Genome-Wide DNA Methylation Profiling Led to the Identification of a Novel ZNF699 Mutation in a Patient with DEGCAGS Syndrome and Severe B Cell Depletion

Background DEGCAGS syndrome is an autosomal recessive disorder characterized by developmental delay and dysmorphic features caused by biallelic ZNF699 variants. Immunodeficiency is reported in a significant number of affected patients. A specific DNA methylation profile has been recently described for this syndrome. Objective To describe the immunological features in a patient with DEGCAGS syndrome in whom diagnosis was suggested by the study of DNA methylation profiling. Methods CGH-array, whole exome, clinical exome, and Sanger sequencing were used to define the genetic diagnosis. DNA methylation was used to assess the pathogenic role of a heterozygous de novo VUS in ADNP gene identified through clinical exome. Results DNA methylation profile ruled out a pathogenic role of the VUS in ADNP gene and suggested a diagnosis of DEGCAGS syndrome, subsequently confirmed through Sanger sequencing, which revealed the homozygous missense c.153C>A variant in ZNF699 gene. Immunological studies revealed a never described before significant reduction of CD4+CD45RA+ naïve T cells (12%) and CD19+ B cells (2%, 33.2 cells/μL) associated with impaired T cell proliferation and recurrent and severe lung infections, suggesting a diagnosis of TlowB-NK+ combined immunodeficiency (CID). Despite severe B cell depletion, immunoglobulin levels and specific antibody responses were normal. Conclusion This report offers for the first time an in-depth characterization of the immunological features in DEGCAGS syndrome and suggests that biallelic loss-of-function ZNF699 variants may represent an additional cause of syndromic CID. The diagnosis was supported by the study of DNA methylation episignature that represents an additional powerful tool to increase the diagnostic yield in unresolved cases.