The mother found an answer after she became a scientist when the child died suddenly.

The secret of some children's unexplained death may be hidden in DNA.

Some children die for some reason.

In the summer of 1997, Maria, the 15-month-old daughter of Laura Gould, had a fever one night. The next morning, the child seemed to be getting better and would dance to the TV. Maria is asleep at noon, and Laura is going to take her to the doctor later. But the child never woke up.

Laura herself is a physiotherapist (also known as a rehabilitation therapist who develops rehabilitation programs for patients' movement problems in order to improve physical function). As a medical worker, she felt that she had ignored the symptoms of her daughter and missed the opportunity to save the child. Laura thought that as long as she consulted a more professional person, she would immediately know where she was wrong.

But when Maria's body was taken to the medical examiner's office, the autopsy did not reveal the cause of her death. After that, Laura turned to other pathologists who couldn't find any explanation.

Recently, a team of researchers from New York University finally found a clue to the genes. The scientists published the results in the Proceedings of the National Academy of Sciences (PNAS), and Laura is a co-author of the study.

Children have genes that parents don't have.

In 2014, Laura and Devinsky launched the SUDC registry and began collecting cases of unexplained sudden death in children aged 1-18, not only from their own biological samples, but also from their parents.

The samples used in the study came from 124 deceased children on the registration form and their living parents. The scientists analyzed their DNA in the hope of identifying genetic mutations that could cause the disease. Generally speaking, when forensic doctors investigate the cause of death, they do not analyze the DNA of the deceased, so such a "molecular autopsy" has the opportunity to fill the blind area of a general autopsy.

There are exons and introns in the DNA sequence. Exons are responsible for encoding proteins. Introns do not encode proteins, but are inserted between different exons to separate them. All kinds of important physiological activities in the human body depend on proteins, so scientists are more concerned about the exons in DNA: if there is a mutation in exons, the proteins produced by cells may have structural abnormalities and some normal functions will be destroyed.

In the exon sequence, scientists focused on 137 genes related to arrhythmias, epilepsy and other diseases. It was found that among 124 children who died of unknown causes, the frequency of non-synonymous mutations in these genes was almost 10 times higher than that of the general population, a significant difference.

The so-called non-synonymous mutation refers to a change in a nucleotide in DNA, resulting in a change in an amino acid in a protein, which is mostly harmful or even fatal; and if a nucleotide changes, the corresponding amino acid does not change, it is synonymous mutation, which will not affect the structure and function of the protein.

Scientists believe that the cause of death of children is likely to be hidden in those genetic mutations. So, what kind of mutations are they?

Eleven of the 124 people had mutations in genes associated with calcium signal transduction. Calcium signals play an important role in the human body: after calcium ions enter the neurons, they can trigger the release of neurotransmitters and transmit information to another cell; and after calcium ions enter the cardiomyocytes, the calcium stored in the "warehouse" can be released into the cytoplasm, greatly increasing the concentration of calcium ions in the cells, thus causing the heart muscle to contract.

As a result, once the workflows of calcium ions are affected, the function of both the brain and heart may be damaged. For example, the team observed a mutation in the RYR2 gene, a gene that expresses ryanodine receptor 2: ryanodine receptor 2 is like a "storekeeper". When calcium ions enter cardiomyocytes, they need to activate the receptor before releasing stored calcium into the cells and causing the heart muscle to contract. After a mutation in this gene, the body cannot normally synthesize ryanodine receptors, and children may have arrhythmias or even cardiac arrest.

Including the RYR2 gene, scientists found mutations in six genes associated with calcium signaling in children, some of which point to heart disease and others that may point to neurological diseases (epilepsy). These may be the reasons for the sudden death of some children.

When the scientists compared the DNA of their children with that of their parents, they found that almost all of these mutations were newborn mutations (de novo mutations), mutations that were not found in the parents' DNA, but appeared in the children's DNA. This may be due to the error of DNA replication during meiosis before the formation of sperm or egg cells, or the variation of the fertilized egg itself in the early stages of embryonic development.

Since the mutation is random, it is almost impossible for a parent to have the same fatal mutation when they give birth twice, the researchers said. So if SUDC happens to a child and parents want to have a second child, the study will also give them some hope.

It's not just a comfort.

Professor Qian Yongyou, a neurologist at New York University and a member of the research team, said: "our study is by far the largest of its kind and proves for the first time that there is a clear genetic factor for sudden unexplained death (SUDC) in children, filling some gaps in this field."

However, the pattern found in 11 people represents only 9% of the 124. Further exploration is needed if we want to find more of the main causes of sudden death of children. Shortly after the study was published, a team led by scientists at Boston Children's Hospital also reported their new results.

In this database, a total of 73 cases contain data on both children and parents. The team targeted potentially fatal mutations in 37 of the children: 13 mutations in genes associated with neurological diseases, 18 mutations in genes associated with heart problems, and 6 mutations associated with systemic diseases.

Six of these children with the risk gene were over 1 year old, that is, cases of unexplained child death (SUDC), which may be used as a supplement to the first study.

For parents who have lost their children, knowing the reason is completely different from not knowing it. Thanks to the efforts of Laura and her colleagues, the little girl Chloe's family finally learned that genetic mutations can affect her heart's ability to maintain a normal rhythm. They had been waiting for three years before they got the answer.

Today, Laura is not only Maria's mother, but also a researcher at New York University's Grossman School of Medicine. For scientists like her, finding the cause of a child's unexplained sudden death is the first step towards treatment. If genetic risk factors can be identified early, there is an opportunity to intervene in children's underlying health problems in a timely manner.

Scientists hope that one day, genes that can cause sudden death in children can be added to the newborn screening list. But before that, there is still a long way to go. After all, current research alone is not enough to say exactly which genetic mutations will have what consequences. If a child is arbitrarily judged to be "at risk of arrhythmia" and intervened, it may create more problems.