Influence of Parent-of-Origin on Intellectual Outcomes in the Chromosome 22q11.2 Deletion Syndrome

Abstract

Learning and intellectual disabilities are hallmark features of 22q11.2 deletion syndrome. Data are limited, however, regarding influences on full-scale IQ (FSIQ). Here, we investigated possible 22q11.2 deletion parent-of-origin effects. In 535 individuals, we compared FSIQ (≥50), 481 with de novo and 54 with inherited 22q11.2 deletions. In the subsets with data available, we examined parent-of-origin effects on FSIQ. We used linear regression models to account for covariates. Median FSIQ was significantly higher in de novo vs. inherited deletions (77; range 50–116 vs. 67; range 50–96, p < 0.0001). Results remained significant using a regression model accounting for age at IQ testing, sex and cohort site. No significant parent-of-origin differences in FSIQ were observed for de novo deletions (n = 81, 63.0% maternal; p = 0.6882). However, median FSIQ was significantly lower in maternally than in paternally inherited familial deletions (65, range 50–86 vs. 71.5, range 58–96, respectively, p = 0.0350), with the regression model indicating an ~8 point decrement in FSIQ for this variable (p = 0.0061). FSIQ is higher on average in de novo than in inherited 22q11.2 deletions, regardless of parental origin. However, parent-of-origin appears relevant in inherited deletions. The results have potential clinical implications with further research needed to delineate possible actionable mechanisms.

Prenatal Screening and Diagnostic Considerations for 22q11.2 Microdeletions

“…Moreover, while there are no significant parent-of-origin differences with de novo 22q11.2 deletions [73], parent of origin may have an impact on intellectual outcomes in inherited 22q11.2 deletions. Median full-scale IQ was reported in a recent study to be significantly lower (on average by eight points) in offspring of an affected mother than an affected father [73]. There are many potential explicatory factors, including assortative mating, possible effects of maternal comorbidities, and/or that the relatively few affected men with 22q11.2DS who reproduce may have less severe neurodevelopmental phenotypes [72].…”

“…Current genetic counselling should also include a discussion of marked phenotypic variability, also within affected families, that concerns every single associated manifestation of 22q11.2DS. For example, cognitive deficits appear to be greater in offspring of parents with 22q11.2DS than in offspring with de novo 22q11.2 deletions [72,73], where parental IQ appears on average to modify the significant effects of the 22q11.2 deletion itself [74]. Moreover, while there are no significant parent-of-origin differences with de novo 22q11.2 deletions [73], parent of origin may have an impact on intellectual outcomes in inherited 22q11.2 deletions.…”

“…For example, cognitive deficits appear to be greater in offspring of parents with 22q11.2DS than in offspring with de novo 22q11.2 deletions [72,73], where parental IQ appears on average to modify the significant effects of the 22q11.2 deletion itself [74]. Moreover, while there are no significant parent-of-origin differences with de novo 22q11.2 deletions [73], parent of origin may have an impact on intellectual outcomes in inherited 22q11.2 deletions. Median full-scale IQ was reported in a recent study to be significantly lower (on average by eight points) in offspring of an affected mother than an affected father [73].…”

22q11.2 Deletion Syndrome: Influence of Parental Origin on Clinical Heterogeneity

“…The phenotype of patients with 22q11.2DS is highly variable, and, to date, the reasons for that are not well understood [6,14]. Although a major contribution of parental origin on the phenotype is not expected in the 22q11.2 region, very few studies in the literature have compared the clinical features of patients with deletions of maternal or paternal origin [21][22][23]. Previous studies described random imprinting of the genes DGCR6 and DGCR6L, which are mapped within the most common region deleted in the 22q11.2DS (between LCRs A and D) [18,19].…”

“…Another study, conducted by Eliez et al (2001), indicated that the parental origin of the deletion could significantly affect brain development and morphology, with reduction in gray matter development attributed to presence of a 22q11.2 microdeletion on the maternal chromosome [22]. More recently, McGinn et al (2022) investigated the influence of the parent of origin on intellectual outcomes in patients with 22q11.2DS and found no significant difference in full-scale IQ (FSIQ) based on the parental origin of de novo deletions [23].…”