RT Journal Article
SR Electronic
T1 High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 43
OP 52
DO 10.1136/jmedgenet-2015-103428
VO 53
IS 1
A1 de Kock, Leanne
A1 Wang, Yu Chang
A1 Revil, Timothée
A1 Badescu, Dunarel
A1 Rivera, Barbara
A1 Sabbaghian, Nelly
A1 Wu, Mona
A1 Weber, Evan
A1 Sandoval, Claudio
A1 Hopman, Saskia M J
A1 Merks, Johannes H M
A1 van Hagen, Johanna M
A1 Bouts, Antonia H M
A1 Plager, David A
A1 Ramasubramanian, Aparna
A1 Forsmark, Linus
A1 Doyle, Kristine L
A1 Toler, Tonja
A1 Callahan, Janine
A1 Engelenberg, Charlotte
A1 Bouron-Dal Soglio, Dorothée
A1 Priest, John R
A1 Ragoussis, Jiannis
A1 Foulkes, William D
YR 2016
UL http://jmg.bmj.com/content/53/1/43.abstract
AB Background Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous whole-exome sequencing study using DNA derived from peripheral blood identified mosaic mutations in DICER1 in two children with overgrowth and developmental delay as well as more typical phenotypes of germline DICER1 mutation. However, very-low-frequency mosaicism is difficult to detect, and thus, causal mutations can go unnoticed. Highly sensitive, cost-effective approaches are needed to molecularly diagnose these persons. We studied four children with multiple primary tumours known to be associated with the DICER1 syndrome, but in whom germline DICER1 mutations were not detected by conventional mutation detection techniques.Methods and results We observed the same missense mutation within the DICER1 RNase IIIb domain in multiple tumours from different sites in each patient, raising suspicion of somatic mosaicism. We implemented three different targeted-capture technologies, including the novel HaloPlexHS (Agilent Technologies), followed by deep sequencing, and confirmed that the identified mutations are mosaic in origin in three patients, detectable in 0.24–31% of sequencing reads in constitutional DNA. The mosaic origin of patient 4's mutation remains to be unequivocally established. We also discovered likely pathogenic second somatic mutations or loss of heterozygosity (LOH) in tumours from all four patients.Conclusions Mosaic DICER1 mutations are an important cause of the DICER1 syndrome in patients with severe phenotypes and often appear to be accompanied by second somatic truncating mutations or LOH in the associated tumours. Furthermore, the molecular barcode-containing HaloPlexHS provides the sensitivity required for detection of such low-level mosaic mutations and could have general applicability.