Cardiac Genetic Investigation of Sudden Infant and Early Childhood Death: A Study From Victims to Families

Abstract

Background Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results Seventy-seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive-evidence arrhythmia-associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double-blind review of clinical-genetic data established genotype-phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P=0.03), whereas novel/ultra-rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive-evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype-phenotype correlations significantly aided variant adjudication. Conclusions Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive-evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.

Keywords: channelopathies; molecular autopsy; sudden infant death syndrome; sudden unexplained death in childhood.

Figure 1. Yield of genetic testing and distribution of genetic variants.

A, Yield of genetic testing in the 77 SIDS and 18 SUDC cases for different variant classes across the 25 major arrhythmia‐associated genes. Statistically significant (P<0.05) comparisons are shown above the bars. B, Distribution of the 29 novel, ultra‐rare, and rare genetic variants across the 25 major genes that yielded >1 genetic variant in the whole cohort. Absolute numbers (n) and relative frequencies (%) are shown within and above the bars, respectively. LB indicates likely benign; LP, likely pathogenic; SIDS, sudden infant death syndrome; SUDC, sudden unexplained death in childhood; and VUS, variant of uncertain significance.

Figure 2. Yield of expanded genetic testing and genetic variant distribution across 101 genes with different levels of evidence of disease association.

A, Distribution of the 19 novel and ultra‐rare genetic variants across 101 genes with different levels of evidence of disease association in 18 SIDS/SUDC cases. Absolute numbers (n) and relative frequencies (%) are shown within and above the bars, respectively. B, Yield of expanded genetic testing according to different variant classes across 101 genes with different levels of evidence of disease association in 18 SIDS/SUDC cases. LB indicates likely benign; LP, likely pathogenic; NA, noncurated genes or genes with anecdotal evidence; SIDS, sudden infant death syndrome; SUDC, sudden unexplained death in childhood; and VUS, variant of uncertain significance.