Genetics and Biomarkers in Congenital Heart Disease

SSA Conference, November 9, 2010

Allen D. Everett, MDAssociate Professor, Pediatric CardiologyHelen B. Taussig Children’s Congenital Heart Center

Translating Congenital Heart Disease for the Non-Cardiologist

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Genetics of Congenital Heart Disease

Genetics of Congenital Heart Disease

• Syndromic-Congenital heart disease associated with other defects such as brain, liver, etc. Uncommon, and tend to be single gene defects– Noonan’s (CHD, hematologic, neurologic) PTPN11– Alagille’s (CHD, liver disease) JAG1– Holt-Oram (CHD, skeletal defects) TBX5

Genetics of Congenital Heart Disease

• Non-syndromic-Congenital heart disease alone. Sporadic and common.– Incidence of gene mutations is low. In Hypoplastic

left heart syndrome, the incidence of mutations in NKX2.5, NOTCH1, HAND1 and GJA1 is 2%.

• Therefore occurrence is related to multifactoral inheritance of a multitude of susceptibility genes (unknown) with low penetrance mutations (being discovered) superimposed on unfavorable environmental conditions (unknown).

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• Chromosomal deletions– 22q11: Tetralogy of Fallot, Interrupted

aortic arch and Tricuspid atresia.– Other less common are 9q34, 1q21.1,

16p11.2 and 17p11.2.– The use of genomic array technologies for

routine genetic screening is identifying an increasing number of chromosome microdeletions in children with CHD.

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Genetics of Congenital Heart Disease

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Genetics of Congenital Heart Disease

MW Wessels and PJ Willems. Clin. Genetics, 2010 78:103

Biomarkers in Congenital Heart Disease

• Biomarker (HUPO): Used to indicate or measure a biological process (for instance, levels of a specific protein in blood or spinal fluid, genetic mutations, or brain abnormalities observed in a PET scan or other imaging test). Detecting biomarkers specific to a disease can aid in the identification, diagnosis, and treatment of affected individuals and people who may be at risk but do not yet exhibit symptoms.

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Biomarkers in Congenital Heart Disease

• Classic example is measurement of specific heart muscle proteins (troponin I) released into the circulation after a myocardial infarction.

• The heart also secretes hormones into the circulation when the workload of the heart is excessive. – Brain naturetic peptide (BNP)

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Biomarkers in Congenital Heart Disease

• BNP – Shown to be a significant diagnostic measure of

heart failure in adults– In patients with pulmonary hypertension, a

significant predictor of sudden death– In children with CHD a potential indicator of poor

heart function and recovery after heart surgery– In the non-surgical setting the levels are so high in

children with CHD that they have little value.– May be useful in detecting transplant rejection.

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Biomarkers in Congenital Heart Disease• Brain Injury Biomarkers

– 36-60% of neonates having surgery for CHD will have evidence of new brain injury on MRI

– Peri-operative brain injury is the most significant morbidity of CHD repair. The average Psychomotor Development Index score after CHD repair is 85, with normal 100.

– Identification of circulating brain specific proteins released with injury (similar to what happens with a myocardial infarction) will help improve and standardize perioperative care to reduce brain injury.

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Translating Congenital Heart Disease for the Non-Cardiologist

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