Summary: Researchers have identified genetic mutations they believe are responsible for midline craniosynostosis.
Source: Rockefeller University.
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.
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?”
About this neurology research article
Funding: Funding provided by National Institutes of Health, Maxillofacial Surgeons Foundation/ASMS, Yale Center for Mendelian Genomics, NIH Medical Scientist Training, Howard Hughes Medical Institute.
Source: Katherine Fenz – Rockefeller University Image Source: This NeuroscienceNews.com image is credited to The Rockefeller University/eLife. Original Research:Abstract for “Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles” by Andrew T Timberlake, Jungmin Choi, Samir Zaidi, Qiongshi Lu, Carol Nelson-Williams, Eric D Brooks, Kaya Bilguvar, Irina Tikhonova, Shrikant Mane, Jenny F Yang, Rajendra Sawh-Martinez, Sarah Persing, Elizabeth G Zellner, Erin Loring, Carolyn Chuang, Amy Galm, Peter W Hashim, Derek M Steinbacher, Michael L DiLuna, Charles C Duncan, Kevin A Pelphrey, Hongyu Zhao, John A Persing, and Richard P Lifton in eLife. Published online September 8 2016 doi:10.7554/eLife.20125
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]Rockefeller University. “Rare and Common Genetic Variants Combine to Cause Skull Fusion Disorder.” NeuroscienceNews. NeuroscienceNews, 8 September 2016. <https://neurosciencenews.com/genetic-variant-skull-fusion-neurology-4992/>.[/cbtab][cbtab title=”APA”]Rockefeller University. (2016, September 8). Rare and Common Genetic Variants Combine to Cause Skull Fusion Disorder. NeuroscienceNews. Retrieved September 8, 2016 from https://neurosciencenews.com/genetic-variant-skull-fusion-neurology-4992/[/cbtab][cbtab title=”Chicago”]Rockefeller University. “Rare and Common Genetic Variants Combine to Cause Skull Fusion Disorder.” https://neurosciencenews.com/genetic-variant-skull-fusion-neurology-4992/ (accessed September 8, 2016).[/cbtab][/cbtabs]
Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles
Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2,000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP – induced osteoblast differentiation (P < 10-20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.
“Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles” by Andrew T Timberlake, Jungmin Choi, Samir Zaidi, Qiongshi Lu, Carol Nelson-Williams, Eric D Brooks, Kaya Bilguvar, Irina Tikhonova, Shrikant Mane, Jenny F Yang, Rajendra Sawh-Martinez, Sarah Persing, Elizabeth G Zellner, Erin Loring, Carolyn Chuang, Amy Galm, Peter W Hashim, Derek M Steinbacher, Michael L DiLuna, Charles C Duncan, Kevin A Pelphrey, Hongyu Zhao, John A Persing, and Richard P Lifton in eLife. Published online September 8 2016 doi:10.7554/eLife.20125