Subclinical Phenotypes and Genotypes in Parents of Children with Non-Syndromic Cleft of Lip and/or Palate

  • Shaho Ziyad Jamil Al-Talabani

Student thesis: Doctoral ThesisDoctor of Philosophy


Introduction: There is now substantial evidence that unaffected parents of NSOFC individuals have been shown to manifest distinctive dento-craniofacial phenotypes / cleft microforms compared to unaffected controls. Identification of the cleft microforms in the sub-phenotypes of clefting will improve the recurrence risk estimation and provide more informative and genetically homogenous groups for gene mapping.

Aim: To assess facial morphology, the prevalence of upper lip sub-epithelial orbicularis oris (MOO) defects and lower lip whorls, and to determine tooth size and arch width dimensions in unaffected parents of children with non-syndromic orofacial clefts (NSOFC) as a cleft-related subclinical phenotype and their association with specific candidate genes.

Methods: Using a case-control study design with 156 participants of Celtic background (81 parents, 75 controls), 2D photographs of the face and lower lip (Nikon D70,, an ultrasound scan of the upper lip (M-Turbo/HFL38X/13-6MHz linear transducer, SonoSite, Bothell, WA), impressions for study models of the upper and lower dental arches were taken, and a saliva sample was collected for collection of human DNA, (Oragene DNA, OG_500 DNA Genotek, Inc. Canada) and analysed using high-density genome-wide human arrays (Cytoscan 750K _array, Affymetrix). Facial dataxxxiiwere analysed using the discriminant analysis test in MorphoJ (, lip data using a Fisher exact test (p<0.0625 Bonferroni correction) and dental data using a Man-Whitney test (p<0.0625 Bonferroni correction) (SPSS version 22). Also, a genotype-phenotype analysis was conducted with the Odds Ratio calculated for 144 SNPs across 20 candidate loci.

Results: There was a significant facial difference between the two groups (p<0.0001, T-square). The frequency of OOM defects was greater in the parents (11.1%) than in controls (4.1%), which was non-significant (p>0.05). There was no significant difference in the prevalence of lip whorls between the parents and controls (p>0.05). However, statistically, significant differences in tooth dimensions were found between the parents and controls (p<0.05).The mesiodistal dimension of the crown of the lower left second premolar showed a statistically significant (p<0.05) association with SNP rs6657063 in the ARHGAP29 gene when the parental-control group factor was included in the analysis.The symmetrical PC5 of the facial morphology showed an association with SNP (rs7972295) in the ADAMTS 20 gene for the father-male control group data.

Conclusion: Non-cleft parents have distinctive facial morphological features and different dental width measurements, but only tooth 35 width - gene association was recorded when the parental - control factor included in the analysis.
Date of Award2016
Original languageEnglish
SupervisorPeter Mossey (Supervisor) & Grant McIntyre (Supervisor)

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