Intergenerational and intrafamilial phenotypic variability in 22q11.2 Deletion syndrome subjects

Abstract

Background22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion syndrome, which occurs in approximately 1:4000 births. Familial autosomal dominant recurrence of the syndrome is detected in about 8-28% of the cases. Aim of this study is to evaluate the intergenerational and intrafamilial phenotypic variability in a cohort of familial cases carrying a 22q11.2 deletion.MethodsThirty-two 22q11.2DS subjects among 26 families were enrolled.ResultsSecond generation subjects showed a significantly higher number of features than their transmitting parents (212 vs 129, P = 0.0015). Congenital heart defect, calcium-phosphorus metabolism abnormalities, developmental and speech delay were more represented in the second generation (P < 0.05). Ocular disorders were more frequent in the parent group. No significant difference was observed for the other clinical variables. Intrafamilial phenotypic heterogeneity was identified in the pedigrees. In 23/32 families, a higher number of features were found in individuals from the second generation and a more severe phenotype was observed in almost all of them, indicating the worsening of the phenotype over generations. Both genetic and epigenetic mechanisms may be involved in the phenotypic variability.ConclusionsSecond generation subjects showed a more complex phenotype in comparison to those from the first generation. Both ascertainment bias related to patient selection or to the low rate of reproductive fitness of adults with a more severe phenotype, and several not well defined molecular mechanism, could explain intergenerational and intrafamilial phenotypic variability in this syndrome.

Neuropsychiatric aspects of 22q11.2 deletion syndrome: considerations in the prenatal setting

“…That a parent carries a 22q11.2 deletion may be known prior to conception, or may be a ‘secondary’ finding following diagnosis of an affected fetus. Generally, parents will have less severe cognitive and neuropsychiatric expression of the 22q11.2 deletion than the offspring, likely because of reproductive fitness effects . Reproductive fitness is greater in women than men with 22q11.2DS; thus, there tend to be more affected mothers than fathers .…”

“…Generally, parents will have less severe cognitive and neuropsychiatric expression of the 22q11.2 deletion than the offspring, likely because of reproductive fitness effects. 38,85,86 Reproductive fitness is greater in women than men with 22q11.2DS; thus, there tend to be more affected mothers than fathers. 86 There are special considerations when counselling a parent who also has a 22q11.2 deletion.…”

Reproductive Health Issues for Adults with a Common Genomic Disorder: 22q11.2 Deletion Syndrome

“…Whether the apparent inter-generational worsening of the 22q11.2DS phenotype in familial cases is solely related to ascertainment and other biases is unclear (Cirillo et al 2014;Costain et al 2011). Assortative mating and in utero effects of a maternal 22q11.2 deletion could contribute to a biological basis for progressive worsening of phenotypic severity in some families.…”

Severe combined immunodeficiency—an update

“…Deletion of 22q11.2 is the most frequent chromosomal change associated with DGS, with an incidence of one in 4000–5000 live births. The alteration is inherited in a familial autosomal dominant pattern in 8–28% of the cases . Most patients have a deletion of 3 Mb that includes about 30 genes, while in 8% of the cases a smaller deletion of 1.5 Mb containing 24 genes is detected.…”

“…The alteration is inherited in a familial autosomal dominant pattern in 8-28% of the cases. 94 Most patients have a deletion of 3 Mb that includes about 30 genes, while in 8% of the cases a smaller deletion of 1.5 Mb containing 24 genes is detected. No specific genotype-phenotype relationship has been documented.…”