Chops Syndrome

A number sign (#) is used with this entry because of evidence that CHOPS syndrome (cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia) is caused by heterozygous mutation in the AFF4 gene (604417) on chromosome 5q31.

Clinical Features

Izumi et al. (2015) reported 3 unrelated children with a multiple congenital anomaly syndrome. All patients had delayed psychomotor development with intellectual disability, short stature, obesity, and somewhat variable dysmorphic facial features, including round face, proptosis, hypertelorism, thick eyebrows and hair, long eyelashes, short nose, and downturned corners of the mouth. Heart defects included patent ductus arteriosus septal defects; 1 child had an anomalous pulmonary vein. Pulmonary manifestations included chronic lung disease and recurrent aspiration pneumonia associated with laryngomalacia in 2 of the patients. Skeletal features included brachydactyly and abnormal vertebral bodies. One patient had a horseshoe kidney, 2 had vesicoureteral reflux, and the only boy had cryptorchidism. All had gastroesophageal reflux. One patient had cataracts and another had hearing loss. Izumi et al. (2015) noted that some of the features were reminiscent of Cornelia de Lange syndrome (see, e.g., CDLS1, 122470).

Molecular Genetics

In 3 unrelated children with CHOPS syndrome, Izumi et al. (2015) identified 3 different de novo heterozygous missense mutations in the AFF4 gene (604417.0001-604417.0003), all of which affected conserved residues in the ALF homology domain. The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that all the mutations resulted in decreased degradation of AFF4 by the ubiquitin E3 ligase SIAH1 (602212) compared to wildtype. All 3 patient cell lines showed upregulation of MYC (190080) and 2 showed upregulation of JUN (165160), both of which are direct transcriptional targets of AFF4. Transcriptome analysis of patient cell lines showed upregulation of several genes, consistent with a gain-of-function effect, and overall changes in gene regulation were similar to those observed in patients with CDLS. Chromatin immunoprecipitation analysis showed a correlation between RNA regulation and chromatin binding levels of paused RNA polymerase II (RNAP2) in both CDLS and CHOPS. The findings suggested that CHOPS results from a disturbance in transcriptional elongation.