The IGF2 gene is located on chromosome 11p15.5 and encodes insulin-like growth factor 2, a protein hormone that regulates cell proliferation, growth, migration, differentiation, and survival. The protein binds and activates Insulin Receptor Tyrosine - A (IR-A) and IGF-1R. The receptor structural change leads to activation of the intracellular tyrosine kinase domain and autophosphorylation with an outcome of growth promoting effect (Blyth et al., 2020). The gene has 5 promoters that are differentially activated during pre and postnatal life. There are 9 exons in total however, only the last 3 exons are coding exons (Röttgering and Szuhai 2019). Additionally, IGF2 is a paternally expressed, maternally imprinted gene with an imprinting control region (ICR1) located between the H19 and IGF2 genes.
IGF2 was first reported in relation to autosomal dominant Silver-Russell syndrome 3 in 2015 (Begemann et al., PMID: 26154720). Silver-Russell Syndrome 3 is caused by heterozygosity pathogenic variants in the paternal copy of the IGF2 gene. Features seen in Silver-Russell syndrome 3 patients include intrauterine growth retardation with relative macrocephaly, feeding difficulties, growth restriction, triangular face, prominent forehead, low-set ears, limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay.
Thirteen variants (5 missense, 3 frameshifts, 3 splice site, 2 nonsense) reported in thirteen probands in eight publications (PMIDs: 26154720, 28848601,28489339, 30152198, 28796236, 30400067, 31803239, 31544945) are include in this curation. The most common mechanism of disease is loss of methylation at the chromosome 11p15. A total of 10.6 pts for genetic evidence was reached, considering case-level data. This gene-disease relationship is supported by expression, biochemical, and two mouse models (PMIDs: 33567274, 2621730, 32459985, 2330056).
In summary, there is definitive evidence supporting the relationship between IGF2 and autosomal dominant Silver-Russell Syndrome 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 10/04/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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