Loss of Imprinting of the Human-specific Imprinted Gene Causes Prenatal Growth Retardation and Dysmorphic Features: Implications for Phenotypic Overlap with Silver-Russell Syndrome

Background: , encoding a zinc-finger protein, is the human-specific maternally expressed imprinted gene located on 16p13.3. The parent-of-origin expression of is regulated by the :TSS-DMR, of which only the paternal allele acquires methylation during postimplantation period. Overexpression of may contribute to some of the phenotypes associated with maternal uniparental disomy of chromosome 16 (UPD(16)mat), and some patients with UPD(16)mat presenting with Silver-Russell syndrome (SRS) phenotype have recently been reported.

Methods: A 6-year-old boy presented with prenatal growth restriction, macrocephaly at birth, forehead protrusion in infancy and clinodactyly of the fifth finger. Methylation, expression, microsatellite marker, single nucleotide polymorphism array and trio whole-exome sequencing analyses were conducted.

Results: Isolated hypomethylation of the :TSS-DMR and subsequent loss of imprinting and overexpression of were confirmed in the patient. Epigenetic alterations, such as UPD including UPD(16)mat and other methylation defects, were excluded. Pathogenic sequence or copy number variants affecting his phenotypes were not identified, indicating that primary epimutation occurred postzygotically.

Conclusion: We report the first case of isolated imprinting defect, showing phenotypic overlap with SRS despite not satisfying the clinical SRS criteria. A novel imprinting disorder entity involving the imprinted domain can be speculated.