University of Groningen

Congenital heart defects and pulmonary arterial hypertensionKerstjens-Frederikse, Wilhelmina

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33

Genetic aspects of congenital heart defects

Chapter 2

W.S. Kerstjens-Frederikse, R.M.W. Hofstra

Translated and adapted from: “Aangeboren Hartafwijkingen bij Volwassenen”

Edited by B.J.M. Mulder, P.G. Pieper, F.J. Meijboom, J.P.M. Hamer. Chapter 23. “

Genetische aspecten van aangeboren hartafwijkingen”. With permission from Bohn, Stafleu en

van Loghum. Houten, the Netherlands, 2013. ISBN 978-90-368-0306-9

PART IGENES, ENVIRONMENT AND HEREDITY IN CONGENITAL HEART DEFECTS

34

Chapter 2

INTRODUCTION

Congenital heart defects (CHDs) occur in approximately 8 per 1000 live births (1:130). The huge

improvement in diagnostics, therapy and care for patients with a CHD in the last decades has

increased the number of adults living with a (corrected) CHD and the relative numbers of surviving

adult patients is expected to increase further. The current estimated prevalence of adults with a CHD

is 3 per 1000 persons in the Netherlands.1 In the last decade we have learnt that heredity plays an

important role in the aetiology of CHD and it has become more and more clear that adult patients

with CHD may have offspring with CHD. As a consequence, clinicians caring for patients with CHD

have a responsibility to inform their patients about this aspect of their disorder. Knowledge about

heredity is important because it may provide information on: (1) syndromic CHD affecting other

organs, (2) prognosis, (3) risk for offspring having CHD, and (4) risks for relatives, who may be eligible

for presymptomatic (genetic) testing.

Genetic counselling

A referral for genetic counselling is indicated when someone has questions about a congenital

and/or hereditary disease present in him- or herself or in relatives. In the Netherlands, genetic

counselling is provided by a medical specialist, a clinical geneticist. Genetic counselling addresses

the nature of the disease, its prevalence, the availability of genetic testing, the interpretation of

genetic test results, the recurrence risks for offspring, the health risks for relatives, and the options

to reduce these risks.

Causes

CHDs may be present in patients with numeric chromosomal anomalies or small chromosomal

anomalies, manifesting as a monogenic syndromic or non-syndromic disease, but also as a complex

genetic disease. Numerical chromosomal anomalies, (for instance trisomy 21, Down’s syndrome) are

amongst the earliest reported genetic causes for CHDs. These chromosomal anomalies cause 10%

of the heart defects seen in live births.2 Though genetic in origin, these anomalies are usually new

(de novo) in children and thus not inherited nor familial.

Small deletions and duplications in chromosomes, which cannot be detected by microscopic

analysis, are detected by molecular techniques, such as multiplex ligation-dependent probe

amplification (MLPA), array comparative genomic hybridization (array CGH) or single nucleotide

polymorphism array (SNP array) analysis. Small chromosomal anomalies probably cause

approximately 15% of the cases of CHDs.3

CHDs are a component of many, mostly rare, hereditary syndromes with multiple congenital

malformations, for instance the autosomal dominant Noonan’s syndrome. Together, these

monogenic syndromes contribute to approximately 5% of the cases of CHDs.2

In the last two decades, quite a few pedigrees have suggested monogenic inheritance in

non-syndromic CHDs (autosomal dominant, autosomal recessive, or X-linked) and several of the

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Genetic aspects of congenital heart defects

2

associated genes have been discovered.4

Formerly, the large group of non-syndromic CHDs was assumed to be non-genetic. However, at

the end of the 20th century, several studies showed recurrence of non-syndromic congenital defects

in pedigrees that was inconsistent with monogenic inheritance. The hypothesis of multifactorial

inheritance was postulated (but has not yet been proven), assuming that these congenital defects

were caused by a combination of mutations in several genes, together with several, mostly

unknown, environmental factors. Environmental factors associated with CHDs are maternal diseases

like diabetes, obesity, rubella infection, phenylketonuria, or the maternal use of alcohol, cigarettes,

amphetamines, anti-epileptic drugs, some anti-depressant drugs or retinoic acid.2, 5 More recently,

the term “complex diseases” has been adopted for diseases that are not plainly chromosomal or

monogenic but which still have a strong genetic component.

The classification of non-syndromic heart defects into monogenic or complex groups is

probably an oversimplification. The concept of a spectrum of disease is more plausible, on one

end of the spectrum consisting of monogenic defects caused by mutations in genes showing

a high penetrance of disease and, at the other end, of complex defects caused by mutations in

several genes with a middle or low penetrance of disease, which may or may not act in concert

with environmental factors. Moreover, approximately 10% of CHDs which were assumed to have a

complex aetiology now appear to be caused by the occurrence of new monogenic mutations.

Many genes associated with non-syndromic familial heart defects have been discovered by

molecular studies in the past decade. This has lead to a better understanding of the aetiology of

CHDs. The availability of advanced techniques able to detect small chromosomal aberrations has

also contributed to the detection of loci and genes involved in CHDs. Several hundreds of genes, but

also micro RNAs and epigenetic factors, like imprinting, methylation and chromatin remodelling,

appear to be involved in the development of the foetal heart.6 All of the above strengthens the

idea that the contribution of genetic factors to CHDs has been underestimated in the past. Current

technologies in molecular genetics and bioinformatics will greatly facilitate the genetic analysis of

these patients and enhance our understanding of the origin of CHDs in the near future.7

.

Category Percentage

numerical chromosomal anomalies 10

microdeletions/microduplications 15

monogenic syndromic diseases 5

monogenic non-syndromic diseases 5-10 (?)

complex diseases 60-65 (?)

Table 1. Classification of genetic causes of congenital heart defects at birth

36

Chapter 2

Chromosomal anomalies

Numerical chromosomal anomalies

Numerical chromosomal anomalies are characterised by the occurrence of one or more complete

extra chromosomes (trisomy, tetrasomy) or the lack of a complete chromosome (monosomy).

Patients with trisomy 13 (Patau’s syndrome), trisomy 18 (Edwards’ syndrome), trisomy 21 (Down’s

syndrome) and monosomy X (Turner’s syndrome) often have CHDs. Most patients with trisomy 13

or 18 do not reach adult age, but most live-born patients with trisomy 21 or Turner’s syndrome

do. Approximately 45% of patients with Down’s syndrome have a CHD; this is most frequently an

atrio-ventricular septal defect, atrial septal defect, ventricular septal defect, or Fallot’s tetralogy. For

the cardiologist, the most important numerical chromosomal anomaly in adult patients is Turner’s

syndrome. This syndrome should be considered in any female patient with a CHD and normal

intelligence, short stature and/or delayed puberty. It is not exceptional for the diagnosis not to be

made until adolescence. Turner’s syndrome is caused by monosomy X (a 45,X karyotype) in 40–

60% of the patients. The other patients have a structural anomaly of an X- (or Y-) chromosome, or

are mosaic, meaning that the mutation is not present in all the somatic cells of an individual. In

Features of Turner’s syndrome

• short stature

• delayed puberty

• nuchal webbing

• low hairline

• large internipple distance

• congenital heart defect, most often aortic coarctation

• lymphedema of hands and feet (in newborns)

• valgus deformity of the forearm

• renal anomalies (e.g. horseshoe kidney)

Turner’s syndrome this means that normal cell lines (46,XX) as well as abnormal cell lines (45,X) are

present in one individual, while combinations with other cell lines, for instance 47, XXX, may also

occur). This explains why the phenotype seen in Turner’s syndrome is quite variable – it is related

to the proportion of normal and abnormal cell lines in the various tissues. However, the proportion

of abnormal cell lines found in blood does not predict that found in other tissues. Though many

women with Turner’s syndrome are infertile, pregnancies have been reported in several women

with –probably mosaic-Turner’s syndrome. The disease may be detected by karyotyping, QF-PCR,

array CGH or SNP array.

Microdeletions and Microduplications

Instead of a complete chromosome, a small part of a chromosome may be lacking (a deletion) or

present as extra material (a duplication). Some of these small anomalies may be visible under the

37

Genetic aspects of congenital heart defects

2

microscope, but modern techniques (MLPA, SNP array, or array CGH)) have a higher resolution for

detecting these small copy number variations. The size of the deleted or duplicated chromosomal

segment at the DNA level is usually large enough to contain several genes.

A deletion or duplication often arises de novo, meaning that it is not present in either parent.

However, a person who has a deletion or duplication has a 50% chance of passing it on to offspring

in each pregnancy. The phenotypic expression of the deletion or duplication may be highly variable

within a family. It is important for the clinician to be able to recognise the effects of several deletions

and duplications, in the first place because they are not particularly rare, and in the second place,

because the severity of the extracardiac features may be highly variable. Quite often a microdeletion

or microduplication is not diagnosed until adult age.

Microdeletion 22q11.2, Velocardiofacial syndrome

Microdeletion 22q11.2 is one of the most prevalent microdeletions (estimated prevalence 1:4000).

The q-arm is the long arm of the chromosome, 11.2 marks the position on this long arm, the

chromosome bands are numbered from the centromere. Historically several syndromes with

overlapping features were clinically recognised, (DiGeorge syndrome, velocardiofacial or Shprintzen

syndrome, asymmetric-crying- face or Cayler syndrome, conotruncal anomaly face syndrome)

which all appeared to be caused by a microdeletion 22q11.2.

There is no clear relation between the phenotype and the size of the deletion. The TBX1 gene is

located in the deleted area and the deletion of one copy of this gene appears to explain most of the

features, including the cardiovascular defects.8 The clinical expression coupled to this microdeletion

Features of microdeletion 22q11.2 1

Craniofacial• microcephaly

• narrow palpebral fissures, periorbital fullness

• hypoplastic alae nasae

• small ears with thickened helix

Cardiovascular

• mainly conotruncal anomalies: truncus arteriosus, interruption of the aortic arch type B, Fallot’s tetralogy, pulmonary valve atresia, right sided aortic arch

• ventricular septal defect

Renal

• renal hypoplasia or agenesis

Neurologic

• hypotonia (often transient)

Mental

• mild mental retardation, though this is highly variable and approximately half of the children attend normal elementary school

• psychiatric diseases (psychosis, schizophrenia)

1 Only a few features may be present, but no one feature is obligatory.

38

Chapter 2

is highly variable and may consist of subtle facial dysmorphic features and hypernasal speech, but

may just as well be a full blown DiGeorge syndrome with severely disturbed T-cellular immunity due

to a hypoplastic thymus gland, hypocalcemia due to hypoplastic parathyroid glands, microcephaly,

cleft palate, a conotruncul heart defect (truncus arteriosus and interruption type B the most

frequent). Typical features of the velocardiofacial syndrome are hypernasal speech, with or without

cleft palate, narrow palpebral fissures, a long face and a conotruncal heart defect (VSD, right-sided

aortic arch, Fallot’s tetralogy). Psychiatric diseases (schizophrenia, psychosis) are frequent.9

Partial tetrasomy 22, Cat-eye syndrome

Total anomalous pulmonary venous return is the typical heart defect for cat-eye syndrome,

but other heart defects may occur. Coloboma of the iris (a defect in the iris tissue resulting in

an abnormal shape of the pupil, a cat-eye) and anal atresia are the most frequent extracardiac-

features. Most patients have a normal intelligence. Cat-eye syndrome is caused by tetrasomy 22,

most often through an extra chromosome containing a duplicated part of chromosome 22 and two

centromeres. The tetrasomy is often mosaic.9

Partial tetrasomy 22 may be detected by karyotyping, array CGH or SNP array.

Microdeletion 20p11.2, Alagille syndrome

The microdeletion 20p11.2 is associated with Alagille syndrome. Most patients have a pulmonary

valve stenosis or Fallot’s tetralogy. Extracardiac features are intra-and extrahepatic atresia or

hypoplasia of the biliary ductus, leading to a variable severity of cholestasis. Subtle facial features:

prominent forehead, deep set eyes, narrow nose, are present, as well as anomalies of the eye

(posterior embryotoxon) and the vertebra (butterfly shaped vertebra). The causative gene in

the deleted chromosomal area is Jagged-1 (JAG1). Mutations in JAG1 are more frequent than

microdeletion 20p11.2 in patients with Alagille syndrome. Mutations in JAG1 are also detected in

patients with Fallot’s tetralogy, without other features of Alagille syndrome.9

Microdeletion 20p11.2 may be detected by Fluorescent-in-Situ-Hybridization (FISH), array CGH or

SNP array.

Microdeletion 7q11.23, Williams (Williams-Beuren) syndrome

Williams syndrome is characterised by supravalvular aortic stenosis (SVAS), mental retardation, a

specific behavioural pattern described as “cocktail-party-behaviour”, specific facial features, and

hypercalcemia. It is caused by a microdeletion at 7q11.23. The genes elastin (ELN), RFC2 and Lim-

kinase are located in the deleted area. The ELN gene is associated with SVAS and mutations in

ELN have been reported in families with autosomal dominant SVAS but without other features of

Williams syndrome.9

Microdeletion 7q11.23 can be detected by FISH, array CGH or SNP array.

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Genetic aspects of congenital heart defects

2

Microdeletion or microduplication 1q21.1

Microdeletion or microduplication of 1q21.1 causes a highly variable phenotype and may feature

several CHDs, including aortic valve stenosis and aortic coarctation. Short stature, mild mental

retardation, microcephaly, cataracts, and subtle facial features (epicanthal folds, widely spaced

teeth) may be present. The microdeletion may be detected in apparently healthy parents, but is

not detected in random healthy controls.10 Microdeletion or microduplication of 1q21.1 can be

detected by array CGH or SNP array.

Monogenic defects

Syndromes with heart defects and monogenic inheritance

Monogenic syndromic heart defects may have very subtle extracardiac features that can easily be

missed. However, it is important that cardiologists who deal with young adults are aware of these

syndromes because the risk for offspring may be high (50% in autosomal dominant disease) and the

severity of the syndromes can be highly variable. Hundreds of syndromes featuring heart defects

have been reported in the medical literature. Here, we briefly summarize the features of only the

most frequent autosomal dominant syndromes that are not associated with (severe) intellectual

disability.2, 9, 11

Non-syndromic heart defects with monogenic inheritance

A rapidly increasing number of families suffering from hereditary, non-syndromic, CHDs are being

detected by targeted family studies. This is particularly seen in AVSD, ASD-II, in heart defects

associated with heterotaxy and in left-sided heart defects (bicuspid aortic valve (BAV), aortic valve

stenosis (AVS), coarctation of the aorta (COA) and hypoplastic left heart syndrome (HLHS).

Several families with AVSD have been reported with a pedigree compatible with autosomal dominant

inheritance with incomplete penetrance, and in some of these families a mutation in CRELD1 has

been detected.12 Mutations in the NKX2.5 and GATA4 genes are reported in familial ASD-II, often

associated with electrical conduction anomalies or pulmonary valve stenosis, respectively.13,14

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Chapter 2

Table 2. Some autosomal dominant syndromes with heart defects that are not associated with intellec-tual disability

Disease (gene) Most frequent heart defect Most common other features

Alagille syndrome (JAG1, NOTCH2)

pulmonary artery stenosis mild craniofacial anomalies, intrahepatic bile duct atresia

Aneurysm-osteoarthritis syndrome (SMAD3)

aortic aneurysm, tortuosity early osteoarthritis

Char syndrome (TFAB2B) persistent ductus arteriosus duck-bill lips

Ehlers-Danlos syndrome (COL3A1 and many other genes)Several types, some are autosomal dominant

atrial septal defect, mitral valve prolapse, rupture of large- and medium-sized arteries

easy bruising, skin fragility, joint hypermobility

Holt-Oram syndrome (TBX5) septal defects thumb anomalies, variable anomalies of the forearm

Loeys-Dietz syndrome (TGFBR1,TGFBR2, TGFB2)

aortic aneurysm, tortuosity hypertelorism, bifid uvula/cleft palate; aneurysms in various arteries

Long qT-syndrome (KCNQ1,KCNH2, SCN5A and many other genes)

prolonged QT-interval, ventricular arrhythmias

syncope, sudden cardiac death

Lymphedema Distichiasis-syndrome (FOXC2)

Fallot’s tetralogy lymphedema, distichiasis (= double row of eye lashes)

Marfan syndrome (FBN1, TGFBR1, TGFBR2)

aortic root dilatation/dissection, valve anomalies

pectus deformity, arachnodactyly, lens dislocation

Myotonic dystrophy (DM1) several arrhythmias myotonia, muscle weakness, cataract, frontal balding

Neurofibromatosis type I (NF1)

pulmonary valve stenosis café-au-lait spots, cutaneous neurofibromas

Noonan syndrome (PTPN11 and many other genes in MAPK-pathway)

pulmonary valve or artery stenosis, ASD, hypertrophic cardiomyopathy

Short stature, short neck with webbing, pectus excavatum and/or carinatum

Tuberous sclerosis (TSC1,TSC2)

rhabdomyomas of the heart depigmented skin lesions, peri-ungual fibromas, adenoma sebaceum, intracerebral calcifications

A third important group of highly hereditary heart defects are the left-sided structural heart defects, also designated “left ventricular outflow tract obstructions” (BAV, AVS, COA, HLHS). When first-degree relatives (parents and sibs) of a paediatric index patient are screened echocardiographically, one or more relatives appear to have a heart defect in 20% of the index cases. Most often this defect is a BAV and most often it was unknown.15 A mutation in NOTCH1 is detected in some of these families.16

CHDs are genetically heterogeneous, meaning that one CHD may be caused by a mutation in one of several different genes. The number of known genes associated with CHDs is increasing rapidly and medical professionals who address heredity issues with patients need to have up-to-date knowledge. The rapid advances in molecular technologies and bioinformatics will provide us with a huge amount of data in the coming years, so it will be a challenge to combine and to interpret these data for the benefit of individual patients.

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Genetic aspects of congenital heart defects

2

Table 3. Some genes associated with non-syndromic monogenic heart defects

Gene Locus Heart defect(s)

ACTA2 10q23.31 TAAD

CFC1 2q21.1 TGA, DORV, HTX

CRELD1 3p25.3 AVSD, HTX

ELN 7q11.23 SVAS

GATA4 8p23.1 ASD-II, AVSD, VSD

GDF1 19p13.11 DORV, TOF, TGA

JAG1 20p11.2 TOF

MED13LMYH6

12q24.2114q11.2

TGAASD

MYH7 14q11.2 Ebstein, LVNC

MYH11 16p13.11 TAAD + PDA

NKX2-5 5q35.1 ASD-II + AV-conduction defects, TOF

NODAL 10q22.1 HTX

NOTCH1 9q34.3 AVS, BAV

TAB2 6q25 TOF, PVS, AVS

ZIC3 Xq26.3 TGA

ZFPM2 8q23.1 TOF

ASD atrial septal defect; AVS aortic valve stenosis; AVSD atrial ventricular septal defect; BAV bicuspid aortic valve; DORV double outlet right ventricle; HTX Heterotaxy; LVNC left ventricular non-compaction; PDA persistent duc-tus arteriosus; PVS pulmonary valve stenosis; SVAS supravalvular aortic stenosis; TAAD thoracic aortic aneurysm/aortic dissection; TGA transposition of the great arteries; TOF Fallot’s tetralogy; VSD ventricular septal defect.

Websites:Genereviews: http://www.ncbi.nlm.nih.gov/sites/GeneTests/Database of genomic variants: http://projects.tcag.ca/variation/Online Mendelian inheritance in man: http://www.ncbi.nlm.nih.gov/omimUniversity of California Santa Cruz Genome browser: http://genome.ucsc.edu/

42

Chapter 2

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