Analysis of DICER1 in familial and sporadic cases of
transposition of the great arteries
Nelly Sabbaghian MSc
Maria C. Digilio MD
Gillian M. Blue PhD
ee Revil PhD
David S. Winlaw MD
William D. Foulkes MBBS PhD
Lady Davis Institute, Segal Cancer Centre,
Jewish General Hospital, Montr
Department of Medical Genetics, Bambino
u Pediatric Hospital, Rome, Italy
Heart Centre for Children, The Children’s
Hospital at Westmead, Westmead, New
South Wales, Australia
University of Sydney, Sydney, New South
McGill University and Genome Quebec
Innovation Centre, Montr
Cancer Research Program, Research
Institute of the McGill University Health
Centre, McGill University, Montr
William D. Foulkes, Research Institute of
the McGill University Health Centre, 1001
Decarie Boulevard, Montr
EM0.6248, Quebec H4A 3J1, Canada.
This work was funded by Alex’s Lemonade
Stand Foundation: https://www.
Objective: We previously identified a pathogenic germline DICER1 variant in a child with transpo-
sition of the great arteries who was a member of a family with DICER1 syndrome. In view of a
report linking Dicer1 knockout in murine cardiomyocytes to cardiac outflow defects, we investi-
gated the involvement of DICER1 in transposition of the great arteries.
Design: We used Fluidigm access array followed by next generation sequencing to screen for var-
iants in the coding exons, their exon/intron boundaries and the 3
untranslated region of DICER1
in patient DNA.
Cases: Germline DNA was collected from 129 patients with either sporadic or familial forms of
transposition of the great arteries from two sites in Australia and Italy.
Results: Most cases (85%) did not have any germline DICER1 variants. In the remaining 15% of
cases, we identified 16 previously reported variants (5 synonymous, 6 intronic, and 5 missense)
and 2 novel variants (1 intronic and 1 missense). None of the identified variants were predicted to
Conclusions: Here, we report that neither likely pathogenic nor pathogenic variants in DICER1
appear to play a major role in transposition of the great arteries.
DICER1, fluidigm, next-generation sequencing, transposition of the great arteries
DICER1 is an endoribonuclease that plays an essential role in modu-
lating the expression of genes by producing mature microRNAs
(miRNA), which are small, single stranded RNA molecules that bind
to and thereby inhibit target mRNAs. DICER1-related diseases are
referred to collectively as DICER1 syndrome and result from germ-
line pathogenic and likely pathogenic variants in individuals with
rare childhood cancers such as: pleuropulmonary blastoma, cystic
nephroma, Sertoli-Leydig cell tumor, embryonal rhabdomyosarcoma,
and other rare tumors.
Several years ago, we identified a patho-
genic germline DICER1 variant (c.2117-1G > A, in intron 13 at the
junction with exon 14, predicted to result in p.Gly706Aspfs*8) in a
child with transposition of the great arteries (TGA), associated with a
bicuspid pulmonary valve, an atrial septal defect and a patent ductus
Later, at the age of 18, he developed a solitary nodule in
the left lobe of the thyroid gland. Two years later, he was found to
have further nodules and cysts in the same lobe. Other heterozy-
gotes for this pathogenic variant in the family also had phenotypes
consistent with DICER1 syndrome.
TGA is a cyanotic congenital heart defect (CHD) characterized by
ventriculo-arterial discordance and represents 5% to 7% of CHD.
often accompanied by other structural changes that allow mixing of
Abbreviations: CHD, congenital heart defect; miRNA, microRNAs; TGA,
Transposition of the great arteries.
Congenital Heart Disease. 2018;13:401–406. wileyonlinelibrary.com/journal/chd
2018 Wiley Periodicals, Inc.
Received: 8 August 2017
Revised: 22 November 2017
Accepted: 22 December 2017