Genetic testing encouraged as part of immunodeficiency management

Key takeaways:

• Genetic testing can yield information on diagnosis, risk for recurrence, prognosis and treatment.
• Genetic diagnoses may increase insurance eligibility.
• Social support and educational resources may help families.

BOSTON — Genetic testing can play a positive role and help improve outcomes in managing immunodeficiencies, according to a presentation at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.

“Why should I be doing genetic testing? Why should I devote 5 to 10 minutes out of my busy schedule?” Ivan Chinn, MD, director, immunogenetics program, Texas Children’s, hypothetically asked during his lecture.

Although demands include completing requisition forms, writing letters of medical necessity and arguing with insurance companies, Chinn said, “genetic testing informs diagnosis, recurrence risk, prognosis and treatment.”

Diagnosis

“We do need a diagnosis because it helps improve health care costs,” Chinn said.

There have not been any extensive studies of the impact of diagnosis on costs in immune disorders, Chinn noted, but one hospital system found that rapid whole genome sequencing saved more than $100,000 per patient with a critical illness.

“Somebody needs to look at this,” he said.

The impact of genetic testing on psychosocial health also has not been extensively studied, Chinn continued. However, he said, the Undiagnosed Diseases Network has found that “the diagnostic odyssey actually produces a huge psychosocial burden on parents.”

Among 65 parents of 39 affected children, 18.2% reported mild depression and 15.9% reported moderate depression. Also, anxiety was mild for 25%, moderate for 13.7% and severe for 2.3%.

“These parents had developed high coping skills,” Chinn said. “I don’t know if that’s a good thing or a bad thing.”

Still, Chinn said, diagnosis is necessary.

“We like to say it justifies costs and it really helps families. It makes a lot of sense,” he said. “But we actually do need those studies to prove that.”

Recurrence risk

“Not all of us have a genetic counselor in our clinic,” Chinn said. “Sometimes, it comes upon us ourselves to try to provide familial counseling once we get one of these genetic diagnoses.”

Chinn also said that “sometimes, the diagnosis alone is not enough,” as he cited a case series involving families with multiple children impacted by immunodeficiencies.

In one case, consanguineous parents had a child with leukocyte adhesion deficiency type 1 (LAD1) who died because of a homozygous variant. The father refused prenatal testing before they had a second child, who also was diagnosed with LAD1 and faced numerous subsequent complications.

Also, the mother of a boy with recurrent infections and an X-linked agammaglobulinemia (XLA) had amniocentesis when she was pregnant with a second son, whom also was then diagnosed with XLA.

Another pair of consanguineous parents with two children who had ataxia-telangiectasia mutations used egg donation to conceive their third child, who was healthy.

Chinn additionally described a case of parents whose child had Wiskott-Aldrich syndrome. After genetic counseling, they decided to get prenatal testing and pursue in vitro fertilization, and their next child was healthy.

“Genetic counseling is absolutely essential. Shared decision-making is also important. You cannot force parents or families to do things they don’t want to do,” Chinn said.

Social support and educational resources also are necessary, Chinn said.

“These materials really need to be sensitive to ethical and cultural issues,” Chinn said, noting that the case series involved parents from the Middle East and adding that the COVID-19 pandemic highlighted a lot of distrust with the medical system, even in the United States.

Physicians should mind economic constraints and legal considerations too, he said.

“Not everyone can afford to do prenatal genetic testing or in vitro fertilization,” Chinn said, adding that physicians are no longer able to counsel patients about abortion in states where it is no longer legal.

Prognosis

The prognosis helps explain what families can expect once their child has a genetic diagnosis, Chinn said.

Chinn described an infant whose newborn screening revealed low but not undetectable T-cell receptor excision circles (TRECs). The gene panel indicated that the infant had the FOXN1 variant, which produces a premature stop codon at residue 255.

“So, what can we tell the family?” Chinn asked. “Now that we have this genetic diagnosis, we can tell them a lot.”

For example, Chinn said, the NIH has found that certain heterozygous FOXN1 variants are associated with low TRECs and T-cell deficiency. But when these patients were followed, T-cell counts increased on their own.

“Most of these patients are OK. Very few of them actually had infections, and very few of them had really many complications at all,” Chinn said. “You can tell them that the T-cell count should improve on their own over time, that severe immune deficiency is not predicted, and we can just watch your child.”

Treatment

“This is probably the main reason why most of us get the genetic testing,” Chinn said. “Genetic testing unquestionably impacts treatment in patients with suspected inborn errors of immunity.”

Multiple studies have found that genetic diagnoses can impact treatment for anywhere from 1 in 10 patients to approximately 1 in 3 patients, Chinn said. Also, the NIH has found that diagnosis can open the doors for treatment in 70% of cases.

“This is really important,” Chinn said.

Chinn also cited the five I’s of treatment: isolation, immunization, insurance, IgG replacement therapy and infectious prophylaxes.

“Does your child need to be in isolation?” Chinn said. “Should they get any immunizations, or should they avoid certain immunizations?”

Patients with genetic diagnoses also may be eligible for disability insurance, he continued.

“If you have a certain genetic diagnosis, you can justify starting an IgG replacement therapy without having to put them through prolonged testing,” Chinn said. “Giving vaccines and checking titers, screen and post, and so on and so forth can take months.”

But with a genetic diagnosis, patients can start right away, he said.

“And then you can start infection prophylaxis when needed,” Chinn said.

Targeted therapies for inborn errors of immunity such as Janus kinase inhibitors and phosphoinositide 3-kinase inhibitors are available.

“Once you have that genetic diagnosis, you can consider starting any of these kinds of medications,” Chinn said, adding that genetic diagnoses also are important for initiating curative therapies.

Chinn described an infant girl who was born with no T cells. Testing identified a 22q11.2 deletion and a lack of B cells. Additional genetic testing found biallelic DCLRE1C deletions. The girl received a hematopoietic stem cell implant from a human leukocyte antigen identical sibling, and her immune system was reconstituted within 4 to 5 months.

“Sometimes it does help to get that additional genetic testing done,” Chinn said. “Genetic testing can help to inform decisions about certain things in terms of transplants.”

Cultured thymus tissue implantations also are available.

“There are options now for gene therapy, and they’re growing every day,” Chinn added. “People are now trying things called gene editing, or, instead of doing gene therapy, whole gene replacement, you just edit the defective gene.”

However, he cautioned, genetic diagnoses are required for gene therapy and editing.

A lack of diagnosis

Testing can still be helpful even when it does not provide a diagnosis, Chinn said.

Chinn cited a case involving an infant boy who developed herpes simplex virus type 2 (HSV-2) lesions on his left thigh at age 15 days. These lesions resolved with 5 days of oral acyclovir treatment but returned 2 days after treatment had finished.

Another 21 days of acyclovir followed, in addition to prophylaxis, but the HSV-2 lesions returned at age 8 months. Providers increased the acyclovir dose and continued prophylaxis.

“Then they said, ‘Is something wrong with his immune system?’” Chinn said. “So, they referred him to allergy and immunology, to me.”

Testing indicated normal numbers of T, B, and NK cells and normal T-cell proliferation of mitogens and antigens, but his CD56 bright-to-dim ratio was diminished. He also had normal NK cell natural cytotoxicity, but the antibody-dependent cytotoxicity was absent.

“He did otherwise have normal CD107A mobilization,” Chinn said.

Plus, cytotoxic T lymphocyte (CTL) function was decreased, and he had no IgG to HSV-2.

“So, we said, ‘Well, OK, there are some immune problems here. Are they due to the virus? Are they due to some inherent genetic problem?’”

Trio exome sequencing did not uncover any known inborn errors of immunity or any novel candidates.

“With that information, we said, ‘We think this child might outgrow this at some point, if we just maybe wait long enough,’” Chinn said. “So, in some sense, not having a genetic diagnosis was kind of encouraging.”

Chinn and his colleagues advised against giving the child any live viral immunizations.

At age 21 months, the child developed a mild breakthrough on his lip despite the prophylaxis, and NK cell antibody dependent cytotoxicity normalized at age 2 years.

“We thought that was encouraging,” Chinn said.

There was another breakthrough on his legs at almost age 3 years even with prophylaxis.

“But then at 4 years of age, he finally developed IgG antibody to HSV-2, and we said, ‘Oh, that’s a really good sign,’” Chinn said. “We actually talked to our infectious disease doctors and said, ‘Maybe we can try stopping the acyclovir,’ which we did.”

An attempt to give the boy the varicella vaccine at that point resulted in a mild case of vaccine-induced varicella that was treated with acyclovir with a return to prophylaxis.

“So that didn’t work,” Chinn said.

The boy experienced another mild breakthrough on his legs at age 4.5 years despite prophylaxis, but at age 5 years, CTL function normalized.

“So, we said, ‘OK, let’s try this again.’ We stopped the acyclovir prophylaxis at 5, and we tried the varicella vaccination again,” Chinn said. “This time, it was successful.”

Podium to practice

Chinn said that genetic testing can benefit patients.

“We can justify the reasons why we need diagnoses in a number of ways. Some of them are supported by good evidence. Some of them are not,” Chinn said. “Still, I would say, get the testing done.”

Chinn also emphasized the need for social support and educational resources for these families.

“They need that trust,” he said. “If they don’t get the trust from our medical system, they won’t listen to their doctors, they might listen to their peers. They might listen to other family members.”

And even when genetic testing does not yield a diagnosis, he said, it can still impact management.

“So, don’t use that as an excuse not to send for testing,” Chinn said.