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Secondary Findings Uncovered in 9 Percent of Parents in Trio Sequencing Study

NEW YORK (GenomeWeb) – Researchers uncovered secondary findings in 9 percent of parents who were sequenced as part of a trio study searching for the cause of a condition affecting their children.

The main goal of HudsonAlpha Institute for Biotechnology's Clinical Sequencing Exploratory Research (CSER) study was to use sequencing to find the genetic roots of developmental delay and intellectual disability in a cohort of children, it also sequenced the parents of those children. In those unaffected parents, the researchers assessed whether they harbored pathogenic or likely pathogenic variants in genes on the American College of Medical Genetics and Genomics' list of incidental results to be returned as well as in other genes in ClinVar and their carrier status for three additional genes.

As they reported in Genetics in Medicine yesterday, Cooper and his colleagues found pathogenic or likely pathogenic variants in 25 parents, including in individuals with no symptoms of disease. They also reported that most parents were open to receiving most of these secondary results.

"This study demonstrates the utility of returning secondary variants, as it may facilitate preventive screening for individuals who are genetically predisposed to serious diseases," the researchers wrote in their paper.

Within sequencing data from 789 parents, the researchers searched for pathogenic or likely pathogenic variants in those ACMG genes and in other genes in ClinVar, as well as performed a carrier screen for cystic fibrosis, sickle cell disease, and Tay-Sachs disease variants.

Cooper and his colleagues also queried the parents as to whether they wanted to receive these secondary findings. While 85 percent wanted all of their results, a small percentage, 1.6 percent, did not want any of them. Others wanted some of their results — often related to breast, ovarian, testicular or prostate cancer risk — but not all. The researchers only returned pathogenic or likely pathogenic results to those who consented to receive them.

Overall, the researchers uncovered such variants in 21 genes in 25 individuals, or 3.2 percent of their cohort.

Five of these individuals had a previous clinical diagnosis, though no known genetic cause of their condition. For instance, the researchers found a splice donor site variant affecting the polycystic kidney disease-linked gene PKD2 in a 36-year-old woman with the condition, and a frameshift variant in the dilated cardiomyopathy-linked genes DSG2 in a 40-year-old woman who experienced post-partum cardiomyopathy.

Other individuals in whom the researchers found secondary findings hadn't been diagnosed with a condition, though the variant uncovered could explain some symptoms they experienced or their family history. They found, for example, a heterozygous missense mutation in CLCN1 in a 29-year-old woman who had complained of leg cramps. CLCN1, they noted, is associated with myotonia congenita, which is marked by muscle stiffness. Her mother, they noted, had been diagnosed with the condition.

Secondary findings, though, were also found in people with no signs of disease, such as a 52-year-old woman with a variant in the long QT-linked gene SCN5A and a 52-year-old man with a variant in the cancer-linked RET gene.

These secondary findings have led a number of the parents to follow up with specialists. A man with a frameshift mutation in PMS2 sought a colonoscopy screening, while a woman with a missense SCN4A variant consulted with a neurologist, Cooper and his colleagues reported.

The carrier screen, meanwhile, uncovered 15 variants in 48 parents, or 6.1 percent of participants. In particular, they found eight cystic fibrosis-linked CFTR variants in 35 people, four Tay-Sachs-linked HEXA variants in five people, and three sickle cell disease-linked HBB variants in eight people. They also uncovered three parent pairs with recessive mutations affecting the same genes.

Cooper and his colleagues said their findings show the utility of returning secondary results.

They added that a challenge in their study arose when the secondary analysis uncovered a finding in a parent, but failed to find a cause of disease in their child, the primary focus of the analysis. Fifty-six percent of the parents who received a secondary finding had a child who did not receive a result.

"This fact highlights the potential financial, emotional, and clinical implications of secondary findings that should be clearly addressed in the informed consent discussion prior to sequencing so that families are aware of all the possible outcomes of this type of testing," the authors wrote.