Gentlemen, I am tormented by questions; resolve them for me. Dostoevsky, Notes from Underground As the blood drips into the vial, I rue how little of genetics I remember. It is April 2017, an eternity since I stared out the window in high school biology. Now I stand here holding Misha’s sweaty palm and relying on a platoon of metaphors to contemplate the secret of my son’s nature. The doctor compares the genome with an instruction manual. Proteins are the syllables that activate the genes. Nucleotides are the letters that carry the code. Think of chromosomes, the object of today’s inquiry, as numbered pages. Once the doctor ships Misha’s sample to the laboratory, a microarray analysis will count them. Are the pages of his manual all present and accounted for? The doctor slightly unnerves me. His toothsome smile and pigeon chest remind me of the pitchmen in commercials for breakfast cereal. In reality, Brian Skotko is Professor at Harvard Medical School and Director of the Down Syndrome Program at Massachusetts General Hospital. Down Syndrome is one of the neurodevelopmental diagnoses attributable to a discrete chromosome variation. I have come to find out whether Misha’s autism diagnosis is likewise attributable. Such genetic variations, as Dr. Skotko explains, may come to roost in a newborn either via inheritance or interactions between egg and sperm. The latter cases, spontaneous occurrences of combined “germline” cells, are “de novo,” new. I remember enough Latin to stay in the conversation. Lo and behold, the microarray discloses a variation in chromosome 11q. The extra letters on that page run along a belt of seven-and-a-half million nucleotides. Neither his mother nor I, nor his sister Niusha, share the duplication. His is de novo, from the germline. All it took for him to draw this lottery ticket was one errant bounce of the buttocks. The standard algorithm classifies variations from “benign” and “likely benign” to “likely pathogenic” and “pathogenic.” Misha’s is a “variation of uncertain significance,” a classification not uncommon in a young field chockablock with reports of de novo variations. Dr. Skotko will consult medical research published on 11q. I will consult rarechromo.org, a global repository of parent reports. If 11q is inculpated in autism, those sources will tell us. When we reconvene, however, we break the same news. The repository contains no reports of 11q. In the published medical research, Dr. Skotko chimes in, “there are no cases that we are aware of that are the same size as Misha’s.” Is the duplication, new to Misha, new in nature as well? Or does a dearth of reporting account for his matchless status? Dr. Skotko cannot say. “Your son,” he does say, “is on the far edge of science.” For the next four years, I take Misha to Boston’s most distinguished hospitals and clinics in search of ballast. He acquires more diagnoses. An occupational therapist at MGH ascribes his wobbly motor control to sensory processing disorder. Margaret Bauman, renowned neurologist at the Integrated Center for Child Development, orders metabolic tests to find out whether mitochondrial DNA disease can explain his puny musculature. It does not. Timothy Buie, equally renowned as a gastroenterologist at Boston Children’s Hospital, orders antibody tests to find out whether he has inflammatory bowel disease or celiac disease. Negative. A neuropsychologist at the Lurie Center for Autism diagnoses Misha with mixed-expressive-receptive language disorder. Does an impairment in his bilateral hearing explain it? Nope, rules out an audiologist. Barry Kran at the New England College of Optometry diagnoses cerebral vision impairment, a neural kink in the process by which objects in the environment become subjects of perceptual discrimination. A neuro-ophthalmologist at Boston Children’s conducts a structural MRI of Misha’s brain. “The MRI was normal,” reports Dr. Gena Heidary. The images reveal no evidence of abnormal anatomy, no signs of injury or stroke or trauma, no underdevelopment of the regions that host executive function. Where is the neural kink? “It is the case that some of our children with CVI have clear injuries to the visual pathways, and we can see it,” Dr. Heidary responds. “We also have children with no clear injuries.” “It seems impossible that Misha has a normal brain.” “We don’t have the sophistication to really tell at the level you’re asking.” Perhaps it is time to revisit the meaning of the 11q duplication. Could his chromosome variation be lurking in the matrix after all? Lineagen, the laboratory that analyzed the microarray, makes a genetic counselor available in October 2021. As we delve in, a strange ambivalence permeates my thoughts. The intellectual historian Mark Lilla breaks out the polarities of my condition in his book Ignorance and Bliss: “How is that we are creatures who want to know and not to know? How is it possible for both desires to inhabit the mind?” BC Emily Palen’s opening statement takes me aback. “It’s very likely the explanation for his diagnosis of autism,” she states. Variations of uncertain significance fall between −0.89 and 0.89 on the algorithmic scale. The likely pathogenic start at 0.90. Initially, Misha’s was scored 0.88. Emily offers that, just before our call, Lineagen’s analysts had rescored his duplication to 0.90, bumping him over the threshold. On what basis and for what reasons the analysts had undertaken to do so? Emily does not say. “Okay, but if we all have some variations, and if Misha’s duplication has never been reported before, then how can you think Misha’s duplication is ‘very likely the explanation’ for his autism?” “What we know about these types of genetic changes — pretty sizable duplications or extra sections of DNA — is they tend to have an impact on brain development, and we know there are several genes in this region that we call ‘highly expressed,’ or more active in brain development, so that’s why I’m suspicious that this is likely related to the developmental difference that we know about in Misha, likely related to that diagnosis of autism.” “But autism isn’t definitively correlated with any genetic conditions, is
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