Sudden unexplained childhood death genetic factors sought

A project will soon be underway at UW Medicine to try to uncover genetic factors that contribute to cases of sudden childhood death for which no cause can yet be determined.

The Sudden Unexplained Death In Childhood Foundation is funding thestudy, which will be conducted by physician-scientists Dr. Danny E. Miller and Dr. Alexandra C. Keefe. The four-year project is funded at $328,133.

Miller and Keefe are assistant professors of pediatrics at the University of Washington School of Medicine. Miller is also an assistant professor of laboratory medicine and pathology. Both practice at Seattle Children’s Hospital.

“This research represents an important step toward understanding the genetic factors that may contribute to sudden unexplained death in childhood,” said Miller. “By using long-read sequencing alongside traditional methods, we hope to provide families with answers that have been historically difficult to obtain and to advance scientific knowledge that could save lives in the future.”

Sudden and Unexplained Death in Childhood, or SUDC, is a category of death for a child ages 1 to 18 for which the cause remains undetermined after a thorough case investigation, including an autopsy, examination of the death scene, and clinical history review. This classification does not include sudden deaths of infants up to the age of 12 months. 

“Families affected by SUDC face unimaginable loss, and our mission is to support both the science and the community,” said Julia Burgess, president of the SUDC Foundation. “Funding this project reflects our commitment to advancing research that brings clarity, guidance, and hope to grieving families nationwide.”

The study will use a tiered genomic approach to examine DNA from postmortem tissues and newborn blood spots from 100 SUDC cases. The researchers also will analyze saliva samples from the biological parents and siblings to distinguish inherited versus new genetic variants that might provide clues about predisposing factors.

The research team will start with trio-based exome sequencing in which they will analyze and compare only the protein-coding portions of the child’s and biological parents’ genome. They would then do low-pass, or shallow, whole genome sequencing. This would be followed by reflexive long-read sequencing for cases where initial testing does not reveal likely pathogenic variants. The approach is expected to increase the overall diagnostic yield, thereby potentially providing answers to families who previously received none. 

Long-read sequencing can generate extensive stretches of DNA code. This enables researchers to more accurately capture complex or large genetic elements that might be missed by short-read sequencing. In short-read sequencing, which has its own advantages, the DNA strands are more fragmented. 

Miller’s and Keefe’s research aims to overcome longstanding barriers in postmortem genetic testing, including limited availability, insurance coverage challenges, and difficulties obtaining usable samples. Findings from this research also will inform clinical guidelines for postmortem sample collection and genetic testing in SUDC cases, support larger-scale studies, and contribute to the broader understanding of sudden death syndromes in children.

Dr. Grace Hillyer, chair of the SUDC Foundation Scientific Advisory Board, said, “The SUDC Foundation is proud to support research that pushes the boundaries of pediatric genetics. Dr. Miller and Dr. Keefe are combining innovative technology with a family-centered approach, offering hope to families affected by SUDC, and creating a model for future investigations in this field.”

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