An Ethical Debate: Genetic testing for familial hypertrophic cardiomyopathy in newborn infants: Clinicians' perspective
BMJ 1995; 310 doi: https://doi.org/10.1136/bmj.310.6983.856 (Published 01 April 1995) Cite this as: BMJ 1995;310:856
- Mark P Ryan, research fellowa,
- Julie French, research nursea,
- Sahar Al-Mahdawi, senior research officerb,
- Petros Nihoyannopoulos, senior lecturera,
- John G F Cleland, senior lecturera,
- Celia M Oakley, professora
- a Department of Clinical Cardiology, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN
- b Department of Biochemistry and Molecular Genetics, St Mary's Hospital Medical School, Imperial College, London W2 1PG
- Correspondence to: Professor Oakley.
Identification of genes for hypertrophic cardiomyopathy has made preclinical diagnosis possible in families with a mutation. As yet, however, no treatment prevents the development of myocardial hypertrophy, and medical intervention has not been shown to improve prognosis. A team from Hammersmith Hospital carrying out research into genetic causes of the disease report that they were asked by a couple to screen their daughter at birth. The couple also give their view of screening. We asked two medical geneticists, a cardiologist, and a paediatrician with an interest in ethics to comment on the implications.
Hypertrophic cardiomyopathy is inherited as an autosomal dominant but has considerable genetic and phenotypic heterogeneity.1 2 Clinical screening is inaccurate. Several patients from affected families in whom the diagnosis had previously been excluded by electrocardiography and echocardiography have since been shown to have a mutation of the cardiac β myosin heavy chain gene MYH7.3 Once a mutation of MYH7 has been identified in a family genetic testing is relatively simple and accurate.4
Genetic or clinical screening of asymptomatic people is contentious as no intervention has been definitively proved to alter prognosis.5 6 We report the genetic testing of a newborn infant enabling preclinical diagnosis of hypertrophic cardiomyopathy.
Case history
John (individual III-5) had hypertrophic cardiomyopathy diagnosed at the age of 24 during clinical family screening initiated after diagnosis of his sister (figure). He was asymptomatic but had evidence of asymmetric septal hypertrophy on echocardiography, with a septal wall thickness of 24 mm. Subsequently, a mutation in exon 13, codon 403 of MYH7 was detected in this family as part of a study aiming to identify genetic defects giving rise to hypertrophic cardiomyopathy. This study had been approved by the hospital ethics committee and all family members gave informed consent after receiving advice from trained counsellors regarding the consequences of screening. The family were informed a mutation had been identified. John, by then expecting a child, asked for genetic testing to be carried out on his child at the earliest opportunity.
At 6 days of age, a heel prick blood sample was collected from the infant (IV-2) in a heparinised capillary tube while sampling for the Guthrie test. DNA was isolated from the blood and exon 13 of MYH7 amplified by the polymerase chain rection.7 Abolition of the Ava-1 restriction enzyme site, a marker for the mutation, showed that the infant carried the mutation, and direct sequencing confirmed the result. On clinical review age 74 days, Sarah was physically normal and had no abnormalities on electrocardiography or echocardiography.
Authors' comment
As would be expected at this age Sarah was clinically normal,8 and only long term follow up will show the disease. Preclinical diagnosis will allow accurate prospective observation of the natural course of hypertrophic cardiomyopathy and allow studies into prevention of the disease. A course of treatment before the expression of left ventricular hypertrophy may prevent the disease occurring.9 Studies on intervention in those expressing clinical features are difficult without a definitive diagnosis, which is often possible only by genetic means. Studies of the effectiveness of prophylactic drugs such as angiotensin converting enzyme inhibitors, β blockers, or calcium antagonists require a genetically defined population with hypertrophic cardiomyopathy.10 Failure to grasp the opportunities that genetic testing offers for this disease will seriously impede the development of effective treatment.
Testing of this child could be criticised on the grounds that no intervention has been proved to alter prognosis,5 but early diagnosis has many advantages. The child can be raised with an emphasis on avoidance of energetic activities rather than be suddenly banned from an established sporting pursuit during adolescence, when the disease is diagnosed clinically. Regular medical review can detect symptoms, arrhythmias, or ischaemia allowing early and appropriate treatment, which may improve prognosis. Diagnostic uncertainty is removed, and advice and support can be given to both child and parents.
The main disadvantage of early detection of a mutation is the stigma placed by society on someone who may never express the condition and whose prognosis is uncertain. There are serious implications for employment, life insurance, and loans. The mutation may merely be a predisposing factor to hypertrophy in the presence of other stimuli, and so its presence alone does not allow accurate prediction of phenotype or prognosis. Education of the public and relevant institutions will be important to remove this prejudice. Detection of a mutation can have important psychological effects for the carrier unless adequate support is given.
Ultimately the choice of undergoing clinical or genetic screening lies with the patient or, in the case of a minor, the parents. As sudden death, the most devastating consequence of this disease, occurs more often in young people,11 genetic testing with the parents' consent is not an infringement of the child's right. Families must be offered a full explanation of the relative merits of screening in a non-directive setting and given continued support regardless of their decision.