Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families

Abstract

BackgroundNonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. Previous genome‐wide association (GWAS) studies have identified multiple loci with small effects; however, many causal variants remain elusive.MethodsIn this study, we address this by specifically looking for rare, potentially damaging variants in family‐based data. We analyzed both whole exome sequence (WES) data and whole genome sequence (WGS) data in multiplex cleft families to identify variants shared by affected individuals.ResultsHere we present the results from these analyses. Our most interesting finding was from a single Syrian family, which showed enrichment of nonsynonymous and potentially damaging rare variants in two genes: CASP9 and FAT4.ConclusionNeither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts.

Factors associated with the presence of cleft lip and / or cleft palate in Brazilian newborns

“…In this study, the variable low schooling presented itself as a protective factor in the quadrennium 2005-2008, but it is known that the lack of information is an aggravating factor in health, being the low schooling a predominant Brazilian feature in the profile of neonatal deaths. 5,6,21 It is emphasized that, from 2009 to 2016, the low schooling was demonstrated as a risk to the fissure, corroborating the literature. 22 In Argentina it was found that the maternal and paternal schooling are also considered risk factors for fissures, 18 as well as in Vietnam, where the low schooling is associated with higher chances of fissure.…”

“…5 Cleft lip and/or cleft palate are due to problems in the process of development during the embryonic or fetal period, causing the disability or lack of fusion between the tissues that comprise these structures. 6 The etiology of the anomaly of lip and/or palate is still not well defined; however, studies show that between 25 and 30% of the cases are the result of hereditary factors, and 70 to 80% have a multifactorial etiology, involving among other things, maternal habits of life during pregnancy (diet, alcohol, tobacco and drugs). 1,7 Various problems arising from the presence of cleft lip and/or cleft palate may affect its patient since birth, such as difficulties in breastfeeding due to impaired sucking, swallowing and breathing; disorders in hearing and phonation, with losses in communication, in addition to the low social acceptance.…”

A novel PTCH1 mutation underlies nonsyndromic cleft lip and/or palate in a Han Chinese family

“…As a genetically complex disease, NSCL/P may have multiple genetic models, including dominant (Birnbaum et al, 2008;Holzinger et al, 2017;Tian et al, 2017) and recessive inheritance (Marazita et al, 2004;Moura, Cirio, & Pimpao, 2012). Based on the family pedigree information in this study, an autosomal dominant Mendelian inheritance model was considered the best fit, although we cannot eliminate the possibility of de novo, homozygous, or compound heterozygous models.…”

Inferring Disease Risk Genes from Sequencing Data in Multiplex Pedigrees Through Sharing of Rare Variants

“…In one Syrian pedigree, the 8 affected relatives did not have any known common ancestor, so a sub-pedigree including 6 affected relatives descending from a common couple of ancestors was used in the analysis, reducing the total number of affected subjects to 151 (Table 2). The sequencing, alignment, and variant calling process was described in Holzinger et al [2017], who also reported on RVs observed in the WGS data from the Filipino and Syrian families.…”