Presentation: Infant or child with congenital heart disease

You review a newborn with congenital heart disease. Tetralogy of Fallot was detected at the 20-week gestation scan, he was born small for gestational age and has a cleft palate. There is a family history of learning difficulties: his mother required extra help at mainstream school, leaving at the age of 16 with few qualifications.

Genomic testing should be considered if:

• there is a family history of congenital structural heart disease or learning difficulties;
• the patient has one of the congenital heart anomalies known to be associated with syndromic diagnoses – specifically tetralogy of Fallot, interrupted aortic arch and truncus arteriosus;
• the patient has any form of congenital heart disease, together with a cleft palate and/or disorder of calcium homeostasis; and/or
• there is a complex or syndromic presentation, for example with other congenital malformations, dysmorphism, growth restriction or microcephaly.

In some cases, the presence of congenital heart disease may indicate a specific syndrome, some of which are listed below.

• 22q11.2 deletion syndrome: This should be considered if the patient presents with:
  • conotruncal heart anomalies;
  • cleft palate;
  • disorder of calcium homeostasis; and/or
  • dysmorphic facial features.
    • See Presentation: Clinical suspicion of 22q11.2 deletion syndrome for more information.
• Williams syndrome: Consider this condition if the patient presents with peripheral pulmonary stenosis and dysmorphic facial appearance.
  • See Presentation: Clinical suspicion of Williams syndrome for more information.
• RASopathies, including Noonan syndrome: Consider these conditions if the patient presents with:
  • pulmonary valve stenosis;
  • early feeding difficulties;
  • normal or high birth weight; and/or
  • cryptorchidism (in males).
    • See Presentation: Clinical suspicion of Noonan syndrome for more information.
• Turner syndrome: Consider this condition if the patient presents with:
  • coarctation of the aorta;
  • short stature;
  • neck webbing; and/or
  • puffy feet or lymphoedema.
    • See Presentation: Clinical suspicion of Turner syndrome for more information.
• Down syndrome: Consider this condition if the patient presents with:
  • an atrio-ventricular septal defect;
  • patent ductus arteriosus;
  • tetralogy of Fallot;
  • characteristic facial features;
  • a widened sandal gap; and/or
  • a single palmer crease.
    • (see Presentation: Clinical suspicion of Down syndrome (trisomy 21) for more information.
• Edwards syndrome: Consider this condition if the patient presents with:
  • ventricular and/or atrial septal defect;
  • patent ductus arteriosus;
  • intrauterine growth restriction or low birth weight;
  • microcephaly;
  • micrognathia; and/or
  • clenched fists with overlapping fingers.
    • See Presentation: Clinical suspicion of Edwards syndrome (trisomy 18) for more information.
• Patau syndrome: Consider this condition if the patient presents with:
  • ventricular and/or atrial septal defect;
  • patent ductus arteriosus;
  • intrauterine growth restriction or low birth weight;
  • microcephaly and craniofacial anomalies;
  • ocular anomalies;
  • holoprosencephaly with midline facial anomalies;
  • anomalies of the central nervous system;
  • renal anomalies; and/or
  • anomalies of the hands and feet.
    • (See Presentation: Clinical suspicion of Patau syndrome (trisomy 13) for more information.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient or family. Congenital heart disease can be caused by either a chromosome anomaly or a gene single anomaly. If none of the specific conditions listed above are suspected, consider the following.
  • R137 Congenital heart disease – microarray: Individual with tetralogy of Fallot, interrupted aortic arch or truncus arteriosus, or other forms of congenital heart disease with cleft palate and/or disorder of calcium homeostasis.
  • R140 Elastin-related phenotypes: Consider this option in those with congenital heart disease of a type associated with Elastin variants (for example, supravalvular aortic stenosis), with an autosomal dominant pattern of inheritance in at least three family members, or supravalvular aortic stenosis characteristic of Elastin variants.
  • R27 Paediatric disorders: This should be considered if there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate chromosomal and single gene causes. The test involves whole genome sequencing (WGS) of a large number of panels simultaneously.
• For tests that do not include WGS, including R137 and R140:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS Genomic Medicine Service test order form with details of the affected individual (proband) and their parents where available, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for whole genome sequencing for support in completing WGS-specific forms); and
  • complete an NHS Genomic Medicine Service record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• R27 is an amalgamation of more than 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube). For more information, see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Simmons MA and Brueckner M. ‘The genetics of congenital heart disease… understanding and improving long-term outcomes in congenital heart disease: a review for the general cardiologist and primary care physician’. Current Opinion in Pediatrics 2017: volume 29, issue 5, pages 520–528. DOI: 10.1097/MOP.0000000000000538

For patients

• NHS England: Whole genome sequencing patient information leaflets
• NHS Health A to Z: Congenital heart disease