Clinical Utility of Exome and Genome Sequencing in an Adult Cohort Referred for Suspicion of Underlying Rare Disease
Laboratory Genetics and Genomics
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction:
Exome sequencing (ES) and genome sequencing (GS) have proven themselves to be powerful diagnostic tools when evaluating for rare disease in children. However, the value of exome and genome sequencing for the purpose of identifying causes of rare disease in adults remains less well documented, and the indications for when it is warranted less clear.
Methods:
A pilot investigation of the 50 most recent adult (18 years +) individuals who had ES or GS through Mayo Clinic Laboratories (MCL) was undertaken. This cohort was evaluated for characteristics including age, sex, indications for testing, history of previous testing, and outcomes of testing, and compared to an identically collected cohort of children.
Results:
The average age of adult probands was 46.6 years (range 18-80; median 49.5); the average age of children was 3.5 years (range newborn to 16 years; median 21 months). Most adults had GS (80%), whereas most children had ES (70%). Fewer adults had testing that included one or more relative as a comparator (16% of adults vs. 38% of children). Sex assigned at birth in the adult group was majority female (70%), compared to 44% of children who were female. Fewer adults had genetic testing prior to ES or GS (54% of adults vs. 82% of children).
Adult probands had a greater average number of phenotypic terms selected related to their reason for testing (10.8 per adult vs. 8.2 per child (range 2-26, median 10 for adults; range 2-19, median 8 for children). In both groups, a neurological or neurodevelopmental primary indication was most common (42% of adults and 50% of children). The number of adults with more than one primary indication for testing was significantly higher (28% of adults vs. 6% of children) (p<.01).
Nine of the 50 adults (18%) had results that were considered either a partial, probable, or definitive solve, compared to 15/50 children (30%). The average age of adults in the partial, probable, or definitive solve group (mean 34.4 years; range 18-67; median 26) was lower than the age of adults in the unsolved group (mean 49.9 years; range 20-80; median 51.5) (p=.026). Seven of the 9 adults in the partial, probable, or definitive solve group (78%) had an underlying neurological or neurodevelopmental primary reason for testing. Of adults submitted with at least one other family member comparator, 25% had a partial, probable, or definitive solve, compared to 42% of children.
Conclusion:
There are challenges in interpreting ES and GS data in an adult population. Notably, adults tend to have more comorbidities than children, reflected by the high number of individuals with multiple primary indications, along with the increased number of clinical features per proband. This complicated the phenotypic picture and at times made the primary constellation of features more difficult to identify. Additionally, adults were less likely to have family members serving as comparators, meaning that the inheritance of identified variants was less likely to be known. The diagnostic yield was higher in those adults submitted with at least one other family member, though increasing the sample size would be beneficial to confirm that this correlation is significant.
Even with the challenges of an adult population, 18% of adults referred for exome or genome sequencing at MCL had primary diagnoses that could be considered a partial, probable, or definitive solve. Further, 2 of the 9 individuals (22%) received a diagnosis on GS that would not have been identifiable on ES. This data supports the utility of offering GS to an adult population with complex disease, with higher diagnostic yield in younger adults with neurologic presentations.
Exome sequencing (ES) and genome sequencing (GS) have proven themselves to be powerful diagnostic tools when evaluating for rare disease in children. However, the value of exome and genome sequencing for the purpose of identifying causes of rare disease in adults remains less well documented, and the indications for when it is warranted less clear.
Methods:
A pilot investigation of the 50 most recent adult (18 years +) individuals who had ES or GS through Mayo Clinic Laboratories (MCL) was undertaken. This cohort was evaluated for characteristics including age, sex, indications for testing, history of previous testing, and outcomes of testing, and compared to an identically collected cohort of children.
Results:
The average age of adult probands was 46.6 years (range 18-80; median 49.5); the average age of children was 3.5 years (range newborn to 16 years; median 21 months). Most adults had GS (80%), whereas most children had ES (70%). Fewer adults had testing that included one or more relative as a comparator (16% of adults vs. 38% of children). Sex assigned at birth in the adult group was majority female (70%), compared to 44% of children who were female. Fewer adults had genetic testing prior to ES or GS (54% of adults vs. 82% of children).
Adult probands had a greater average number of phenotypic terms selected related to their reason for testing (10.8 per adult vs. 8.2 per child (range 2-26, median 10 for adults; range 2-19, median 8 for children). In both groups, a neurological or neurodevelopmental primary indication was most common (42% of adults and 50% of children). The number of adults with more than one primary indication for testing was significantly higher (28% of adults vs. 6% of children) (p<.01).
Nine of the 50 adults (18%) had results that were considered either a partial, probable, or definitive solve, compared to 15/50 children (30%). The average age of adults in the partial, probable, or definitive solve group (mean 34.4 years; range 18-67; median 26) was lower than the age of adults in the unsolved group (mean 49.9 years; range 20-80; median 51.5) (p=.026). Seven of the 9 adults in the partial, probable, or definitive solve group (78%) had an underlying neurological or neurodevelopmental primary reason for testing. Of adults submitted with at least one other family member comparator, 25% had a partial, probable, or definitive solve, compared to 42% of children.
Conclusion:
There are challenges in interpreting ES and GS data in an adult population. Notably, adults tend to have more comorbidities than children, reflected by the high number of individuals with multiple primary indications, along with the increased number of clinical features per proband. This complicated the phenotypic picture and at times made the primary constellation of features more difficult to identify. Additionally, adults were less likely to have family members serving as comparators, meaning that the inheritance of identified variants was less likely to be known. The diagnostic yield was higher in those adults submitted with at least one other family member, though increasing the sample size would be beneficial to confirm that this correlation is significant.
Even with the challenges of an adult population, 18% of adults referred for exome or genome sequencing at MCL had primary diagnoses that could be considered a partial, probable, or definitive solve. Further, 2 of the 9 individuals (22%) received a diagnosis on GS that would not have been identifiable on ES. This data supports the utility of offering GS to an adult population with complex disease, with higher diagnostic yield in younger adults with neurologic presentations.