A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live
births. Approximately half of infants with CP have a syndromic form,
exhibiting other physical and cognitive disabilities. The other half have
nonsyndromic CP, and to date, few genes associated with risk for
nonsyndromic CP have been characterized. To identify such risk factors, we
performed a genome-wide association study of this disorder. We discovered a
genome-wide significant association with a missense variant in GRHL3
(p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the
result in an independent sample of case and control subjects. In both the
discovery and replication samples, rs41268753 conferred increased risk for
CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively).
In luciferase transactivation assays, p.Thr454Met had about one-third of
the activity of wild-type GRHL3, and in zebrafish embryos, perturbed
periderm development. We conclude that this mutation is an etiologic
variant for nonsyndromic CP and is one of few functional variants
identified to date for nonsyndromic orofacial clefting. This finding
advances our understanding of the genetic basis of craniofacial development
and might ultimately lead to improvements in recurrence risk prediction,
treatment, and prognosis.