Paternally Inherited IGF2 Mutation and Growth Restriction

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• Mutations in Insulin-like Growth Factor 1 (IGF1) and IGF1 Receptor (IGF1R) are known causes of growth restriction.
• Data on the role of Insulin-like Growth Factor 2 (IGF-II) mutations in human growth disorders were previously lacking.

Purpose of the Study:

• To investigate the role of IGF2 mutations in intrauterine and postnatal growth restriction.
• To analyze the inheritance pattern and phenotypic consequences of an identified IGF2 variant.

Main Methods:

• Genetic analysis of a multigenerational family with growth restriction.
• Identification and characterization of a novel IGF2 variant (c.191C→A, p.Ser64Ter).
• Phenotypic assessment of affected family members, including growth parameters and dysmorphic features.

Main Results:

• A pathogenic IGF2 variant was identified in four family members with severe growth restriction.
• The growth restriction phenotype was exclusively observed in individuals inheriting the variant via paternal transmission, consistent with IGF2 maternal imprinting.
• Affected individuals exhibited severe prenatal and postnatal growth restriction and dysmorphic features.

Conclusions:

• IGF-II plays a critical role in both prenatal and postnatal human growth.
• Deficient IGF-II levels due to genetic variants are implicated in severe growth restriction and features consistent with Silver-Russell syndrome.
• Paternal transmission of IGF2 variants can lead to significant growth impairment due to maternal imprinting.