On a muggy midsummer morning in Brooklyn in 1916, 4-year-old Eugene was practicing somersaults, flipping and rolling, as nearby, his mother stitched white lace onto a blue dress. Next to her stood a tall, heavy mirror perched on a stand that the seamstress could rotate to view the garment from different angles.
Suddenly, as the boy was rolling upward, he careened into the mirror. Like tall grass in the wind, the mirror swayed for a moment, then came crashing down on the boy. He died instantly – or so went the family lore.
That tragedy lies behind the riveting medical detective story of "The Dressmaker's Mirror," an excellent new book by geneticist Susan Weiss Liebman, research professor at the University of Nevada, Reno.
Two More Cases
Eugene was Dr. Liebman's paternal uncle. But his early death wasn't the direct inspiration for the book – it was the sudden death of her niece Karen, 36 and pregnant with her first child.
While dining out with her husband, Karen suddenly jolted forward and collapsed. Her heart had stopped. She had been healthy, the only hint of illness a slight but persistent cough and breathlessness. In retrospect, Dr. Liebman realized these signs had been present for years. Karen's doctor had attributed the symptoms to the pregnancy.
Karen died on November 16, 2008 – coincidentally, the same date that Dr. Liebman's father had died 28 years earlier, at age 66, from a presumed heart attack.
Another piece to the emerging familial pattern was Karen's mother, Dr. Liebman's sister Diane. After doctors persistently attributed Diane's fatigue, weakness, cough, and labored breathing to bronchitis, pneumonia, and a nebulous "virus," she was finally diagnosed with dilated cardiomyopathy (an enlarged heart) at age 57. Diane died from it at age 73, in 2016. Her enlarged heart had been an early incidental finding – a key clue that eluded physicians seeking horses, not zebras, the common mantra of diagnosis.
It was Diane's daughter-in-law, a newly-minted physician, who advised consulting a cardiologist. Then things finally sped up. An echocardiogram revealed an enlarged left ventricle. And Diane's ejection fraction – the percentage of blood that the left ventricle pumps out, typically 54% to 74% for a woman - was only 19% - well below the 30% considered severely abnormal.
Diane was, and had been, in heart failure. The correct diagnosis finally came in 2001: dilated cardiomyopathy, DCM.
"When we got Karen's autopsy report on her heart two weeks after her death, early December 2008, and it said dilated cardiomyopathy, we immediately connected this information to her mother's, my sister Diane's, diagnosis of DCM 7 years earlier. With the report on Karen's heart it now was clearly genetic. But we didn't know if it was a new mutation in my sister or inherited from one of our parents," Dr. Liebman said.
Genetic Analysis
The next step: identifying the gene that, when mutant, caused the family's heart condition. Researchers are continually discovering and "curating" (describing) gene variants – aka mutations. The National Institutes of Health maintains a database of gene variants, ClinVar.
An initial blood test for the ten known mutations for DCM at the time of Karen's death was negative. A further round of tests on other genes also didn't identify anything.
And that's when Dr. Liebman's expertise came in. Although her research uses yeast, not humans (just as mine was in fruit flies), the principles of inheritance are the same in any organism. She knew the search for causative genes hadn't been exhaustive.
So she contacted Dr. Elizabeth McNally, a specialist in genetic heart disease at the University of Chicago. Dr. McNally checked Diane's DNA for new mutations as they were discovered. But still no hits.
Gene Discovered: FLNC
Waiting for discoveries of new mutations to trickle in wasn't fast enough. So, in 2014, Dr. McNally sequenced Diane's exome – the protein-encoding portion of the genome – and finally zeroed in on the gene. She began testing how this mutation affected cardiac muscle cells cultured from the sisters' reprogrammed blood cells. But this didn't give her direct evidence that a mutation in this gene lay behind the family's DCM.
About then Dr. McNally changed institutions and Dr. Liebman's requests for follow-up were lost. She had no idea that progress had been made.
In fact, Dr. McNally's group had published a report in 2014 in Circulation: Genomic and Precision Medicine that had named the hypothesized causative gene, FLNC.
FLNC encodes a protein, filamin C, which maintains the precise crosslinking of actin protein filaments into sarcomeres, the tiny units of skeletal and cardiac muscle. Without filamin C, heart muscle slowly falls apart. But the implication of the gene remained tentative until by 2016 experiments with model organisms strengthened the link.
Diane had had the mutation; her sister does not. And the nature of the mutation in the Liebman family explains why it is so devastating – it is tiny, but with a huge impact.
Genes come in pieces. Exons are regions that are transcribed and translated into the corresponding amino acid sequences of proteins. Introns – short for "intervening sequences"- are cut out before a protein forms. The Liebman's mutation changes a single DNA base that borders on an intron and prevents the intron from being cut out properly. This disrupts the proper synthesis of the protein.
Medical Detective Work Uncovers a Founder Effect
Dr. Liebman got to work, reading technical reports and contacting researchers and families to find other affected families.
"Two families with the mutation were Ashkenazi Jewish. Since my family is also Ashkenazi, this suggested the mutation might be a founder mutation," Dr. Liebman shared with me.
As the name suggests, founder mutations are brought into an area from a few settlers. and then come to not only persist, but comprise more of the population, if people have children among themselves. Today's Ashkenazim descend from as few as 350 or so individuals, population bottlenecks that by chance retained certain individuals with rare mutations. These mutations then comprise more of the population if people have children among themselves.
Bottlenecks have strangled our genetic diversity over time, the echoes of reverberating hate (See The Genomic Scars of Antisemitism).
After consulting the most complete DNA databases at the time, Dr. Liebman discovered that one in 800 Ashkenazim had the mutation. And it didn't appear in any other ethnic groups.
"So now I knew the mutation was not new to my sister. It had been around for centuries," Dr. Liebman told me.
Identifying the Correct Branch of the Family Tree
Which parent had transmitted the mutation to Diane, who passed it to Karen?
Family history pointed to the paternal side: Diane and Dr. Liebman's father had died of what was deemed a heart attack at age 66, and his mother died in her sleep at 59. That suggested autosomal dominant inheritance – male or female can pass on the trait, and only one mutation is necessary to develop symptoms.
Dr. Liebman got to work.
She used google, 23andMe, and Ancestry.com to fill in the branches and leaves of the family tree, to find and alert relatives and advise them to have frequent diagnostic tests as well as genetic testing. Her efforts remind me of when, coincidentally at about the same time, I discovered that I have a dozen or more half-siblings, thanks to a long-ago mystery sperm donor. I told my story in a New York Times Modern Love podcast.
Other cases emerged as Dr. Liebman widened her circle of contacts.
Then in 2017, a chance conversation at a cousin's 50th birthday party revealed his version of the dressmaker's mirror accident. He'd been told that the mirror fell when their grandparents weren't home, and had left Dr. Liebman's father in charge.
The differing tales sent Dr. Liebman to hunt down her uncle Eugene's death certificate, which is reprinted in the book. And she discovered that the cause hadn't been an accident or injury at all, but congestive heart failure following five days in the hospital. A second mutation in another gene might explain the onset in a very young child..
"I read the cause of death in December 2020 and was shocked to see heart failure. This clinched it. The mutation was very likely from my father," Dr. Liebman said.
But why the invented story?
"I think they did it to protect their surviving son, my father, and their later issue, Uncle Cyrus, from being shunned by potential marriage partners. It was common for Jews to hide suspected hereditary defects," Dr. Liebman wrote.
In 2021, she and her colleagues published a Comment in the International Journal of Cardiology, "A founder mutation in FLNC is likely a major cause of idiopathic dilated cardiomyopathy in Ashkenazi Jews." And so FLNC can now be added to lists of genes to screen in Ashkenazi populations.
Should We Sequences Genomes of All Newborns?
Dr. Liebman sent me her book shortly after my most recent post at DNA Science, A Genetic Crystal Ball: When Newborn Genome Sequencing Findings Explain Illnesses in -Relatives. And so I asked her whether she thought that the whole genome (or exome) DNA sequencing that led to solving her family's mystery should be done routinely, and broadly, on infants in the general population. Would that lead to diagnoses, or cause undue stress?
"I applaud the idea of universal sequencing in infants for genes that are actionable in infancy or childhood."
Liebman also pointed out that "most pathogenic mutations just increase the chance of disease, they do not guarantee disease. The FLNC mutation in my family can cause DCM or sudden death depending on other genes in the person and environmental factors."
Karen's pregnancy might have been a contributing factor that enabled the family's mutation to become deadly.
The American College of Medical Genetics and Genomics maintains a list of "actionable' conditions detected with exome and genome sequencing. That is, a genetic disorder is valuable to detect if treatment is possible.
CODA
In addition to the riveting family story, The Dressmaker's Mirror is a page turner.
I was skeptical when I received it – I've written and read many genetics books over the years, and expected to be bored or to find oversimplification errors. But once I picked the book up, I couldn't put it down, even when knowing the outcome from the press release the publisher, Rowman & Littlefield, had sent.
I share Ashkenazi ancestry with Dr. Liebman, as well as growing up on the same Brooklyn streets. We have an astounding number of other coincidences. I applaud her efforts to get to the bottom of a family mystery. Including her family's gene on testing panels for heart disease will undoubtedly save lives.
