Nav: Home

Rare and common genetic variants combine to cause skull-fusion disorder

September 08, 2016

During the first year of life, the human brain doubles in size, and continues growing through adolescence. But sometimes, the loosely connected plates of a baby's skull fuse too early, a disorder known as craniosynostosis. Variants of this disorder can produce facial and skull deformities, and put potentially damaging constraints on a young brain.

A research team led by Rockefeller University President Richard P. Lifton, then at Yale University, has identified mutations responsible for a type of craniosynostosis that affects the suture running along the top of the skull. The results appear in eLife.

"While this discovery will immediately help us diagnose and counsel patients, it also has much broader relevance for understanding the genetics of complex traits, including many human diseases," says Lifton, who is head of Rockefeller's Laboratory of Human Genetics and Genomics and was a Howard Hughes Medical Institute investigator prior to moving to Rockefeller.

He and his team at Yale, including John Persing and colleagues in the Section of Plastic and Reconstructive Surgery, found that rare mutations in one gene collaborate with common variants near a second to cause midline craniosynostosis. As such, this disorder is a unique example of how an interaction between genes can contribute to disease.

Sporadic inheritance

Midline craniosynostosis occurs when the suture in front of or behind the soft spot atop a baby's skull closes early, producing a ridge or other distortions and, in some cases, neurological problems. First author Andrew Timberlake, an M.D.-Ph.D. student in Lifton's lab at Yale, used social media to recruit many of the 191 families who participated in this study.

By plotting out the inheritance of the disorder through the families, the team noticed that it showed up unpredictably within them. Clearly, they thought, something more than simple dominant or recessive inheritance was at play. When they sequenced the participants' protein-coding genes, or exomes, mutations in one gene, SMAD6, caught their attention. This made sense; SMAD6 is a protein that inhibits so-called BMP signaling, which promotes bone formation. But not everyone carrying these rare SMAD6 mutations had midline craniosynostosis. In fact, none of the parents who shared the SMAD6 mutation with their affected children had a history of craniosynostosis--a finding that initially surprised researchers.

A partner in crime

The team then looked to find mutations that might affect the same bone formation pathway. Some previous work implicated common changes near one such gene, BMP2, so they looked for these variations among the families.

"It was amazing to then find that the affected children had inherited both the SMAD6 mutation and the common BMP2 variant. In each case, the SMAD6 mutation came from one parent and the BMP2 risk variant came from the other parent, explaining why neither parent had craniosynostosis," Timberlake says.

The researchers believe that the risk variants near BMP2 increase the levels of the bone-promoting BMP signaling, thereby amplifying the effect of the loss of SMAD6's ability to inhibit the process. The result: The gap between the skull bones fuses ahead of schedule.

Among the families studied, those who carried the rare, damaging SMAD6 mutation plus a common BMP2 risk variant always had midline craniosynostosis, while those with only a SMAD6 mutation, but no BMP2 risk allele, were much less likely to suffer from the disorder. This knowledge should help doctors and genetic counselors better assess the risk within families.

New insight on disease risk

The researchers suggest that a similar dynamic may be at play in other rare genetic disorders that don't appear to follow classical Mendelian inheritance patterns.

"Our results offer a clear demonstration of the interaction between rare and common variants," Lifton says, "offering one explanation to a lingering question in genetics: Why do some individuals with potent rare mutations develop disease, while others with the same mutations do not?"
-end-
About The Rockefeller University

The Rockefeller University is the world's leading biomedical research university and is dedicated to conducting innovative, high-quality research to improve the understanding of life for the benefit of humanity. Our 79 laboratories conduct research in neuroscience, immunology, biochemistry, genomics, and many other areas, and a community of 1,800 faculty, students, postdocs, technicians, clinicians, and administrative personnel work on our 14-acre Manhattan campus. Our unique approach to science has led to some of the world's most revolutionary and transformative contributions to biology and medicine. During Rockefeller's 115-year history, 24 of our scientists have won Nobel Prizes, 21 have won Albert Lasker Medical Research Awards, and 20 have garnered the National Medal of Science, the highest science award given by the United States.

Rockefeller University

Related Genetics Articles:

Genetics researchers find new neurodevelopmental syndrome
Researchers have identified a gene mutation that causes developmental delay, intellectual disability, behavioral abnormalities and musculoskeletal problems in children.
The genetics of cancer
A research team has identified a new circular RNA (ribonucleic acid) that increases tumor activity in soft tissue and connective tissue tumors.
New results on fungal genetics
An international team of researchers has found unusual genetic features in fungi of the order Trichosporonales.
Mouse genetics influences the microbiome more than environment
Genetics has a greater impact on the microbiome than maternal birth environment, at least in mice, according to a study published this week in Applied and Environmental Microbiology.
New insights into genetics of fly longevity
Alexey Moskalev, Ph.D., Head of the Laboratory of Molecular Radiobiology and Gerontology Institute of Biology, and co-authors from the Institute of biology of Komi Science Center of RAS, Engelgard's Institute of molecular biology, involved in the study of the aging mechanisms and longevity of model animals announce the publication of a scientific article titled: 'The Neuronal Overexpression of Gclc in Drosophila melanogaster Induces Life Extension With Longevity-Associated Transcriptomic Changes in the Thorax' in Frontiers in Genetics - a leading open science platform.
More Genetics News and Genetics Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...