TY - JOUR
T1 - Addition of H19 'loss of methylation testing' for Beckwith-Wiedemann syndrome (BWS) increases the diagnostic yield
AU - Lennerz, Jochen K.
AU - Timmerman, Robert J.
AU - Grange, Dorothy K.
AU - DeBaun, Michael R.
AU - Feinberg, Andrew P.
AU - Zehnbauer, Barbara A.
N1 - Funding Information:
Supported by National Institutes of Health grant CA54358 (to A.P.F.).
PY - 2010/9
Y1 - 2010/9
N2 - Beckwith-Wiedemann syndrome (BWS) is a clinical diagnosis; however, molecular confirmation via abnormal methylation of DMR2(LIT1) and/or DMR1(H19) has clinical utility due to epigenotype-tumor association. Despite the strong link between H19 hypermethylation and tumor risk, several diagnostic laboratories only test for hypomethylation of LIT1. We assessed the added diagnostic value of combined LIT1 and H19 testing in a large series of referred samples from 1298 patients, including 53 well-characterized patients from the St. Louis Children's Hospital BWS-Registry (validation samples) and 1245 consecutive nationwide referrals (practice samples). Methylation-sensitive enzymatic digestion with Southern hybridization assessed loss of normal imprinting. In the validation group, abnormal LIT1 hypomethylation was detected in 60% (32/52) of patients but LIT1/H19-combined testing was abnormal in 68% (36/53); sensitivity in the practice setting demonstrated 27% (342/1245) abnormal LIT1 and 32% (404/1245) abnormal LIT1/H19-combined. In addition, H19 methylation was abnormal in 7% of LIT1-normal patients. We observed absence of uniparental disomy (UPD) in 27% of combined LIT1/H19-abnormal samples, diagnostic of multilocus methylation abnormalities; in contrast to studies implicating that combined LIT1/H19 abnormalities are diagnostic of UPD. The overall low detection rate, even in validated patient samples and despite characterization of both loci and UPD status, emphasizes the importance of clinical diagnosis in BWS.
AB - Beckwith-Wiedemann syndrome (BWS) is a clinical diagnosis; however, molecular confirmation via abnormal methylation of DMR2(LIT1) and/or DMR1(H19) has clinical utility due to epigenotype-tumor association. Despite the strong link between H19 hypermethylation and tumor risk, several diagnostic laboratories only test for hypomethylation of LIT1. We assessed the added diagnostic value of combined LIT1 and H19 testing in a large series of referred samples from 1298 patients, including 53 well-characterized patients from the St. Louis Children's Hospital BWS-Registry (validation samples) and 1245 consecutive nationwide referrals (practice samples). Methylation-sensitive enzymatic digestion with Southern hybridization assessed loss of normal imprinting. In the validation group, abnormal LIT1 hypomethylation was detected in 60% (32/52) of patients but LIT1/H19-combined testing was abnormal in 68% (36/53); sensitivity in the practice setting demonstrated 27% (342/1245) abnormal LIT1 and 32% (404/1245) abnormal LIT1/H19-combined. In addition, H19 methylation was abnormal in 7% of LIT1-normal patients. We observed absence of uniparental disomy (UPD) in 27% of combined LIT1/H19-abnormal samples, diagnostic of multilocus methylation abnormalities; in contrast to studies implicating that combined LIT1/H19 abnormalities are diagnostic of UPD. The overall low detection rate, even in validated patient samples and despite characterization of both loci and UPD status, emphasizes the importance of clinical diagnosis in BWS.
UR - http://www.scopus.com/inward/record.url?scp=77956864599&partnerID=8YFLogxK
U2 - 10.2353/jmoldx.2010.100005
DO - 10.2353/jmoldx.2010.100005
M3 - Article
C2 - 20616360
AN - SCOPUS:77956864599
SN - 1525-1578
VL - 12
SP - 576
EP - 588
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
IS - 5
ER -