Scott D. McLean, MD

My gap-year transit continues across space and time, looping from the nebulae of clinical medicine to the dense gravities of a writing world and back again, rife with principles of uncertainty.

Yesterday I learned that some of our work on holoprosencephaly will soon be published in Genetics in Medicine. Huzzah! I’m not sure what can be shared just now, as various details still need to be arranged – copyright options, press release, proofs, typesetting, copy editing, champagne, plaudits, dancing the jig. These are not for me, but I’ll try the jig. I am well behind the peloton as a minor contributor, author #19 out of 41, well pleased to draft behind one of our genetic counselors, Emily Magness (MS, CGC), who did work while I played Words With Friends. The lead and senior authors are French, and they have the enviable tasks – to sort out the logistical details, bask in glory, and respond to letters to the editor. The other contributors are American, French, Dutch, Turkish, Saudi, Singaporean, German, and Indian. Congratulations to you all!

Why so many authors? Genetics is complicated. OK? Why, you ask? Because it’s genetics. I think we can get away with this hand waving for a few more months, until everyone give us that look and mutters, “It’s only genetics. C’mon.”

Emily and I contributed as gene hunters. Yes, that does sound suspiciously like bounty hunters! Don’t be judgy. Despite what you see on TikTok and NetFlix, the reality of gene discovery is messy. Like cinnamon buns with extra icing but without plates, forks, tongs, or 6 napkins. Yum. Let me tell you how it all played out.

In late 2015 I saw a 4-month-old girl with seizures and slow development, hypotelorism, and an absent nasal bridge. The brain MRI showed holoprosencephaly. (The abbreviation – HPE – is easier to pronounce and remember.) She needed help, and while her neurologist treated the epilepsy, we in genetics took on the job of trying to understand what might be the cause, as that answer might be the key to treatment, at least to answers for the family. Several types of genetic tests found a few items that looked cattywampus, but not enough to claim Eureka. One semi-mysterious gene looked interesting, and we submitted its particulars to a free clearinghouse called GeneMatcher. This put us into a small group of fellow searchers who were interested in this gene, in particular whether misspellings and grammatical errors of the gene might be the cause of birth defects and neurologic problems.

Did this go according to plan? Heavens to Betsy. No. Some experts weighed in and opined that this gene was weak sauce. The inheritance patterns were not clear. Years passed. The phenotypes did not seem uniform. We lost track of our patient.

This seemed like a dead end.

But not so much.

Almost exactly 2 years ago we saw another patient in the NICU with a midline cleft lip and palate, hypotelorism, and HPE. Exome sequencing within a few weeks showed that the same gene was lookin’ cattywampus agin. This time, there was no hesitation about what to do, no shuffling of feet, no hemming and hawing. We knew the players, who was taking the lead, where the chips might fall, and who was mixing the metaphors. (Me)

The manuscript describing this HPE gene is of the highest quality. 23 pathogenic variants were identified in 20 affected individuals, the craniofacial features clearly described, including the well-known single central maxillary central incisor, a classic clue to HPE. The multi-colored illustrations of the transmembrane protein, the locations of the deleterious variants (bad things!), and the pictures of a few of the kids are well done. I’m proud.

But there’s more to this story.

This child has not thrived. The nature of the brain malformations has meant severe severe severe delays, not walking, not talking, surgeries for the cleft lip and palate, feeding through a tube, visits to doctors and hospitals three times a week, no vacations, insurance saying you can’t, we won’t, friends of mom and dad, who are still teenagers, not coming over to visit, to watch the game, to hang out. Where are they? Not many people to talk to who might “get it.” Tough life.

Pretty common for couples, young or old, wealthy or poor, well-educated or not, to break up. Or not. Which would be better? That’s a bad question, but it’s better than the answer.

Think of how the trajectory of hope goes awry.

A couple in our neighborhood had a daughter who, in childhood, many years ago, suffered a catastrophic brain injury, not genetic, but nonetheless. For years upon years they pushed their adult child in a stroller along the sidewalks in the gloaming to feel the breeze and the last rays of light from the West, the jostles of the large rubber wheels along the sidewalk cracks, the swoop of the curbs, the growls of the cars eager to roll past stop signs. Birds. Mom singing her favorite songs; Dad tousling hair.

And one day she was gone.

Parents of babies who are now gone, who are lucky enough to find the soul and luck in their deepest cardiomyocytes to stay together, will still walk with each other in the last light of day. Quietly. There are no words they need to say. There never were.

They walk side by side, slowly and gently and sadly with a sadness forged in some revelation of the truth that they have met their fate, a fate that is not fair, that does not demand or require acceptance because it is what it is, something beyond despair, beyond choice.