Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21

Abstract

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

Epidemiologic trends of infants with orofacial clefts in a multiethnic country: a retrospective population-based study

“…The prevalence of the groups with OFC of different ancestries in this study were almost similar to their forebears in the old countries. This corroborated with findings linking ethnic-specific prevalence of OFC to ancestral genes 15 .…”

Genome-wide Association Study of Non-syndromic Orofacial Clefts in a Multiethnic Sample of Families and Controls Identifies Novel Regions

“…The AFR and CSA groups are also geographically diverse (although CSA has a low FST genetic diversity coefficient), which could have led to weaker associations; there are only two genome-wide significant associations in CSA, even though this is our largest group consisting of 1,050 affected and 2,988 unaffected participants. In a previous whole genome sequence study that included only the CSA participants from Colombia, we observed a genome-wide significant association in chromosome 21q22.3 (Mukhopadhyay et al, 2020), but no corresponding association is seen either in this current study or the two previous studies that used CSA participants (Leslie et al, 2016;Leslie et al, 2017). The variants in the chromosome 21q22.3 in Colombian CL/P trios were observed to have similar allele frequencies across the subpopulations that make up the CSA group, but yielded no significant association when non-Colombian CSA participants were analyzed separately.…”

Epidemiologic Trends of Infants With Orofacial Clefts in a Multiethnic Country: A Retrospective Population-based Study

“…The prevalence of the ethnic groups with OFC in this study resembled those in the old countries of their forebears. This corroborates with ndings that indicate ethnic-speci c prevalence of OFC seemed to be linked to ancestral genes [16].…”