De Novo Mutations In 555 Trios Implicate Chromatin Modification, Transcriptional Regulation, And Retinoic Acid Signaling In Syndromic Craniosynostosis
Andrew Timberlake, MD PhD1, Garrett Allington, BS2, Emre Kiziltug, BS2, Erin Wolfe, BS3, John Persing, MD4, Richard P. Lifton, MD PhD5, Gene Dx, .6, Kristopher T. Kahle, MD PhD7.
1NYU, New York, NY, USA, 2Yale School of Medicine, New Haven, CT, USA, 3Miller School of Medicine, Miami, FL, USA, 4Yale University, New Haven, CT, USA, 5Rockefeller University, New York, NY, USA, 6GeneDx, Gaithersburg, MD, USA, 7Massachusetts General Hospital, Boston, MA, USA.
PURPOSE: Craniosynostosis (CS) is the most common congenital cranial anomaly. Several Mendelian forms of syndromic CS are well-described, but the genetic etiology of a substantial fraction of cases remains undefined.
METHODS: We analyzed exome sequence data from 555 proband-parent trios with syndromic CS who had tested negative for mutations in known CS genes in order to identify novel genetic causes of syndromic CS.
RESULTS: We identified a marked excess (observed 98, expected 33, P=1.4x10-19) of damaging de novo mutations (DNMs) in genes highly intolerant to loss of function mutation (pLI>0.9). Thirty probands harbored damaging DNMs in 21 genes not previously implicated in CS that are involved in chromatin modification and remodeling (4.7-fold enrichment, P=1.1x10-11). 17 genes had multiple damaging DNMs and 13 genes surpassed thresholds for genome-wide significance. A recurrent gain-of-function DNM in the retinoic acid receptor alpha (RARA) was identified in two probands with a novel CS syndrome. CS risk genes overlap with autism and other neurodevelopmental disorders, are highly expressed in cranial neural crest cells, and converge in networks that regulate chromatin modification, gene transcription and osteoblast differentiation.
CONCLUSIONS: Our results identify >20 novel CS loci and have major implications for genetic testing and patient counseling.
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