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Birth Defects Res. 2017 Jul 17;109(13):1030-1038. doi: 10.1002/bdr2.23605.

Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing.

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Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.



Orofacial clefts (OFCs), including nonsyndromic cleft lip with or without cleft palate (NSCL/P), are common birth defects. NSCL/P is highly heterogeneous with multiple phenotypic presentations. Two common subtypes of NSCL/P are cleft lip (CL) and cleft lip with cleft palate (CLP) which have different population prevalence. Similarly, NSCL/P can be divided into bilateral and unilateral clefts, with unilateral being the most common. Individuals with unilateral NSCL/P are more likely to be affected on the left side of the upper lip, but right side affection also occurs. Moreover, NSCL/P is twice as common in males as in females. The goal of this study is to discover genetic variants that have different effects in case subgroups.


We conducted both common variant and rare variant analyses in 1034 individuals of Asian ancestry with NSCL/P, examining four sources of heterogeneity within CL/P: cleft type, sex, laterality, and side.


We identified several regions associated with subtype differentiation: cleft type differences in 8q24 (p = 1.00 × 10-4 ), laterality differences in IRF6, a gene previously implicated with wound healing (p = 2.166 × 10-4 ), sex differences and side of unilateral CL differences in FGFR2 (p = 3.00 × 10-4 ; p = 6.00 × 10-4 ), and sex differences in VAX1 (p < 1.00 × 10-4 ) among others.


Many of the regions associated with phenotypic modification were either adjacent to or overlapping functional elements based on ENCODE chromatin marks and published craniofacial enhancers. We have identified multiple common and rare variants as potential phenotypic modifiers of NSCL/P, and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Birth Defects Research 109:1030-1038, 2017. © 2017 Wiley Periodicals, Inc.


complex trait; genetic epidemiology; orofacial cleft

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