How to use genetic testing after sudden infant death syndrome

Since the early 1990s, the rate of sudden infant death syndrome (SIDS) has reduced by over 80% in the UK, principally due to public health education regarding safer sleep, in particular the ‘Back-to-Sleep’ campaign, and to a smaller degree the introduction of newborn screening for metabolic conditions.1 2 Despite this, SIDS is still one of the leading causes of postneonatal infant death in developed countries. The triple risk hypothesis states that SIDS occurs due to having (1) a vulnerable infant (2) during a critical development period and (3) a minor exogenous stressor (figure 1). Genetic testing is likely to develop a bigger role in identifying vulnerabilities in the future as research in this field progresses and testing becomes easier.3

When an infant dies unexpectedly (SUDI), a full review of the clinical history, death scene investigation, clinical investigations (including biochemistry, toxicology, microbiology, virology and metabolic tests) and postmortem will be arranged. If no cause of death is found then the diagnosis is SIDS or unexplained SUDI (see table 1).

A small proportion of these cases may be linked to an underlying cardiac genetic cause.4–6 In order to assess the need for genetic testing, a full clinical family history, including three generations, should be established. If there is a family history of sudden death or a known inherited cardiac condition, or if a family member is symptomatic, then examination, resting and exercise ECG should be offered to first-degree and symptomatic relatives. Additionally, following postmortem, a detailed assessment of cardiac molecular pathology may provide further information that points towards a genetic diagnosis.

In the absence of a family history or suggestive pathological findings, current genetic testing is unlikely to provide answers. If a specific diagnosis is suggested, specific genetic testing should be offered after consultation with clinical genetics. Royal College of Pathologists' (RCPATH) guidance states genetic testing should only be carried out after discussion with the coroner (or Procurator Fiscal in Scotland), with family’s consent and with appropriate healthcare follow-up.3

Genetic testing may identify an inherited monogenic disorder that may have clinical significance for other family members and provide information about recurrence risks in other offspring. Genetic counselling is essential at the outset to ensure the family understands the possible outcomes of testing and that the likelihood of obtaining a genetic diagnosis is relatively low. Once results are obtained, it is vital that these are interpreted correctly.

If a genetic variant is identified, then strict classification of pathogenicity according to American College of Medical Genetics and Genomics' (ACMG) guidance must be established (see table 2). If a variant is thought to be pathogenic or likely pathogenic, then cascade genetic screening of the family is required, starting with parents.

Table 2

ACMG variant classifications

The chance of identifying a rare pathogenic variant is higher the more relevant genes are tested but this strategy also increases the likelihood of identifying a variant of unknown significance, which is difficult to interpret. Clinical evaluation of parents may help to guide classification of variants identified. Incomplete penetrance and variable expression of inherited genetic conditions also have to be considered.

Research groups have been using next generation sequencing of gene panels and whole exome sequencing to identify genetic variants that may cause increased vulnerability to sudden death in infancy. Some report up to 34% of SUDI cases have variants in genes associated with cardiac and metabolic conditions.4–6 However, population data found that variants, which have been associated with SUDI/SIDS, may be relatively common in the general population.6 7 Monogenic causes for SUDI are likely to account for less than 5% of cases after taking into account functional impact. However, increased numbers of variants and single nucleotide polymorphisms in many genes have been linked to increasing vulnerability suggesting the majority of SUDI cases are likely to be multifactorial and heterogeneous.7

The relative contribution of mechanical and genetic causes of sudden death appears to change with age.8–10 Genetic variants are more than twice as likely to be found if sudden death occurs after 4 months of age.6 Current research appears to focus on genetic variants that cause sudden death in older individuals. Looking for variants in a broader range of genes which play a role during this critical time period may provide further information, for example, genes involved in brain development and respiratory regulation.11 12 Currently, there is no strong evidence for a monogenic non-cardiac cause of SUDI.2 13

Further research needs to provide functional analysis of relevant genetic variants in order to define pathogenicity using the ACMG classification.14 15 In the future, hopefully we will have access to technology that is able to easily achieve this.

With whole genome and exome sequencing, genetic variants are more readily identifiable than ever before. Whole exome high throughput sequencing could provide a comprehensive and efficient way to identify rare variants in a patient’s DNA and potential underlying cause of SUDI. Families often want extensive investigation into their child’s death, to provide answers, help the grieving process and reduce anxiety in future pregnancies. Despite this, monogenic causes are likely to be found in only a fraction of cases. Therefore, current practice should be to discuss testing with a clinical geneticist when family history or pathology findings suggest the possibility of underlying cardiac or other genetic cause.

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