Next-generation genomic sequencing allows clinicians and researchers to identify a wide variety of genetic variants that could lead to disease based on constantly evolving information. Now, a new multi-institutional study led by researchers at Children’s Hospital of Philadelphia (CHOP) has learned more about secondary findings – variants identified through sequencing but separate from the primary diagnosis of a patient – in a large, diverse cohort of patients enriched for African American ancestry.
The findings, recently published in the journal Genetics in Medicine, also identified genes that could be added to future standard lists of frequent secondary findings in sequencing.
Genomic sequencing is often performed to look for variants associated with disorders that are driven by genetic mutations. At CHOP, genomic sequencing is used to help diagnose a variety of congenital and developmental disorders as well as certain types of cancer. Secondary findings are interpreted as potentially pathogenic variants in genes associated with medically actionable conditions, which are distinct from the symptoms associated with an initial diagnosis. The American College of Medical Genetics and Genomics (ACMG) maintains a list of secondary findings, many of which are associated with cardiomyopathy. Currently, there are 82 genes on the secondary findings list, with more being added with new discoveries as more patients receive genome sequencing.
However, many of these secondary findings have been found in adult populations and have not necessarily reflected diverse populations of patients. The goal of this study was to apply sequencing to a large sample of pediatric patients with diverse racial and ethnic backgrounds. Translational research studies like this have the potential to significantly expand the ever-growing ACMG secondary findings gene list, capturing a broader range of medically actionable genetic variants identified in multiethnic cohorts with potential therapeutic implications.
“By applying these findings to a pediatric population of patients, we could identify pathogenic or likely pathogenic secondary findings that could reduce health risks later in life,” said first study author Amir Hossein Saeidian, PhD, a current second-year laboratory genetics and genomics fellow at Baylor College of Medicine who conducted this research at the Center for Applied Genomics (CAG) at CHOP. “For example, if a patient had a secondary finding of a variant that could lead to cardiomyopathy, that patient could start interventions earlier or avoid heart-straining activities that could put them at higher risk for complications.”
Using ACMG secondary finding guidelines and other genetic variant criteria, the researchers systematically identified pathogenic and likely pathogenic variants in established disease-causing genes in a population of 16,713 participants who were predominantly African American. The study found 1,464 pathogenic or likely pathogenic variants, including 427 unique variants in ACMG secondary finding genes and 265 in genes not yet included on the ACMG list, suggesting that more genes could be added to the list in the future.
In particular, the gene TTR, which helps produce the protein transthyretin to transport vitamin A and thyroid hormones throughout the body when functioning normally, was the most frequently mutated gene in African Americans, a finding that might not have been emphasized in a less diverse cohort of patients. Overall, variants of potential medical importance were found in 8.76% of all participants, including both ACMG genes (5.81%) and non-ACMG genes (2.95%).
“Our biobank is the fundamental resource a study like this can be done, and we are grateful that our patient families have contributed to making research like this a success,” said senior study author Hakon Hakonarson, MD, PhD, director of the CAG at CHOP. “This study allows us to take these research findings, further validate them clinically, and add any such actionable variant to the electronic health records of the patients who made this possible and help these families make informed decisions about their health in a genetic counseling setting.”
Saeidian et al., “Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants.” Genet Med. Online July 31, 2024. DOI: 10.1016/j.gim.2024.101225
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Next-generation genomic sequencing allows clinicians and researchers to identify a wide variety of genetic variants that could lead to disease based on constantly evolving information. Now, a new multi-institutional study led by researchers at Children’s Hospital of Philadelphia (CHOP) has learned more about secondary findings – variants identified through sequencing but separate from the primary diagnosis of a patient – in a large, diverse cohort of patients enriched for African American ancestry.
The findings, recently published in the journal Genetics in Medicine, also identified genes that could be added to future standard lists of frequent secondary findings in sequencing.
Genomic sequencing is often performed to look for variants associated with disorders that are driven by genetic mutations. At CHOP, genomic sequencing is used to help diagnose a variety of congenital and developmental disorders as well as certain types of cancer. Secondary findings are interpreted as potentially pathogenic variants in genes associated with medically actionable conditions, which are distinct from the symptoms associated with an initial diagnosis. The American College of Medical Genetics and Genomics (ACMG) maintains a list of secondary findings, many of which are associated with cardiomyopathy. Currently, there are 82 genes on the secondary findings list, with more being added with new discoveries as more patients receive genome sequencing.
However, many of these secondary findings have been found in adult populations and have not necessarily reflected diverse populations of patients. The goal of this study was to apply sequencing to a large sample of pediatric patients with diverse racial and ethnic backgrounds. Translational research studies like this have the potential to significantly expand the ever-growing ACMG secondary findings gene list, capturing a broader range of medically actionable genetic variants identified in multiethnic cohorts with potential therapeutic implications.
“By applying these findings to a pediatric population of patients, we could identify pathogenic or likely pathogenic secondary findings that could reduce health risks later in life,” said first study author Amir Hossein Saeidian, PhD, a current second-year laboratory genetics and genomics fellow at Baylor College of Medicine who conducted this research at the Center for Applied Genomics (CAG) at CHOP. “For example, if a patient had a secondary finding of a variant that could lead to cardiomyopathy, that patient could start interventions earlier or avoid heart-straining activities that could put them at higher risk for complications.”
Using ACMG secondary finding guidelines and other genetic variant criteria, the researchers systematically identified pathogenic and likely pathogenic variants in established disease-causing genes in a population of 16,713 participants who were predominantly African American. The study found 1,464 pathogenic or likely pathogenic variants, including 427 unique variants in ACMG secondary finding genes and 265 in genes not yet included on the ACMG list, suggesting that more genes could be added to the list in the future.
In particular, the gene TTR, which helps produce the protein transthyretin to transport vitamin A and thyroid hormones throughout the body when functioning normally, was the most frequently mutated gene in African Americans, a finding that might not have been emphasized in a less diverse cohort of patients. Overall, variants of potential medical importance were found in 8.76% of all participants, including both ACMG genes (5.81%) and non-ACMG genes (2.95%).
“Our biobank is the fundamental resource a study like this can be done, and we are grateful that our patient families have contributed to making research like this a success,” said senior study author Hakon Hakonarson, MD, PhD, director of the CAG at CHOP. “This study allows us to take these research findings, further validate them clinically, and add any such actionable variant to the electronic health records of the patients who made this possible and help these families make informed decisions about their health in a genetic counseling setting.”
Saeidian et al., “Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants.” Genet Med. Online July 31, 2024. DOI: 10.1016/j.gim.2024.101225
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