Identification of a novel de novo AFF4 variant (c.778A>G) associated with CHOPS syndrome

CHOPS (cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia) syndrome is an extremely rare disorder with multiple congenital anomalies caused by missense variants in the ALF transcription elongation factor 4 gene (AFF4). This study aimed to identify causative variants in a Chinese family with CHOPS syndrome. A Chinese girl with short stature, obesity, and developmental delay underwent comprehensive clinical and genetic evaluations, including karyotyping analysis, multiple ligation-dependent probe amplification, detection of aberrant methylation, whole exome sequencing, Sanger sequencing, and copy number variation analysis, followed by in silico analyses. Reverse transcription, polymerase chain reaction, and Sanger sequencing were performed to evaluate the gene expression levels. The patient exhibited cognitive impairment, coarse facial appearance, obesity, short stature, skeletal involvement, and ophthalmic abnormalities. Genetic analyses identified a de novo heterozygous c.778A>G (p.Met260Val) variant in AFF4 in the proband, absent in parents and little sister, with no other remarkable results. This novel variant was classified as pathogenic, without apparent effect on relative gene expression. The identification of this de novo missense variant as the genetic cause of CHOPS syndrome in this Chinese family broadens the genetic and phenotypic spectrum of the disorder.