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Developmental Biology - Stillbirth

New Genetic Analyses May Give Answers to Stillbirths

Columbia researchers have uncovered an array of new genes that cause stillbirth, significantly increasing the understanding of the condition's genetic foundations...

New findings suggest genetic analysis could be used to counsel parents who have previously experienced stillbirth, and help unlock new human biology.

Using both standard and advanced analysis techniques, a team led by David Goldstein PhD and Ronald Wapner MD of Columbia University, Vagelos College of Physicians and Surgeons (VP&S) has identified the likely genetic cause of stillbirth in one of every 10 cases studied.
"This study shows that careful genetic analyses can often identify the precise genetic causes of stillbirth, demonstrating the importance of diagnostic sequencing in all cases of unexplained stillbirth. Of equal importance, the work highlights how little we currently understand about the biology of stillbirth..."

David Goldstein PhD, Director, Institute for Genomic Medicine, Columbia University Irving Medical Center.

The study is published online in the New England Journal of Medicine. Kate Stanley MS, research associate and Jessica Giordano MS, research genetic counselor, were co-first authors of the work.

Presumed Genetic Underpinning — But Few Studies

Stillbirth is defined as the in utero death of a fetus after 20 weeks' gestation. It occurs in approximately one in 100 pregnancies and is about 10 times more common than sudden infant death syndrome.

In the majority of cases, the cause of stillbirth is unknown. Some have been linked to maternal infection and preeclampsia. Another 10% to 20% are attributed to large and easily detectable chromosomal abnormalities. Only a few genes have been implicated.
"Unlike postnatal childhood conditions that are presumed to be strongly genetic, stillbirth had yet to be systematically analyzed with modern genome sequencing approaches. All too often, we have no explanation to give parents who experience a stillbirth. Not only are they devastated, they're often left to wonder if it's something they did wrong or if it might happen again."

Ronald J. Wapner MD.

Finding Genetic Causes

As genomic sequencing has been particularly useful in diagnosing otherwise unexplained childhood disorders and fetal structural defects, the Columbia team decided to search via gene sequencing for genetic variants that may cause stillbirth.

Researchers sequenced 246 stillborn fetuses for all protein-encoding genes where known disease-causing genetic variants occur. They used new statistical analyses to identify any genetic mutations that may have caused the death of the fetus.
The combination of traditional sequencing and new analytical techniques revealed small changes in 13 genes that caused fetal death; six of these genes had not previously been linked to stillbirth.

"Although these are small changes in only a single site in the genome, they are in effect, genomic sledgehammers. They either dramatically change or knock out essential genes and appear responsible — on their own — for fetal demise," explains Goldstein.

These small genetic changes explained 8.5% of stillbirths in the study. When combined with a previous analysis of larger genomic alterations in this same group, researchers determined that 18% of the stillbirths had a known genetic cause.

This analysis also showed a critical difference compared with the study of postnatal genetic conditions.
"Interestingly, some of the changes we found in genes known to cause postnatal diseases and conditions appeared to have more profound effects than the mutations linked to postnatal disease."

David Goldstein PhD

Clinical Implications

Currently, the analyses required to find causal genetic causes of a stillbirth can be conducted in only a few academic medical centers.

But eventually the findings from this study - and future studies - will help physicians counsel parents and guide clinical care.
"To a woman who's just had a stillbirth, specific knowledge about the cause is critical. They often blame themselves and some decide not to have any more children. If the stillbirth can be attributed to a genetic mutation that has only occurred in the fetus, not in the parents, the same problem is unlikely to occur in future pregnancies. That knowledge would change the way we would provide care," Wapner says, "and facilitate closure and bereavement for families."

Ronald J. Wapner MD

Unlocking Human Biology

Most genetic diagnostic studies focus on genes already known to cause disease. However, because stillbirth has been understudied, the team wanted to test whether genetic changes in genes not currently linked to disease contribute to stillbirth.
Researchers used a bioinformatic tool pioneered by the Goldstein lab, which focuses on genes under the strongest natural selection in humans - known as "intolerant" genes. With it the team revealed at least 5% of stillbirths are likely due to mutations in intolerant genes not currently linked to any known human disease.

"These novel disease genes appear to be critical for early human development, and the only way to discover them is through the analysis of fetuses that do not develop," Goldstein says.

"We're opening up new frontiers in biology and the more we understand about basic human development, the more we can potentially intervene."

In the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to chromosomal abnormalities. However, the causal nature of single-nucleotide variants and small insertions and deletions in exomes has been understudied.

We generated exome sequencing data for 246 stillborn cases and followed established guidelines to identify causal variants in disease-associated genes. These genes included those that have been associated with stillbirth and strong candidate genes. We also evaluated the contribution of 18,653 genes in case–control analyses stratified according to the degree of depletion of functional variation (described here as “intolerance” to variation).

We identified molecular diagnoses in 15 of 246 cases of stillbirth (6.1%) involving seven genes that have been implicated in stillbirth and in six disease genes that are good candidates for phenotypic expansion. Among the cases we evaluated, we also found an enrichment of loss-of-function variants in genes that are intolerant to such variation in the human population (odds ratio, 2.15; 95% confidence interval [CI], 1.46 to 3.06). Loss-of-function variants in intolerant genes were concentrated in genes that have not been associated with human disease (odds ratio, 2.22; 95% CI, 1.41 to 3.34), findings that differ from those in two postnatal clinical populations that were also evaluated in this study.

Our findings establish the diagnostic utility of clinical exome sequencing to evaluate the role of small genomic changes in stillbirth. The strength of the novel risk signal (as generated through the stratified analysis) was similar to that in known disease genes, which indicates that the genetic cause of stillbirth remains largely unknown. (Funded by the Institute for Genomic Medicine.)

Kate E. Stanley, BA, Jessica Giordano, MS, CGC, Vanessa Thorsten, MPH, Christie Buchovecky, PhD, Amanda Thomas, PhD, Mythily Ganapathi, PhD, Jun Liao, PhD, Avinash V. Dharmadhikari, PhD, Anya Revah-Politi, MS, CGC, Michelle Ernst, MS, CGC, Natalie Lippa, MS, CGC, Halie Holmes, MS, CGC, Gundula Povysil, MD, PhD, Joseph Hostyk, BS, Corette B. Parker, Dr.P.H., Robert Goldenberg, MD, George R. Saade, MD, Donald J. Dudley, MD, Halit Pinar, MD, Carol Hogue, PhD, MPH, Uma M. Reddy, MD, MPH, Robert M. Silver, MD, Vimla Aggarwal, MB, BS, Andrew S. Allen, PhD, Ronald J. Wapner, MD, and David B. Goldstein, PhD.

The research was supported by the Institute for Genomic Medicine at Columbia University Irving Medical Center with grants from the National Institute of Child Health and Human Development (HD45925, HD45944, HD45952, HD45953, HD45954, and HD45955)

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Aug 17 2020   Fetal Timeline   Maternal Timeline   News

Still birth is defined as death of a fetus after 20 weeks of pregnancy. New research reveals 13 genes can cause fetal death, six of which were not previously linked to stillbirths. CREDIT Stock Photo.

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