The Carriers by Anne Skomorowsky: An Honest Review

I received an eARC of "The Carriers: What the Fragile X Gene Reveals about Family, Heredity, and Scientific Discovery" by Anne Skomorowsky from the publisher Columbia University Press via Netgalley in exchange for an honest review.

It had been ubiquitously understood that being a carrier of a genetic disease implies that the risk for developing the disease is valid only for the carrier’s offspring. This standard had been annulled by exceptions, and one such exception is a genetic disorder most commonly known as: Fragile X Syndrome (FXS).¹ Unsuspecting individuals with Fragile X Syndrome, their parents, and their grandparents had been distressed for generations by ostensibly unrelated medical issues.

This genetic disorder is one of the most commonly inherited—through accumulation over time across generations—forms of developmental and intellectual disabilities, which is marked by severe cognitive and behavioural problems, including comorbid autism. According to the National Fragile X Foundation, “The prevalence of FXS in males is estimated to be between 1 in 4000 and 1 in 7000, and in females between 1 in 6000 and 1 in 11,000.”

It wasn’t just one damn thing after another. It was genes.

In her book, psychiatrist Anne Skomorowsky passes on to us, readers, the narratives of several affected carriers, their families, their doctors, and many others, in a gripping read about a tiny mutation on the X chromosome which could affect character and fate but remained invisible—until now.

Before a problem can be understood, someone has to notice it, there has to be a language to describe it, and the right people have to investigate it.

A Mini Crash Course on Genetics (and Epigenetics)

To showcase the basic science behind this book—for the detailed science is too complex to summarise herein in this review, one ought to go over a customised mini crash course on genetics (and epigenetics):

Chromosomes X and Y prescribe whether a baby is a boy or a girl. With very few exceptions, girls have two X chromosomes and boys have one X and one Y chromosome. Mutations on the X chromosomes are known as X-linked mutations. What this means is that they are much more consequential for boys than girls.

Girls nearly always have a normal X chromosome which compensates for any mutated gene on their other X chromosome. However, boys don’t have the spare X chromosome girls have (the other chromosome they have is a Y chromosome), meaning that if their X chromosome has a mutated gene on it, there won’t be any compensation.

To better understand this, it would be easier to look at a more typical X-linked disease: haemophilia, which killed off sons of the Russian Empire while leaving their mothers unscathed.² A characteristic of people with haemophilia is that they have a defect in the gene—found on their X chromosome—that codes for the factor VIII protein, which is necessary for blood to clot. Without factor VIII, the affected person would bleed extensively from minor injuries and die if untreated. For the Russian monarchy, the mothers who carried the mutated factor VIII gene on one of their X chromosomes, passed on the mutation to their sons (50% chance), while they themselves stayed unafflicted as their other X chromosome—with no mutation—allowed them to produce factor VIII proteins up to healthy levels.

On the other hand, it is now established that Fragile X Syndrome is different, because it is inherited as an X-liked dominant disorder. This means that in women, the mutated X chromosome dominates over the unmutated one, leading to symptoms of the disease. Having said that, the inheritance of the fragile X gene doesn’t seem to follow the classic rules of X-linked inheritance, dominant or recessive. For instance, males with a mutated X chromosome can be unaffected carriers.

What the central dogma of molecular biology³ overlooked was that parts of the DNA that did not code for proteins, which was often dismissed as “Junk DNA“, could also be significant in health and disease. This is an iconic example of the importance of epigenetic⁴ changes to DNA.

—I’ll stop here before I continue spiralling outwards and away from the review.

The Science

Fragile X mental retardation 1 (fmr1) is a gene that codes for the FMRP, a protein necessary for the proper development and function of neurons in the brain. This gene is turned off in most⁵ patients with Fragile X Syndrome, meaning that they can’t produce the needed protein.

Like all genes, the stretch of nucleotides (the letters that make up DNA) upstream of the fmr1 gene regulates its activity, this is the promoter region. In the case of fmr1, this upstream sequence contains repeats of three specific nucleotides: cytosine, guanine, and guanine (CGG). Most individuals have between 5 and 44 CGG repeats. Those with a repeat range between 55 and 200⁶ are called premutation carriers, which basically means that they are at risk (which increases as the number of CGG repeats increases) of having children with a premutation (with more CGG repeats) or even a full mutation of Fragile X Syndrome (having a sequence of CGG repeats above 200).

How this comes into effect is that the fmr1 promoter becomes silenced via an epigenetic mechanism that involves DNA methylation of the CGG repeats and the surrounding regions. In turn, this decreases in the fmr1 transcription (from DNA to RNA), which subsequently leads to the loss of the FMRP, the protein that is needed for typical brain development.³

These variations in the CGG repeats can lead to diverse, adult-onset health problems or produce “a touch of fragile X syndrome” in some carriers. This is critical as it means that some carriers would have a really hard time raising their children with Fragile X Syndrome, especially if they themselves have limited or deteriorating executive functions.

This is an important fact about premutation carriers: they are raised by premutation carriers.

The Narrative

The author interweaves the stories of those affected by Fragile X—on its wide spectrum of baffling effects—and the science behind all what those affected have endured. An example account tells the story of Jessie, a 22-year-old patient who’s been worried about her premature menopause and her father who’s been developing tremors and other divergent ailments. They both later knew—after being genetically tested—that they suffer from fragile X-associated primary ovarian insufficiency and tremor/ataxia syndrome, respectively. They both have a premutation.

The stories of the great work done at the Medical Investigations for Neurodevelopmental Disorders (MIND) at the University of California by their team of perceptive and dedicated researchers, such as Dr. Randi Hagerman, was a page-turner. —Dr. Hagerman wrote the book’s foreword.

The chapter of the so-called village of fools showed us the captivating but tragic occurrences that had a great deal of impact on a whole community. These observations and accounts date back to the foundation of the town of Ricaurte, Columbia in the 1813. The empathetic curiosity and wondrous work of physician Wilmar Saldarriaga Gil recently uncovered to the residents of Ricaurte that most of their health misfortunes and strange behaviours had been hidden in their genes.

When doctors listen closely to their patients, with enough care, they are not just being kind. They are part of a process of discovery.

Shoutout: Julia Bell

Julia Bell (1879–1979) was an English scientist who co-discovered FXS¹. Bell came of age just as middle-class women were gaining access to universities. She was one of fourteen children, loved literature, and could wield a statistic with empathy. In addition to being a mathematician, she was also a medical doctor who had an impact on medical genetics that might have made her a more familiar name had she been a man.

“How very incurious most of us appear to be with regard to remarkable occurrences which do not touch upon our immediate needs and occupations.”

—Julia Bell, MA, MRCP in Plural Births with a New Pedigree

My Recommendation

Anyone who’s been gripped by the title of the book or its description would find it a delightful read, especially those interested in the biomedical sciences. The book is tightly wrapped around stories, human stories, which makes it a great read-for-leisure publication. This is because I don’t believe the author meant for the book to be used as a scientific reference. Its purpose: shedding light on an otherwise obscure genetic disorder.

It’s a great book that introduces a rather peculiar syndrome to the average reader. An intriguing genetic disorder with captivating accounts from the people affected by it, and the journey of its scientific discovery.

¹Also known as Martin-Bell Syndrome (it was described by James Purdon Martin and Julia Bell in the 1940s) or Marker X Syndrome.

²Siddhartha Mukherjee, The Gene (New York: Simon & Schuster, 2016).

³The central dogma of molecular biology implies that flawed proteins, masterminded by flawed RNA copied from flawed DNA, cause disease.

⁴The mutation is not in the protein-coding part of the gene, but in the area around it.

⁵Not every carrier is a patient or will ever be one. Many carriers are totally unaffected by the mutation, which adds to the complexity of the subject matter.

⁶Individuals who have an intermediate number of repeats (45 to 54) do not have FXS and are not at risk for having children with FXS. However, they have a higher chance of developing minor symptoms related to other fragile X-associated disorders.