Evaluation of Potential Modifiers of the Palatal Phenotype in the 22q11.2 Deletion Syndrome

Abstract

Objective-To evaluate potential modifiers of the palatal phenotype in individuals with the 22q11.2 deletion syndrome.Design-Data from 356 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the palatal phenotype. Specifically, subjects with and without velopharyngeal inadequacy and/or structural malformations of the palate were compared with respect to gender, race, and genotype for variants of seven genes that may influence palatal development.Methods-The chi-square test or Fisher exact test was used to evaluate the association between palatal phenotype and each potential modifier. Odds ratios and their associated 95% confidence intervals were used to measure the magnitude of the association between palatal phenotype, subject gender and race, and each of the bi-allelic variants.Results-The palatal phenotype observed in individuals with the 22q11.2 deletion syndrome was significantly associated with both gender and race. In addition, there was tentative evidence that the palatal phenotype may be influenced by variation within the gene that encodes methionine synthase.Conclusions-Variation in the palatal phenotype observed between individuals with the 22q11.2 deletion syndrome may be related to personal characteristics such as gender and race as well as variation within genes that reside outside of the 22q11.2 region. Keywords chromosome 22q11.2 deletion; genes; genotype; palate; penetrance; phenotype Hemizygous deletion of the chromosome 22q11.2 region results in a syndromic phenotype that encompasses the DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Population-based estimates of the prevalence of this deletion range from 1 in 4500 to 1 in 7100 births (Botto et al., 2003;Tezenas du Montcel et al., 1996;Oskarsdottir et al., 2004), making it the most frequent known interstitial deletion in humans. The majority of individuals with the 22q11.2 deletion syndrome have a de novo three-megabase deletion. However, approximately 10% of patients with the 22q11.2 deletion syndrome have an inherited deletion, and approximately 10% have a smaller deletion (1.5 Mb) (Saitta et al., 2004;Yamagishi and Srivastava, 2003).The phenotypic consequences of hemizygous deletion of chromosome 22q11.2 are remarkably variable and can include cardiac, thymic, parathyroid, craniofacial, developmental, neurologic, and behavioral manifestations. None of these features appears to be fully penetrant, and each exhibits variable expressivity. For example, approximately 75% of patients with the 22q11.2 deletion syndrome have a cardiac defect, and a range of malformations (e.g., tetralogy of Fallot, interrupted aortic arch, septal defects) is observed among those who have such a defect (McDonald-McGinn et al., 1997;Ryan et al., 1997).The variability in the 22q11.2 deletion syndrome phenotype is largely unexplained. Variability is observed across unrelated patients and between affected family members who have presumably inherited identical deletions (Desmaze et al., 1993;McLe...

Evaluation of potential modifiers of the cardiac phenotype in the 22q11.2 deletion syndrome

“…In summary, our analyses of these data indicate that the variation in the cardiac phenotype observed between individuals with the 22q11.2 deletion syndrome is not associated with sex, race, or five variants in four folate‐related genes. These findings are in contrast to those from previous analyses of the same study population, aimed at identifying modifiers of the palatal phenotype (Driscoll et al, 2006). Specifically, analyses of the palatal phenotype in individuals with the 22q11.2 deletion syndrome indicated that this aspect of the phenotype (i.e., the palatal phenotype) is significantly associated with both sex and race, and possibly with the MTR A2756G variant.…”

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“…Due to insufficient information on the rest, we cannot comment on the prevalence and degree of cognitive deficits/developmental problems. We also found a lower frequency of palatal problems in our cohort, compared to that reported in 22q11DS which is 60–70% [Driscoll et al, 2006; Ruotolo et al, 2006; Shprintzen, 2008]. However, we ascertained information regarding the palate based only on the presence or absence of structural abnormalities, specifically overt cleft or submucous cleft.…”

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“…These malformations seem to be more frequent in girls and white patients with this syndrome. Along with Driscoll et al, 19 we believe that genes outside the deleted region may modify the phenotype.…”

“…The phenotypic variability of this syndrome remains unexplained. According to Driscoll et al, 19 there may be a correlation with sex and ethnic origin for the occurrence of velopalatal anomalies. These malformations seem to be more frequent in girls and white patients with this syndrome.…”