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Sequencing Leads to Diagnoses in Significant Subset of Immune Conditions in NIAID Program

NEW YORK – Clinical sequencing may lead to molecular diagnoses in around one-third of families affected by undiagnosed immune conditions, new research suggests, including diagnoses with potential treatment implications.

At the American College of Medical Genetics and Genomics annual meeting on Friday, National Institute of Allergy and Infectious Diseases lead genetic counselor Morgan Similuk presented findings from the first 1,000 immune disease-affected families participating in a clinical sequencing program at a NIAID tertiary care center in Bethesda, Maryland.

"We have developed a program of clinical molecular genetic analysis in a large cohort of participants referred for diverse immunologic phenotypes," Similuk and her coauthors wrote in an abstract accompanying the presentation, adding that "[c]linicians and researchers should consider the contribution of non-immune disease genes to complex phenotypes."

When establishing the program, the team set out to establish, implement, and continue evolving best practices in a clinical research genomics setting, Similuk explained. This included steps for doing molecular evaluations and timely diagnostic testing in a CLIA-certified lab, documenting those findings in individuals' electronic medical records, and developing strategies for sharing and working with genomic and phenotypic data to facilitate related research efforts, she explained.

"We tried to level out the playing field," she said. "Starting in 2017, we offered exome sequencing — it's now genome sequencing — to nearly all patients that come to NIAID for clinical research."

Along with potentially diagnostic findings, the team provides EMR reports that document negative or inconclusive findings, as well as any secondary findings that involve pathogenic or likely pathogenic variants in genes unrelated to the condition being considered. Results are also returned directly to patients and their family members.

From 2017 to 2019, the researchers did clinical exome sequencing on more than 1,500 individuals from 1,000 families with immune system-related phenotypes, including affected individuals with extensive and wide-ranging clinical indications.

"We're a tertiary care center, so this population might be enriched for complex clinical presentations," Similuk noted. "But also, the immune system flows throughout your body … so it's very consistent with the way immunology works to have [for example] involvement of your eyes and of your skin and a risk of cancer, all related to a defect of the immune system."

Around 80 percent of the families had self-reported European ancestry that was confirmed with ancestry analyses on available sequence data. A smaller proportion of the participating families had either admixed American, African, East Asian, or South Asian ancestry.

Through clinical grade analyses on these protein-coding sequences, the investigators identified variants linked to 362 molecular diagnoses in 328 of the affected individuals. Of those, nearly 70 percent of the diagnoses involved conditions with autosomal dominant inheritance, while almost 22 percent were classified as autosomal recessive, and just over 9 percent were X-linked conditions.

In a subset of 374 individuals assessed by chromosomal microarray testing, the team tracked down 18 diagnostic copy number variants — a molecular diagnostic yield of roughly 4.5 percent.

Across the suite of suspicious variants identified in the patients, Similuk noted that more than 19 percent had not been reported in the literature. Moreover, around one-quarter of the affected genes or regions had not been implicated in immune function previously, along with diagnoses based on alterations in non-immune, noninfectious disease genes.

In a 5-year-old child with a history of complex fungal infections affecting the brain, lungs, and other parts of the body, for example, the researchers identified a PMP22 duplication that led to a diagnosis of Charcot-Marie-Tooth peripheral neuropathy that had been missed in previous neurology consultations. Although that condition did not influence her infection history, Similuk explained, the diagnosis did have treatment implications, since certain anti-fungal medications are contraindicated for individuals with Charcot-Marie-Tooth peripheral neuropathy.

"This diagnosis not only helped us better understand her neurological phenotype," she noted, "but also allowed us to make a more informed choice about her anti-fungal therapy."

Along with additional cases involving new immune-related genes, the team identified several patients with multiple molecular diagnoses, and flagged secondary findings in almost 3 percent of the participants.

The team has also established guidelines for reanalyzing sequences from the program's participants, to continue incorporating insights coming out of genetic studies. Cases are reviewed and reanalyzed within 15 to 34 months of the first analysis, or as requested by healthcare providers. Such reanalyses have already led to nearly two-dozen new diagnoses.

The NIAID investigators estimated that their sequencing- or CNV-based molecular diagnoses opened the door to new treatment options for nearly 70 percent of the newly diagnosed patients, Similuk reported, including supportive or preventive therapies, targeted treatments, or stem cell transplants.

"These genomic data will enrich our understanding of basic immunity, molecular diagnostics, and clinical care both for the 1,000 families included here, as well as many of the families who will be evaluated in the coming years," she and her coauthors wrote.