A Genetic Crystal Ball: When Newborn Genome Sequencing Findings Explain Illnesses in Relatives

In 2019, I wrote about how sequencing the genomes of newborns might compromise their privacy if genetic information was not adequately protected as they grew up. Now five years later, researchers are recognizing a perhaps unexpected benefit of newborn DNA analysis – explaining seemingly unrelated symptoms in relatives.

Newborn Screening for Metabolites, not DNA

Screening newborns for telltale molecules other than DNA has been around for decades. Blood from a heel prick shortly after birth is tested for various molecules (metabolites) that serve as biomarkers of specific conditions.

The Recommended Uniform Screening Panel (RUSP) tests for 61 disorders. The list varies by state (see Baby’s First Test). Illinois tests for 57 conditions, for example, and California for 80. Separate programs have expanded the RUSP over the years.

The goal of newborn screening is to identify “actionable” conditions early enough to prevent or treat symptoms. But some people see newborn screening as creating “patients-in-waiting,” causing anxiety among new parents.

Although newborn screening can detect genetic disease, it doesn’t analyze DNA. It identifies too high or too low levels of certain amino acids and acylcarnitines, indicating disrupted metabolism of proteins and fats, respectively. The technique used is tandem mass spectrometry.

Sequencing DNA to classify gene variants is different. Genes are a cell’s instructions for linking precise sequences of amino acids into proteins.

Newborn Screening for DNA: GUARDIAN and BabySeq

Two programs have recently published findings on the value of sequencing a newborn’s DNA.

The Genomic Uniform-screening Against Rare Disease in All Newborns (GUARDIAN) study from New York-Presbyterian Hospital evaluated 4,000 children born at six New York City hospitals from September 2022 to July 2023. It sequenced the genes behind 156 early-onset genetic conditions and 99 neurodevelopmental disorders associated with seizures.  The selected conditions are treatable, especially if detected early. Findings were recently published in JAMA.

Wider in scope is BabySeq, which began in 2018. It sequenced exomes (the protein-encoding portion of a genome) or entire genomes, and identified 954 genes in which mutations fit three criteria:

• the associated condition begins during childhood
• if a mutation is present, so are symptoms (high penetrance)
• the condition is treatable, to some extent

BabySeq also looked for a few actionable adult-onset-only conditions from the American College of Medical Genetics and Genomics (ACMG) secondary findings list, such as familial cancer syndromes.

According to the announcement of BabySeq in Pediatrics:

“The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The BabySeq Project is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns.”

BabySeq tracked the children for five years, with initial findings reported in the July 2023 issue of The American Journal of Human Genetics.

The project enrolled 127 healthy infants and 32 sick infants from ICUs at two Boston hospitals. It also looked for a few actionable adult-onset conditions from the American College of Medical Genetics and Genomics (ACMG) secondary findings list.

The genomes of 17 of the children revealed actionable disease-causing mutations.

Among the 14 healthy babies, four would develop an enlarged and weakened heart – dilated cardiomyopathy – due to mutations in the TTN gene, which encodes a muscle protein (titin). Frequent EKGs and echocardiograms can detect the initial symptoms, which can then be treated with medication or devices. Affected children would avoid certain stimulants, choose certain sports, and follow a heart-healthy diet.

Another child had a narrow aorta, also detectable and fixable, and another had a vitamin (biotin) deficiency, treatable with supplements. Two newborns had BRCA2 mutations, leading three relatives to have surgery to prevent the associated cancers. Another child will be able to avoid hearing loss as a teen thanks to early detection.

Babies in the ICU for one condition were found to have another, revealed in DNA. A child hospitalized for a heart condition also had G6PD deficiency, which causes hemolytic anemia when eating certain foods. And an infant hospitalized for respiratory distress had inherited Lynch syndrome, which causes adult-onset colorectal, endometrial, gastric, and ovarian cancers.

A few of the children had mutations that would later affect metabolism of certain cancer and anti-inflammatory drugs.

An Unanticipated Benefit of Newborn DNA Sequencing: Explaining Relatives’ Illnesses

When BabySeq began in 2018, criticism centered on burdening parents with names of scary conditions that might not manifest for years – or ever. But after the five years of the study, the value of detecting treatable conditions before they manifest emerged: a newborn’s mutations may suddenly offer a new interpretation of symptoms in parents and siblings, aunts and uncles, grandparents, and cousins. This approach is especially valuable for extremely rare genetic conditions, which a health care provider who is not also a geneticist might not recognize.

Geneticists term multiple, seemingly unrelated symptoms stemming from a mutation in a single gene pleiotropy. Consider the rare Marfan and even rarer Alström syndromes.

Marfan Syndrome

Some symptoms of Marfan syndrome are obvious, if considered together: long arms, legs, fingers, and toes; a narrow, long face; a sunken or prominent chest due to collapsed lungs; and flat feet. scoliosis, and highly flexible joints. But a patient with only one or two of these traits might escape notice. And some Marfan symptoms don’t appear until adulthood, such as myopia, cataracts, and dislocated lenses. 

Diagnosis of Marfan’s typically follows cardiac events, such as leaky heart valves or a torn (dissected) aorta that can bulge and rupture (an aneurysm). If the weakening is detected early, a synthetic graft can replace the section of artery wall and save the person’s life. But sometimes Marfan’s makes its presence known as an emergency.

That happened to playwright Jonathan Larson, who wrote Rent, about the early days of AIDS. He died suddenly in 1996, the day before Rent opened on Broadway, due to an aortic dissection later recognized as having been caused by Marfan syndrome. According to The Marfan Foundation, “he displayed many of the outward signs, but had never been diagnosed. Two New York City hospital emergency departments failed to recognize the signs of aortic dissection or that Jonathan had many features of Marfan, which put him at high risk for aortic dissection.”

Other famous folks who had Marfan syndrome are Abraham Lincoln, Julius Caesar, King Tut, and Olympic swimmer Michael Phelps.

A dominant mutation in the gene FBN1 causes Marfan syndrome. The gene encodes the protein fibrillin-1, which comprises the elastic fibers of connective tissue, affecting blood vessels, bones, and cartilage. The condition is inherited from one parent about 75 percent of the time; other cases arise from a new mutation. Testing a patient’s parents can reveal whether the mutation is new or inherited, which has implications for other family members.

Genome sequencing can reveal Marfan syndrome even if a newborn doesn’t have the telltale long limbs and sunken or protruding chest, or whose provider doesn’t recognize the signs. And so a genetic diagnosis might instantly explain how an aunt died of an aortic aneurysm, a sibling with dislocated lenses and a long face, a grandparent who couldn’t serve in the military due to flat feet, and a cousin who is a gifted dancer thanks to great flexibility.

Alström Syndrome

The incidence (population frequency) of Marfan Syndrome is 1 in 5,000, fairly high for a single-gene disorder. In contrast, Alström syndrome affects from 1 in 10,000 to fewer than 1 in 1,000,000 people. Only 1200 cases have been recognized. But newborn genome sequencing can change that.

The list of symptoms for Alström syndrome is so long, and the sets of symptoms among patients so variable, that it’s understandable that practitioners might not recognize the underlying genetic cause. And like Marfan’s, some Alström symptoms do not appear until adulthood.

Alström syndrome affects vision and hearing; causes childhood obesity, insulin resistance and diabetes mellitus; dilated cardiomyopathy; degenerating kidneys; and can involve the liver, lungs, and bladder as well as hormone secretion. Intelligence is typically spared, but children may be short and experience developmental delays.

The varied symptoms arise from a mutation in a gene, ALMS1. It encodes a protein that forms a base from which tail-like cilia emerge from cells. The atypical cilia cause diseases called “ciliopathies,” for “sick cilia.” Because cilia control movement of substances within and among cells and control cell division, when they are impaired, many symptoms arise.

Unlike the dominant inheritance of Marfan syndrome, in which one affected parent passes on the condition, Alström syndrome is recessive; two carrier parents are unaffected but transmit their mutations. So if newborn genome sequencing identifies a child with two copies of a mutation in ALMS1, then the parents are presumably both carriers. Siblings face a 25 percent risk of inheriting the condition.

CODA

More time is needed to assess the potential impact of newborn DNA sequencing. But I think that the potential sacrifice of some privacy in identifying mutations, especially actionable ones, promises to improve the health of many other individuals.