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.

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]. 

Heterotaxy/situs ambiguous (HTX)

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.

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].

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).

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. 

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: rbh-tr.genomics@nhs.net or geneticslab@rbht.nhs.uk 
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)