Family Lore, a Variant of Uncertain Significance, and CADASIL

Abstract

An infant presents in extremis. After the medical team stabilizes him, the race is on to figure out why he got so sick in the first place. The consulting genetics team thinks that it is unlikely his problems are due to a genetic cause, but his extreme, confounding presentation is enough to justify trio exome sequencing. When the results reveal an unexpected, paternally inherited variant of uncertain significance (VUS) in NOTCH3, fresh questions arise. The infant's presenting symptoms and descriptive diagnoses, including hematemesis, epistaxis, and gastric ulcers, certainly do not fit the mold of CADASIL. However, closer inspection of his family history yields tantalizing clues: a father and paternal grandfather with seizures, and a paternal grandfather with unexplained mood disturbances in middle age. Combining details gleaned from the family history and medical literature, the clinical genetics and laboratory genetics team collaborated, reclassified the VUS as likely pathogenic, and offered a new unifying diagnosis to explain much of the family's lore.

Little Eric* (*name changed to protect patient privacy) was two months old when his life took a turn that no one in his family expected. Admittedly, his story was unusual long before he was even born. After the birth of Eric's older sister, their mother continued to bleed long after the expected recovery period, and her serum HCG levels remained stubbornly, mystifyingly, elevated. She was no longer pregnant, but her body was behaving at once as if she were nourishing an embryo, with all that nausea, but also as if she were having a miscarriage, with all that bleeding. It turned out that she had a rare kind of gestational trophoblastic disease called an epithelioid trophoblastic tumor. The malignant kind. Therefore, she underwent treatment and had a full recovery, but not before freezing her eggs to preserve the fertility that could very well be compromised by the chemo that would save her life.

Eric was conceived from one of those eggs retrieved from his mother's ovaries. At birth, he was a big, beautiful baby, with a generous head size and chubby arms and legs. Things were going fine at first. He fed well, slept well, and did all the things an infant is supposed to do. But shortly after he turned 2 months old, things went horribly awry. His parents put him down for a nap and returned a few hours later to find blood on his sheets from an apparent nosebleed. Later, he vomited, the stuff dark brown with flecks of red mixed in. Naturally, his family rushed him to the ER, where medical terms were applied to their baby boy: Epistaxis. Hematemesis. Cyanosis. Tachycardia. Tachypnea. His skin changed from a rich brown to a dusky blue, his pulse quickened to over 200 beats per minute, and his breaths came twice a second. His little body was scrabbling for a foothold on life. He was intubated to protect his airway. Then his heart stopped. Then resuscitation for 15 min. Nine rounds of epinephrine. Fifteen minutes until ROSC. By the time the medical team got his little heart restarted, his belly was mysteriously rock-hard and swollen.

Surgeons cut into his abdomen next, searching for a cause for all this trouble. There was fluid, much more fluid than belonged there, and his liver looked congested, backed up and full of blood from poor circulation. A camera went down his esophagus, revealing ulcers in his stomach and small intestine, though no one could say why a two-month-old baby would have such bad gastritis. As is often the case in medically mystifying scenarios, a cloud of suspicion began to form around his parents. The medical team specializing in child protection was quickly consulted. Thankfully, a dilated eye exam showed no bleeding in his retinas, and though there were rib fractures detected on the dozen x-rays of his entire tiny skeleton, these were attributed to his resuscitation in the ER. They concluded that his parents were not, in fact, the cause of Eric's medical mystery. Perhaps cold comfort, but at least Eric's parents didn't have to contend with a CPS inquiry on top of caring for their bewilderingly sick infant.

Somewhere along the line, the team caring for Eric in the ICU decided to involve Genetics. It is a trope most geneticists know: Medical mystery? No idea why a patient is having the problems they are having? “Weird” story? Ruled out everything else? Then surely it must be genetic. Truth be told, the genetics team was unconvinced. We saw a big baby with dry skin and what appeared to be a full-body rash (dermatology consultants later called it xerosis from severe eczema). We saw a presenting history more suggestive of infection or untreated GERD. But we also saw a baby who was intubated and edematous, whose ears were swollen with fluid. A baby with flaky, dry skin. A baby whose presentation we could not understand. We considered hereditary hemorrhagic telangiectasia. Maybe the baby had a large, honking AVM in his gut, a flashing neon sign with an arrow pointing toward it: “IT'S MY FAULT.” Yet the endoscopy had shown no such thing. So we got the family history, got consent, and rolled the dice, as we so often do, with orders for trio exome sequencing.

Trio exome sequencing revealed a heterozygous, paternally inherited variant of uncertain significance (c.3427C>T p.(R1143C)) in NOTCH3 (RefSeq: NM_000435.3). We were caught off guard. Nothing about Eric's story had made us think of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, OMIM #125310), an autosomal dominant disorder classically described as having mid-adult onset with variable expressivity. CADASIL is typically characterized by recurrent ischemic strokes, transient ischemic attacks, and cognitive decline with progression to dementia. Other common symptoms include migraines with aura, mood disturbance, and apathy (Hack, Rutten, and Lesnik Oberstein 2000). Magnetic resonance imaging of individuals with this disorder shows diffuse white matter hyperintensities, subcortical infarcts, and sometimes microhemorrhages (Hack, Rutten, and Lesnik Oberstein 2000; Wang 2018).

As the team gathered to review and interpret the exome results, one member brought up the family history. Did not the dad say he had had a “brain infarct” when he was 4 years old? And did not both the dad and his dad say they had seizures in childhood? Maybe we were onto something, after all (see Pedigree in Figure 1).

FIGURE 1 ∣.

Pedigree showing the inheritance pattern of the c.3427C>T p.(R1143C) variant in NOTCH3 in a family with presentations suggestive of CADASIL.

Next, we looked to the medical literature. The variant we found in Eric and his father had been previously reported in two other patients with CADASIL (Mizuta et al. 2017; Ni et al. 2022), suggesting likely pathogenicity. Unfortunately, both papers described groups of individuals with CADASIL, with no specific phenotypic information about the people who had the c.3427C>T variant. Yet we were confident about our hunch—the father's seizures and unexplained childhood “brain infarct” suggested that this variant could be pathogenic. If we could identify it in the paternal grandfather who also had unexplained seizures, we would have even more evidence to support our hunch. So we sent an email to the lab, laying out our thought process, and the lab agreed to test the paternal grandfather for free. When his sequencing confirmed the presence of the familial variant in NOTCH3, we felt vindicated. The lab changed the variant classification from VUS to likely pathogenic.

A few months later, the senior author (CNM) saw Eric and his mother for a follow-up in the clinic. Dr. Murali explained the genetic team's diagnostic odyssey, tracing the deductions and medical literature and search for evidence that led the team to conclude that, indeed, Eric, and his father, and his father's father before him, all have CADASIL. She explained what CADASIL was, and when she mentioned that mood disorders affect many patients, Eric's mother expressed a look of recognition. Her father-in-law, she relayed, had been a wonderful family man while his children were young, but around mid-life, he suddenly “went dark,” withdrawing from family life and falling into depression. The family had always thought that he just got tired of playing the role of husband and father. Now they knew that his actions were born of a genetic diagnosis, over which he had no control. What a difference a diagnosis can make.

For a while, Eric's parents considered pre-implantation genetic testing on their remaining embryos to avoid transferring ones with the familial NOTCH3 variant. After all, as his mother said, if Eric's father presented at age 4 years with his “brain infarct” and Eric presented at 2 months with a whole slew of frightening symptoms, what if their next affected child presented even earlier? Yet at the next follow-up, Eric's mother shared that she and her husband had decided to just try conceiving naturally. The last several years of their lives had been marked by hyper-medicalization, starting from the moment when she was diagnosed with that epithelioid trophoblastic tumor. They wanted to go back to basics, to see what would happen if they relinquished a little control and focused not on diagnoses but simply on their family. Most geneticists might feel uncomfortable with such a decision. Surely, if patients can prevent having a child with a genetic diagnosis, should not they?

But truth be told, though this story illustrates the triumph of medical genetics, the benefits of collaboration between the lab and the clinic, and the truths that can be revealed by a curious and astute medical team, it also illustrates that uncertainties remain. As a group, we authors are confident that Eric's father's seizures, and his grandfather's seizures and mood disorder, are a result of their familial NOTCH3 variant. But we can't say with any certainty whether Eric's severe presentation as a two-month-old was related to NOTCH3 at all. We have combed the literature and found no reports of hematemesis or epistaxis in people with NOTCH3 variants. When we submitted Eric's story as a case report to two journals, reviewers at both journals raised concerns about the true pathogenicity of the NOTCH3 variant, about the likelihood (or lack thereof) that CADASIL was the cause of anything that brought Eric to the hospital that fateful spring day. While we agree that it is unclear if CADASIL was the cause of Eric's presentation, our team is confident of the pathogenicity of the variant and its segregation with the phenotype in the family. Perhaps we'll never know why Eric fell so gravely ill. In a strange way, his diagnosis with CADASIL was incidental, but is not that so often the case in genetics? The truth is, most of us have no idea what secrets lie within our genomes. But for this family, in this story, the revelations of the genome had wide-reaching effects.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.