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Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate.


ABSTRACT: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ?5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.

SUBMITTER: Mangold E 

PROVIDER: S-EPMC4833214 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate.

Mangold Elisabeth E   Böhmer Anne C AC   Ishorst Nina N   Hoebel Ann-Kathrin AK   Gültepe Pinar P   Schuenke Hannah H   Klamt Johanna J   Hofmann Andrea A   Gölz Lina L   Raff Ruth R   Tessmann Peter P   Nowak Stefanie S   Reutter Heiko H   Hemprich Alexander A   Kreusch Thomas T   Kramer Franz-Josef FJ   Braumann Bert B   Reich Rudolf R   Schmidt Gül G   Jäger Andreas A   Reiter Rudolf R   Brosch Sibylle S   Stavusis Janis J   Ishida Miho M   Seselgyte Rimante R   Moore Gudrun E GE   Nöthen Markus M MM   Borck Guntram G   Aldhorae Khalid A KA   Lace Baiba B   Stanier Philip P   Knapp Michael M   Ludwig Kerstin U KU  

American journal of human genetics 20160324 4


Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced it  ...[more]

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