Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios

Madison R Bishop; Kimberly K Diaz Perez; Miranda Sun; Samantha Ho; Pankaj Chopra; Nandita Mukhopadhyay; Jacqueline B Hetmanski; Margaret A Taub; Lina M Moreno-Uribe; Luz Consuelo Valencia-Ramirez; Claudia P Restrepo Muñeton; George Wehby; Jacqueline T Hecht; Frederic Deleyiannis; Seth M Weinberg; Yah Huei Wu-Chou; Philip K Chen; Harrison Brand; Michael P Epstein; Ingo Ruczinski; Jeffrey C Murray; Terri H Beaty; Eleanor Feingold; Robert J Lipinski; David J Cutler; Mary L Marazita; Elizabeth J Leslie

doi:10.1016/j.ajhg.2020.05.018

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios

Am J Hum Genet. 2020 Jul 2;107(1):124-136. doi: 10.1016/j.ajhg.2020.05.018. Epub 2020 Jun 22.

Authors

Madison R Bishop¹, Kimberly K Diaz Perez¹, Miranda Sun², Samantha Ho¹, Pankaj Chopra¹, Nandita Mukhopadhyay³, Jacqueline B Hetmanski⁴, Margaret A Taub⁵, Lina M Moreno-Uribe⁶, Luz Consuelo Valencia-Ramirez⁷, Claudia P Restrepo Muñeton⁷, George Wehby⁸, Jacqueline T Hecht⁹, Frederic Deleyiannis¹⁰, Seth M Weinberg¹¹, Yah Huei Wu-Chou¹², Philip K Chen¹³, Harrison Brand¹⁴, Michael P Epstein¹, Ingo Ruczinski⁵, Jeffrey C Murray¹⁵, Terri H Beaty⁴, Eleanor Feingold¹⁶, Robert J Lipinski², David J Cutler¹, Mary L Marazita¹¹, Elizabeth J Leslie¹⁷

Affiliations

¹ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
² Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA.
³ Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA 15219, USA.
⁴ Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
⁵ Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
⁶ Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
⁷ Fundación Clínica Noel, Carrera 50 # 63-131, Medellín, Colombia.
⁸ Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA 52242, USA.
⁹ Department of Pediatrics, McGovern Medical School and School of Dentistry, UT Health at Houston, Houston, TX 77030, USA.
¹⁰ UCHealth Plastic and Reconstructive Surgery, Colorado Springs, CO 80907, USA.
¹¹ Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA 15219, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15219, USA.
¹² Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
¹³ Craniofacial Centre, Taipei Medical University Hospital and Taipei Medical University, Taipei, Taiwan.
¹⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹⁵ Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
¹⁶ Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15219, USA.
¹⁷ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: ejlesli@emory.edu.

Abstract

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

Keywords: de novo mutations; orofacial clefts; trios; whole genome sequencing.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Asian People / genetics
Cleft Lip / genetics*
Cleft Palate / genetics*
Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods
Humans
Male
Mutation / genetics*
Polymorphism, Single Nucleotide / genetics
White People / genetics
Whole Genome Sequencing / methods

Abstract

Publication types

MeSH terms

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