Paediatric or syndromic cardiomyopathy

Alagille syndrome

Alagille syndrome (ALGS) is a variable, complex multisystem disorder. Cardiac findings range from benign heart murmurs to significant structural defects and occur in 90%-97% of individuals with ALGS [47]. The incidence of ALGS is estimated at 1:30,000-1:50,000 live births, but due to the variable phenotype, it is likely to be underdiagnosed [47]. ALGS is inherited in an autosomal dominant manner with incomplete penetrance, however approximately 50%-70% of pathogenic variants arise de novo [47]. Pathogenic variants in JAG1 are found in more than 89% of patients who meet diagnostic criteria. Approximately 7% of affected individuals have exon or whole gene deletions of JAG1 [47]. Variants in NOTCH2 cause 1-2% of cases of ALGS.

Gene name Transcript Clinical sensitivity
JAG1 ENST00000354958 89-94% [47,48]

Carney complex

Carney complex is a rare autosomal dominant multiple neoplasia syndrome characterized by cardiac, endocrine, cutaneous, and neural myxomatous tumors, as well as a variety of pigmented lesions of the skin and mucosae. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and manifest as intracardiac obstruction of blood flow, embolic phenomena, and/or heart failure. Sequence analysis of the PRKAR1A coding region has a pathogenic variant detection rate of approximately 60% with approximately 30% of these variants having arisen de novo [49]. Deletions and duplications account for around 10% of cases [49]

Gene name Transcript Clinical sensitivity
PRKAR1A ENST00000589228 60% [49,50]

Heterotaxy/situs ambiguous (HTX)

Gene name Transcript Clinical sensitivity
ACVR2B ENST00000352511.4 n/a
ARMC4  ENST00000305242  n/a
C21orf59  ENST00000290155  n/a
CCDC103  ENST00000417826 n/a
CCDC11 ENST00000398545  
CCDC151  ENST00000356392   
CCDC39 ENST00000442201   
CCDC40  ENST00000397545   
CFC1 ENST00000359216.4   
CRELD1  ENST00000326434 <1% [51]
DNAAF1 (LRRC50)  ENST00000378553   
DNAAF2  ENST00000298292   
DNAAF3  ENST00000527223   
DNAH11  ENST00000409508   
DNAH5  ENST00000265104   
DNAI1 ENST00000242317   
DNAI2  ENST00000582036   
DNAL1 (LC1) ENST00000553645   
DYX1C1  ENST00000321149   
HEATR2  ENST00000297440   
LEFTY2  ENST00000366820.5   
LRRC6  ENST00000519595   
MMP21  ENST00000368808   
NME8 (TXNDC3)  ENST00000199447   
NODAL  ENST00000287139   5.10% [51]
PKD1L1  ENST00000289672.2   
SPAG1  ENST00000388798   
WDR16  ENST00000352665  
ZIC3  ENST00000287538   
ZMYND10  ENST00000231749   

Holt-Oram syndrome

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. All individuals have an upper-limb defect, however the severity of this and other findings is highly variable, even among families with the same variant. Congenital heart malformations, most commonly ostium secundum, atrial septal defect and ventricular septal defect, occur in approximately 75% of affected individuals [52]Based on limited data, HOS is estimated to occur in about 1:100,000 live births [52] and is inherited in an autosomal dominant manner. About 74% of individuals who meet diagnostic criteria have an identifiable pathogenic variant in TBX5 and approximately 85% of these have arisen de novo [52,53]. Deletions have been reported to be causative but are likely to account for less than 1% of cases [52]. If the clinical phenotype is unclear further genes associated with possible differential diagnoses can be interpreted upon request. See SALL-4-related disorders below.

Gene name Transcript Clinical sensitivity
TBX5 ENST00000310346 74% [52, 53]

NKX2-5-related disorders

The cardiac homeobox protein Nkx2-5 is essential in cardiac development, and mutations in CSX (which encodes Nkx2.5) cause various congenital heart malformations, most commonly atrial septal defect and atrioventricular conduction disease (AVCD) [54]. Other cardiac features include variable conotruncal heart malformations, hypoplastic left heart syndrome 2, tetrology of Fallot and ventricular septal defect 3. The inheritance pattern for all of the above has been reported as autosomal dominant, with the exception of conotruncal heart malformations, which have been reported to show autosomal recessive inheritance in consanguineous families [55].

Gene name Transcript Clinical sensitivity
NKX2-5 ENST00000329198  

Noonan spectrum disorders

Noonan syndrome (NS) is a genetically and phenotypically heterogeneous disorder characterized by short stature, congenital heart defects, and developmental delay of variable degree. Congenital heart disease occurs in 50%-80% of individuals, most commonly pulmonary valve stenosis or hypertrophic cardiomyopathy. Other cardiac features include structural heart defects such as atrial or ventricular septal defects or tetralogy of Fallot [56]. NS is reported to occur in between 1:1000 and 1:2500 persons, with mild expression likely to be overlooked [56]It is inherited in an autosomal dominant manner and approximately 50% of individuals diagnosed with NS have a pathogenic variant in PTPN11. Although many individuals with NS have a de novo mutation, an affected parent is recognized in 30%-75% of families [56]. The TruSight ICC panel also includes genes associated with related RASopathy phenotypes including cardiofaciocutaneous syndrome (BRAF, KRAS, MAP2K1, MAP2K2), Costello Syndrome (HRAS) and LEOPARD Syndrome (RAF1, BRAF, PTPN11).

Gene name Transcript Clinical sensitivity
PTPN11 ENST00000351677 50% [56]
RAF1 ENST00000251849  3-17% [56- 58
SOS1  ENST00000426016  10-13% [56
KRAS  ENST00000311936  <5% [56
BRAF  ENST00000288602  <2% [56, 59
MAP2K1  ENST00000307102  <2% [56, 60
NRAS  ENST00000369535  <1% [56] 
CBL  ENST00000264033  n/a 
HRAS  ENST00000311189  n/a 
MAP2K2  ENST00000262948  n/a 
SHOC2  ENST00000369452  n/a 
RIT1 n/a  

SALL4-related disorders

SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS), three phenotypes previously thought to be distinct entities [61]. Cardiac features may include atrial septal defect, ventricular septal defect, tetralogy of Fallot and conduction defects. Additional clinical manifestations may affect the eyes, upper and lower extremities, kidneys, ears, GI tract, face, spine, CNS and pituitary. SALL4-related disorders are inherited in an autosomal dominant manner, with approximately 40-50% of cases being caused by a de novo pathogenic variant [61]. Penetrance is reported to be ~95% so molecular testing may be appropriate for unaffected individuals for family planning. Heterozygous deletions either of the whole SALL4 coding region or of single exons [62] as well as truncating variants [63] have been reported to be pathogenic. 

Gene name Transcript Clinical sensitivity
SALL4 ENST00000217086  


Clinical genetics and genomics laboratory 

Ground floor (level 2), Sydney wing, Royal Brompton Hospital, Sydney Street, London, SW3 6NP

Telephone: +44(0)207 352 8121, ext 83009
Email: or 
Opening hours: Monday to Friday, 9am to 5pm
Head of laboratory: Dr Deborah Morris-Rosendahl

Useful documents

Molecular genetic testing request and consent form (pdf, 431KB)

Non-NHS molecular genetic testing request and consent form (pdf, 493KB)