O60: AFF2 gene variants identified through carrier screening for Fragile XE syndrome

Fragile XE syndrome (FRAXE) is an X-linked condition caused by pathogenic variants in the AFF2 gene and associated with borderline, mild, or moderate intellectual disability. ACMG recommends including AFF2 on carrier screening (CS) panels. Pathogenic AFF2 variants include CCG repeat expansions in the full variant range, which cause methylation and silencing of AFF2 expression, as well as single nucleotide variants (SNVs) and copy number variants (CNVs) that impair AFF2 protein functionality. While panel sequencing can detect SNVs and CNVs, additional assays are needed to detect trinucleotide repeat expansions.