Abstract
Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.
| Original language | English |
|---|---|
| Pages (from-to) | 806-816 |
| Number of pages | 11 |
| Journal | Journal of the Endocrine Society |
| Volume | 2 |
| Issue number | 7 |
| Early online date | 18 Jun 2018 |
| DOIs | |
| Publication status | Published - 1 Jul 2018 |
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Keywords
- GnomAD
- mutation
- paraganglioma
- penetrance
- pheochromocytoma
- SDHA
Cite this
}
Pathogenicity and penetrance of germline SDHA variants in pheochromocytoma and paraganglioma (PPGL). / Maniam, Pavithran; Zhou, Kaixin; Lonergan, Mike; Berg, Jonathan; Goudie, David; Newey, Paul (Lead / Corresponding author).
In: Journal of the Endocrine Society, Vol. 2, No. 7, 01.07.2018, p. 806-816.Research output: Contribution to journal › Article
TY - JOUR
T1 - Pathogenicity and penetrance of germline SDHA variants in pheochromocytoma and paraganglioma (PPGL)
AU - Maniam, Pavithran
AU - Zhou, Kaixin
AU - Lonergan, Mike
AU - Berg, Jonathan
AU - Goudie, David
AU - Newey, Paul
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.
AB - Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.
KW - GnomAD
KW - mutation
KW - paraganglioma
KW - penetrance
KW - pheochromocytoma
KW - SDHA
U2 - 10.1210/js.2018-00120
DO - 10.1210/js.2018-00120
M3 - Article
VL - 2
SP - 806
EP - 816
JO - Journal of the Endocrine Society
JF - Journal of the Endocrine Society
SN - 2472-1972
IS - 7
ER -