TY - JOUR
T1 - Quantifying evidence toward pathogenicity for rare phenotypes
T2 - The case of succinate dehydrogenase genes, SDHB and SDHD
AU - Garrett, Alice
AU - Loveday, Chey
AU - King, Laura
AU - Butler, Samantha
AU - Robinson, Rachel
AU - Horton, Carrie
AU - Yussuf, Amal
AU - Choi, Subin
AU - Torr, Beth
AU - Durkie, Miranda
AU - Burghel, George J
AU - Drummond, James
AU - Berry, Ian
AU - Wallace, Andrew
AU - Callaway, Alison
AU - Eccles, Diana
AU - Tischkowitz, Marc
AU - Tatton-Brown, Katrina
AU - Snape, Katie
AU - McVeigh, Terri
AU - Izatt, Louise
AU - Woodward, Emma R
AU - Burnichon, Nelly
AU - Gimenez-Roqueplo, Anne-Paule
AU - Mazzarotto, Francesco
AU - Whiffin, Nicola
AU - Ware, James
AU - Hanson, Helen
AU - Pesaran, Tina
AU - LaDuca, Holly
AU - Buffet, Alexandre
AU - Maher, Eamonn R
AU - Turnbull, Clare
AU - Cancer Variant Interpretation Group UK (CanVIG-UK)
PY - 2022/1
Y1 - 2022/1
N2 - PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain.METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features.RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD).CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.
AB - PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain.METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features.RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD).CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.
KW - Adrenal Gland Neoplasms/genetics
KW - Germ-Line Mutation
KW - Humans
KW - Phenotype
KW - Succinate Dehydrogenase/genetics
KW - Virulence
UR - https://www.sciencedirect.com/science/article/pii/S1098360021011187?via%3Dihub
U2 - 10.1016/j.gim.2021.08.004
DO - 10.1016/j.gim.2021.08.004
M3 - Article
C2 - 34906457
SN - 1098-3600
VL - 24
SP - 41
EP - 50
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 1
ER -