The role of clinical, genetic and segregation evaluation in sudden infant death

• NGS approach is the option of choice in SIDS cases.
• Genetic data interpretation is the main challenge.
• Familial genetic testing should be performed to clarify pathogenicity of new variants.
• Multidisciplinary team is crucial to translate genetic data into clinical practice.

Sudden infant death syndrome (SIDS) is the leading cause of death in the first year of life. Several arrhythmogenic genes have been associated with cardiac pathologies leading to infant sudden cardiac death (SCD). Our aim was to take advantage of next generation sequencing (NGS) technology to perform a thorough genetic analysis of a SIDS case.A SIDS case was referred to our institution after negative autopsy. We performed a genetic analysis of 104 SCD-related genes using a custom panel. Confirmed variants in index case were also analyzed in relatives. Clinical evaluation of first-degree family members was performed.Relatives did not show pathology. NGS identified seven variants. Two previously described as pathogenic. Four previously catalogued without clinical significance. The seventh variation was novel. Familial segregation showed that the index case’s mother carried all same genetic variations except one, which was inherited from the father. The sister of the index case carried three variants.We believe that molecular autopsy should be included in current forensic protocols after negative autopsy. In addition to NGS technologies, familial genetic testing should be also performed to clarify potential pathogenic role of new variants and to identify genetic carriers at risk of SCD.