ClinVar Genomic variation as it relates to human health

The copy number gain at 11p15.5 involves numerous protein-coding genes and overlaps the imprinting control region 1 (ICR1), which regulates the expression of IGF2 (expressed on the paternal allele) and H19 (expressed on the maternal allele). Please note that, the imprinting control region 2 (ICR2), which regulates the expression of CDKN1C, KCNQ10T1, and KCNQ1, is NOT involved in this copy number gain. Duplications of 11p15.5 can cause either Beckwith-Wiedemann syndrome (OMIM 130650) or Silver-Russell syndrome (SRS, OMIM 180860), depending on the parent of origin for the duplicated chromosome 11 segment. Russell-Silver syndrome (RSS) is characterized by intrauterine growth etardation accompanied by postnatal growth deficiency. Maternally derived duplications of 11p15.5 are associated with SRS (GeneReviews [Internet]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1324/). Beckwith-Wiedemann syndrome (BWS), is a growth disorder variably characterized by neonatal hypoglycemia, macrosomia, macroglossia, hemihyperplasia, omphalocele, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, renal abnormalities, and ear creases/pits. Paternally derived duplications of 11p15.5 are associated with BWS (GeneReviews [Internet]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1394/). In the literature there are several reports of individuals with Beckwith-Wiedemann syndrome and duplications that overlap only IC1, not IC2. These duplications have arisen on the paternal allele, and typically methylation of IC1 was increased, while methylation of IC2 was normal (Wang 29270226; Baskin 24154661; Heide 29223973). Additionally, one patient was reported to have a triplication of the IC1 interval that falls almost entirely within the current interval, and the proband expressed the expected Beckwith-Wiedemann syndrome phenotype. Consistent with imprinting patterns, her father who had transmitted the triplication, and had inherited it maternally, displayed characteristics of Silver-Russell syndrome (Jurkiewicz 2017). There are no similar copy number gains of this region in the general populations of the Database of Genomic Variants. Thus, the clinical significance of this copy number variant (CNV) is pathogenic. References: Baskin et al., Hum Genet. 2014 Mar;133(3):321-30. PMID: 24154661. Heide et al., J Med Genet. 2018 Mar;55(3):205-213. PMID: 29223973. Jurkiewicz et al., Am J Med Genet A. 2017 Jan;173(1):72-78. PMID: 27612309. Wang et al., Mol Cytogenet. 2017 Dec 19;10:46. PMID: 29270226.