One of the most anticipated returns to normalcy following the pandemic is the in-person conference. Like the mythical Phoenix bird arising from…
The history of genetics begins, not with Gregor Mendel’s pea experiments, but with people long ago noticing family resemblances and vulnerabilities so distinctive that shared environment alone can’t explain them.
In the new literary fiction masterpiece The Covenant of Water, author-physician Abraham Verghese traces an unusual trait through three generations of a Christian family in India, against the historical backdrop of the coalescence of three states into Kerala, on the Malabar Coast, spanning 1900 to 1977. “The family … suffers a peculiar affliction: in every generation, at least one person dies by drowning – and in Kerala, water is everywhere,” reads the jacket cover.
Through time, the drownings have been ascribed to bad luck and a familial recklessness, rather than to anything as cut in stone as an inherited condition. Frequent drownings seem more coincidence, harder to explain biologically than bleeding from missing a clotting factor or impaired breathing from cystic fibrosis. But the 700+ page tale is indeed about a rare manifestation of a rare condition.
The narrative captures the dread of an autosomal dominantly inherited disease, striking every generation, males and females. Dr. Verghese names all of the characters except the patriarch, who passed down the mutation behind the illness that isn’t revealed until well into the saga. Perhaps keeping him nameless is a metaphor for the mysterious origin of what the family calls “the Condition.”
(Spoiler alerts ahead for the technical details – I will not reveal the spectacular, surprising ending, which has to do with relationships, not genetics.)
An Aversion to Water, Mysterious Drownings, and Poor Balance and Hearing
Instances of difficulties around water pepper the narrative, beginning with bathing a two-year-old:
“When she first tried it, JoJo fought her. Still, she poured water over his head, but then he turned pale, his eyelids fluttering like a moth’s wings and his eyeballs rolling in their sockets. …”
JoJo died at age 10, when he fell from a tree into an irrigation ditch, face down, and drowned. Years later, the boy’s half-brother, Philipose, has a similar problem:
“… he bathes willingly, but alarms her whenever she empties the pail over his head: his eyes close but then open to reveal his rolling eyeballs, and often his limbs turn floppy.”
Philipose is fearless, and hard-of-hearing. At age 9, he dives into a river just to prove he can do it. But he can’t. “The frenzied flailing stirs up mud and spins Philipose in circles, first on his belly, then on his back, then he heads down, white soles flashing.” He’s saved, to then “disgorge the mud he borrowed from the river.” Water eventually wins decades later.
Big Ammachi, Philipose’s mother, reminds him often of his father’s aversion to water. She recognizes that the familial problem with water may be more than coincidence or imitation. She prays, “I beseech You once more: If You won’t heal the Condition, please send us someone who can.” It becomes a mantra.
In the next generation, Philipose’s firstborn, Ninan, is a compulsive tree climber who also has difficulty with water. “He’s like his grandfather and his father in another way: water poured over his head disorients Ninan, sends his eyes bobbing to one side then drifting back to the midline only to hammer sideways again. He has the Condition,” Big Ammachi thinks.
Ninan perishes as a young boy, climbing a tree. “Suspended upside down, his face white, bloodless, frozen into a surprised expression, his body crooked in a manner that defies the senses. A pointed, amputated branch of the tree grows out of his chest, blood congealed around its exit in a ragged fringe.”
When Ninan dies, Big Ammachi shows the boy’s mother, Elsie, a secret document. Others have documented the family curse.
The Water Tree
A pedigree, called the Water Tree, extends back ten generations. The chart depicts both relationships (reflecting genotypes) and traits (phenotypes), more informative than a simple genealogy. A crucifix over wavy lines appears with the symbols of the drowned; wavy lines alone indicate an aversion to water. Written notes mention dizziness, staggering, deafness, weakness on one side of the face, and increasing severity with age. Boys and men dominate, but that may be because women leave when they marry, their genetic trails lost.
Big Ammachi’s husband had revealed the Water Tree when the she started to assemble the puzzle pieces of the aquatically challenged family she had married into at age twelve. “She understands at once that it is a catalog of the malady that has shattered the family, but unlike Matthew’s gospel, this is a secret document, hidden in the rafters, to be viewed only by family members, and only when they absolutely must see it.”
But Elsie shrugs off the significance of the Water Tree: “Every family has something,” she persists, unaware that her lineage brings in the same mutation. For The Covenant of Water is based on the genetic phenomenon of a Founder effect: a gene variant (mutation) arriving at a new location and, over time, taking over.
The Water Tree reveals so much consanguinity along its entwined branches that the typical linearity of a family history circularizes, as cousins, some distant, unknowingly have children together. The degree of shared ancestry is astonishing.
The Condition Described
Years after Ninan’s death, Elsie and Philipose have another child, Mariamma. She becomes fascinated with the family curse, which drives her to become a doctor. She will fulfill Big Ammachi’s plea and prophecy.
“Mariamma thinks about the Condition. Already, with the knowledge of anatomy and physiology that she has, she thinks the Condition must involve parts of the brain associated with hearing and balance. Perhaps … immersion in water causes signals to spill over to parts of the brain that should be off limits.”
Jumping ahead about 500 pages, a much older Philipose dies a watery death aboard a train that plunges into a river. He can’t right himself. Down is up and up is down, and he drowns. He’s brought to Mariamma’s hospital, where his autopsied brain finally reveals the basis of the Condition.
“Little yellow bumps” appear on the acoustic nerves in each of Philipose’s inner ears. They are benign tumors, during the 1970s called acoustic neuromas.
The tumors arise in the acoustic nerve fibers, which receive signals about balance from the inner ear’s labyrinth. On each side, a labyrinth houses three fluid-filled circular canals, and movement of the fluid as it swishes back and forth tells the brain the body’s position in three-dimensional space. Growing tumors may also press on one side of the face, causing the familial lopsidedness, as well as on the nerve fibers that provide hearing.
Tumors in both ears indicates that the condition is genetic – which Mariamma of course already suspected. In hereditary tumor and cancer syndromes, such as retinoblastoma and the BRCA cancers, mutations are in all cells, whereas in sporadic (noninherited) conditions, only the affected cells have mutations.
The Condition Named
Some genetic disease names change when we discover their molecular underpinnings.
In the 1970s, the Condition was called neurofibromatosis type 2, because it shares acoustic neuromas with neurofibromatosis type 1 (once called von Recklinghausen disease), which also causes characteristic skin bumps and pigmented patches called café-au-lait spots. Today, the Condition is called vestibular schwannomatosis, but the gene name – NF2 – persists. The Condition affects 1 in 60,000 people, half of the cases sporadic.
Several companies provide genetic testing for vestibular schwannomatosis. It is diagnosed with MRI and treatable with surgery.
The name refers to Schwann cells, which wrap around neurons like band-aids around fingers, providing the fatty insulation that makes speedy nerve transmission possible. In the Condition, Schwann cells overgrow into benign tumors in the whitish, glistening nerve sheaths, aka Schwannomas, like bubble wrap instead of a band-aid.
Most tumors in the Condition dot the vestibular nerve, affecting balance and hearing. But they may also appear in the brain, spine, skin, peripheral nerves, and even the eyes. Hence, the panoply of symptoms that course through the ten generations of Big Ammachi’s family represented in the Water Tree.
The diagnosis of neurofibromatosis type 2 immediately explains Philipose’s peculiarities, Mariamma thinks:
“Since her father got unreliable signals or NO signals from his labyrinths, he must have compensated quite unconsciously by relying heavily on his eyes to see the ground, to find the horizon. He also relied on sensation in his feet, telling him his feet were on the ground. In the dark when he couldn’t see well, couldn’t see the horizon, or whenever his feet were in water and had nothing to push against, he was lost.”
A Powerful Founder Effect
Mariamma makes it her life’s work to flesh out the Water Tree, adding branches as she encounters the telltale symptoms and “bad luck” in other families. She eventually recognizes affected females, known for what were deemed their “eccentricities.” They climb trees, refuse to be modest or docile, avoid water, and one has an obsession with snakes. All report headaches, dizziness, and facial weakness, the Condition hiding in plain sight because of expectations of female docility.
All those with the Condition presumably descended from a common ancestor who introduced the mutation when Doubting Thomas converted families to Christianity in the Malabar region of Kerala in the eighth century. In the circular extended kindred, “tracing the spokes back to the center will bring them to the ancestor with the altered gene with whom it all began,” Mariamma concludes.
Founder effects are well known in genetics – I cover them extensively in my textbook. They explain uniquely prevalent, otherwise rare, single-gene conditions among the Amish, Mennonites, French Canadians, Finns, and Ashkenazi Jewish people, among others. More recently, COVID underwent repeated founder effects as SARS-CoV-2 mutations arose and recombined, fueling viral hopping about the globe.
The Molecular Explanation
The mutation behind the Condition is in a gene that encodes a protein called merlin, which is part of the scaffolding that provides distinctive forms to cells. Merlin is also a tumor suppressor protein, and when missing or altered, the result is overgrowth, as well as degenerating neural connections. Besides hearing loss and poor balance, the impaired or absent protein causes tinnitus, muscle weakness, and cataracts.
I read many descriptions of the Condition, and mention of drowning is not prevalent. I finally found it in an historical account in Gene Reviews:
“Individuals with vestibular tumors need to be aware of insidious problems with balance and underwater disorientation, which can result in drowning.”
The first case reported in the medical literature, in 1822, described a 21-year-old, Michael Blair, who lost hearing and sight, and upon autopsy was found to have tumors of the dura mater (outer covering of the brain) and the brain, as well as a ‘tumour of the size of a small nut, and very hard, being attached to each” auditory nerve.
A study from 1933 that reported a five-generation family with 38 members who lost hearing and vision in early adulthood established the familial form of the Condition, aka vestibular schwannomatosis.
Abraham Verghese captures the fear of a disease that courses through a family, striking every generation until, by chance, it doesn’t. Huntington disease is inherited in this manner, as are familial forms of Alzheimer disease.
Ironically, while I was reading The Covenant of Water, the cover story of the July 23 New York Times magazine featured The Vanishing Family, by Robert Kolker. It is about a different autosomal dominant condition, frontotemporal dementia (FTD), ravaging a family of nine adult siblings. Genetic testing is available. How will those destined to not have the condition plan to care for those who will? Like some members of Big Ammachi’s family, these brothers and sisters also live with the denial, anger, and angst of an autosomal dominant syndrome. But unlike the Condition, Huntington disease and FTD still have no treatments – which presents the dilemma of choosing to know one’s fate with a genetic test before symptoms begin.
Judging from the Facebook groups I’m in that discuss fiction, many readers, or at least those most likely to post comments, can’t follow the unfamiliar names and places or become flummoxed by the medical details of The Covenant of Water. I urge them to stick with it, for this soaring narrative conveys the terror of inherited disease in a way that my own non-fiction – textbooks and articles – never could. It is an unforgettable book. Thank you, Dr. Verghese.