Haploinsufficiency of Elastin Gene May Lead to
Familial Cardiopathy and Pulmonary Emphysema
Jacoba J Louw,1,2* Geert Verleden,3Marc Gewillig,1and Koenraad Devriendt2
1Department of Congenital and Pediatric Cardiology, University Hospitals Leuven, Belgium
2Centre for Human Genetics, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium
3Lung Transplantation Unit, University Hospitals Leuven, Belgium
Manuscript Received: 9 June 2011; Manuscript Accepted: 16 April 2012
TO THE EDITOR:
Wan et al.  reported in this journal a non-smoking adult
person with Williams–Beuren syndrome and emphysema, and
raised the question if defects in the elastin gene are associated
with increased susceptibility toward developing chronic obstruc-
tive pulmonary disease (COPD) and emphysema. Additional sup-
with early onset COPD [Kelleher et al., 2005; Cho et al., 2009], as
wellas the fact that changes in the elastingenearealso described in
cases of autosomal dominant form of cutis laxa (OMIM 123700)
alveolar growth [Wendel et al., 2000; Shifren et al., 2006]. Mice
ing patterns. An increased inflammatory response to cigarette
positive, mouse ELN gene null) animals, with about one third of
normal elastin expression levels and significantly decreased colla-
gen levels, showed grossly abnormal pulmonary structure with
severe congenital emphysema that is present from birth but not
progressive. Finally, mice deficient in elastin (ELN?/?) exhibit
abnormalities in the lungs that are morphologically similar to
emphysema [Shifren et al., 2006].
with both cardiac and pulmonary manifestations, i.e., peripheral
pulmonary emphysema. The family is Caucasian and the parents
The index patient, a boy, was referred shortly after birth to our
Tertiary Pediatric Cardiology Unit after a cardiac murmur was
heard at the first clinical examination. The diagnosis of an impor-
pulmonary arteries. This initially led to mild right ventricular
hypertrophy, which subsequently regressed with sufficient growth
of the pulmonary arteries. A notch in the ascending aorta was also
present on echocardiography, but without a pressure gradient and
only a minimal degree of aortic insufficiency, thus posing no
subsequent left ventricular hypertrophy, by the age of 2 years
surgical correction was necessary with angioplasty.
The father of our patient is known to have supra-aortic stenosis
underwent bilateral lung transplantation due to pulmonary
years. Alpha 1-antitrypsin deficiency (A1AT) was excluded; 2.03g/L
in serum as well as absence of the following recurrent mutations:
p.E342K (Z-variant) in exon 5 and p.E264V (S-variant) in exon 3.
Furthermore, the paternal grandfather died at the age of 45 years
due to pulmonary emphysema. He was also a smoker and was
known to have a cardiopathy, although more specific detail is not
Neither our index patient, nor his father had any dysmorphic
features, as determined by an experienced clinical geneticist. The
father of our patient and his grandfather have no siblings, but have
the same phenotype, i.e., cardiopathy and a history of pulmonary
Jacoba J Louw, M.D., UZ Leuven - Pediatric Cardiology, Herestraat 49
Leuven 3000, Belgium. E-mail: firstname.lastname@example.org
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 00 Month 2012
How to Cite this Article:
Louw JJ, Verleden G, Gewillig M, Devriendt
K. 2012. Haploinsufficiency of elastin gene
may lead to familial cardiopathy and
Am J Med Genet Part A.
? 2012 Wiley Periodicals, Inc.
emphysema presenting at a young age. There were no reported
phenotypes in the rest of the family.
Due to the paternally known cardiopathy, the suspicion of a
haplosufficiency in the elastin genewith dominantinheritance was
an ELN probe did not show a deletion in this gene, but a hetero-
zygous ELN point mutation was found in both the father and our
a change in the start codon methionine, and due to the fact that no
other in-frame methionine is present in the elastin mRNA, this
mutation is predicted to lead to the absence of the elastin protein.
This mutation has not been reported before, and is not a known
polymorphism or rare variant.
mutation in this elastin gene might be responsible for an earlier or
more severe presentation of pulmonary emphysema. Additional
susceptible to emphysema. Additional known emphysema risk
factors, i.e., a carrier status for A1AT deficiency could also have
aneffect butwereexcluded in the father. Our index patient andhis
thus too young to correctly perform pulmonary function testing.
Considering that he currently has no respiratory symptoms, we
chose not to perform a CT scan, as this will not have any clinical
implications. Furthermore, his father only presented with respira-
tory symptoms in the third decade.
This family size is too small to be able to make a conclusion of
segregation with disease. Only two affected individuals are alive,
andboth carrytheelastinmutation.The grandmotheroftheindex
was not available for testing, and the mother and siblings of our
phenotype and a normal cardiac echocardiography.
secondary smoking. In a more general way, this observation lends
further support to the notion that haploinsufficiency for ELN is a
risk factor for emphysema.
early-onset chronic obstructive pulmonary disease. Cell Mol Biol 40:
Kelleher CM, Silverman EK, Broekelmann T, Litonjua AA, Hernandez M,
Cell Mol Biol 33:355–362.Epub 2005 Aug 4.
Rodriguez-RevengaL,IranzoP,BadenasC,PuigS,Carri? oA,Mil? aM.2004.
A novel elastin gene mutation resulting in an autosomal dominant form
of cutis laxa. Arch Dermatol 140:1135–1139.
Mecham Robert P. 2006. Elastin protein levels are a vital modifier
affecting normal lung development and susceptibility to emphysema.
Am J Physiol Lung Cell Mol Physiol 292:L778–L787.
with severe lung disease: Synthesis and matrix deposition of mutant
tropoelastin. J Invest Dermatol 124:1193–1199.
distal airway development in mice lacking elastin. Am J Respir Cell Mol
function and emphysema in Williams-Beuren syndrome. Am J Med
Genet Part A 152A:653–656.
2 AMERICAN JOURNAL OF MEDICAL GENETICS PART A