 gene, one from each parent, in order to be affected. Each time Indi's parents conceive, they have a 25% chance of producing an affected offspring with mutations in both copies of the gene, a 25% chance of producing a healthy non-carrier with two normal copies, and a 50% chance of producing an asymptomatic carrier with one mutated copy and one normal copy.
Because the disorder and its causative mutation have now been identified, should Indi's parents choose to have another child, it will be much simpler to test subsequent pregnancies. Really, this is one of the cruelest things about devastating genetic disorders. Sometimes, it takes losing a child to save the ones who come after from immense suffering.