Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences

Abstract

The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

Heterogeneous phenotypes in families with duplications of the paternal allele within the imprinting center 1 (H19/IGF2:TSS‐DMR) in 11p15.5

“…3,4 Here, we report on three unrelated families with inheritance of duplications affecting the IC1 region in 11p15.5 ( Figure 1) Previous reports on IC1 duplications comprising the H19 and IGF2 genes indicate that gains of the paternal allele are associated with a BWS phenotype. 3,4 We now report on two families (families 1 and 2) with BWS in the children but nearly normal phenotypes in the fathers with the same duplications of the complete paternal IC1 allele, including H19 and IGF2. The reason for these clinical discrepancies even in the same family is currently unclear, but they might be compatible with the clinical variability in BWS.…”

“…The reason for these clinical discrepancies even in the same family is currently unclear, but they might be compatible with the clinical variability in BWS. 3 The identification of patient 3 and his sister with an H19 duplication provides further evidence that duplications restricted to the maternal H19 copy cause a (mild) growth retardation phenotype and features reminiscent to SRS.…”

“…Thomas Eggermann, 1 Florian Kraft, 1 Katja Kloth, 2 Eva Klopocki, 3 Irina Hüning, 4 Maja Hempel, 2 and Erdmute Kunstmann, 3 1…”

“…The impact of copy number variants (CNVs) affecting 11p15.5 is difficult to predict, as it depends on the parent-of-origin, the type and genomic content of the affected allele. 3 For duplications encompassing both ICs in 11p15.5, a strict clinical correlation is obvious with a SRS phenotype in case of a gain of the maternal allele and BWS features in case of a paternal gain. The interpretation of 11p15.5 CNVs becomes more ambiguous in case only one IC is affected, or only parts of it.…”

“…Due to the complex spatial and regulatory organization of the 11p15.5 imprinting regions, cis-(and trans-)acting modifiers can be postulated. 3…”