Genetic Compensation in a Human Genomic Disorder

Abstract

Cytogenetic studies of the parents of a girl with the DiGeorge (or velocardiofacial) syndrome, who carried a deletion at 22q11.2, revealed an unexpected rearrangement of both 22q11.2 regions in the unaffected father. He carried a 22q11.2 deletion on one copy of chromosome 22 and a reciprocal 22q11.2 duplication on the other copy of chromosome 22. Genetic compensation, which is consistent with the normal phenotype of the father, was shown through quantitative-expression analyses of genes located within the genetic region associated with the DiGeorge syndrome. This finding has implications for genetic counseling and represents a case of genetic compensation in a human genomic disorder.

The guanine nucleotide exchange factor Net1 facilitates the specification of dorsal cell fates in zebrafish embryos by promoting maternal β-catenin activation

“…The phenotypic differences between mutants and morphants may be due to the activation of a compensatory network in mutants [76,77]. Actually, net1 MO1 or siRNA1 injection caused dorsal fate defects in wild-type embryos, but did not influence the dorsal development of mutants (Supplementary information, Figure S13F and S13G), indicating the specificity of the MOs and siRNAs used to knock-down zebrafish net1 in our study and the insensitiveness of the net1 mutants to net1 MOs and siRNAs.…”

“…Surprisingly, net1 mutants display no obvious developmental defects; and are also, importantly, insensitive to the injection of net1 MOs or siRNAs. Previous biochemical and genetic studies as well as clinical reports indicate that compensatory changes may allow organisms to adapt to genetic mutations [77,83,84]. Such properties have also been described in zebrafish genetic studies.…”

Reciprocal 22q11.2 Deletion and Duplication in Siblings with Karyotypically Normal Parents

“…To our knowledge, this family is the first where both a deletion and a duplication carrier have been identified in a single sibship. We first hypothesized that the occurrence of fam- ilies with both deletion and duplication siblings was a consequence of dosage compensation in one of the parents [Carelle-Calmels et al, 2009;Alkalay et al, 2011;Fernández et al, 2012]. Dosage compensation is defined as a rearrangement resulting in a 22q11.2 deletion and the reciprocal duplication in 2 homologous chromosomes.…”

Chromosomale Ursachen der geistigen Behinderung

“…Interessanterweise konnte jüngst beim gesunden Vater einer Patientin mit Mikrodeletion 22q11 gezeigt werden, dass Compound-Heterozygotie für eine Deletion und eine Duplikation in 22q11.2 kompensatorisch wirken [7]. Das damit verbundene 100%ige Wiederholungsrisiko für Nachkommen mit Imbalance in diesem Bereich unterstreicht die Notwendigkeit, auch gesunde Eltern mittels FISH zu untersuchen.…”