Clinical and molecular spectrum of CHOPS syndrome

Abstract

CHOPS syndrome is a multisystem disorder caused by missense mutations in AFF4. Previously, we reported 3 individuals whose primary phenotype included cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, and short stature. This syndrome overlaps phenotypically with Cornelia de Lange syndrome, but presents distinct differences including facial features, pulmonary involvement and obesity. Here, we provide clinical descriptions of an additional 8 individuals with CHOPS syndrome, as well as neurocognitive analysis of 3 individuals.All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows and long eyelashes. All 11 individuals had short stature and obesity. Congenital heart disease and pulmonary involvement were common, and those were seen in about 70% of individuals with CHOPS syndrome. Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones and low bone mineral density. Our observation indicates that obesity, pulmonary involvement, skeletal findings are the most notable features distinguishing CHOPS syndrome from Cornelia de Lange syndrome. In fact, 2 out of 8 of our newly identified patients were found to have AFF4 mutations by targeted AFF4 mutational analysis rather than exome sequencing. These phenotypic findings establish CHOPS syndrome as a distinct, clinically-recognizable disorder.Additionally, we report 3 novel missense mutations causative for CHOPS syndrome that

Variants in the degron ofAFF3cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy

“…Consistent with this hypothesis, transiently transfected FLAG-tagged AFF3 A258S and AFF3 V260G proteins were more stable than wild-type FLAG-tagged AFF3 ( Figure 1E ). The previously reported AFF4 de novo variants p.(P253R), p.(T254A), p.(T254S), p.(A255T), p.(R258W) and p.(M260T) that also affect the degron motif (K P 253 T 254 A 255 YV R 258 P M 260 ) ( Figure 1A ) were similarly shown to reduce clearance of the ALF transcription factor by SIAH 16, 17 .…”

“…All AFF3 variants described here and CHOPS syndrome-associated AFF4 de novo missense previously published 16, 17 map within the degron motif of the ALF domain. This highly conserved 9 amino acid sequence [xPxAxVxPx] ( Figure 1A-B ) mediates interaction with the SIAH E3 ubiquitin ligase and regulates their degradation 1 .…”

“…The sequences of the degron motif of AFF3 and AFF4 are shown above. The residues modified in the KINSSHIP probands described in this manuscript and individuals affected by CHOPS 16, 17 are highlighted in bold and numbered. The extent of the 500kb deletion previously described 35 is indicated here.…”

“…Six de novo missense variants in AFF4 were recently linked with CHOPS ( C ognitive impairment and coarse facies, H eart defects, O besity, P ulmonary problems, S hort stature and skeletal dysplasia) syndrome 16, 17 (OMIM#616368). They were suggested to act through reduced clearance of AFF4 by SIAH, a hypothesis supported by the fact that surviving adult Aff4 null mice have only azoospermia and no features of CHOPS syndrome.…”

“…Upregulation of AFF4 resulted in dysregulation of genes involved in skeletal development and anterior/posterior pattern formation such as MYC, JUN, TMEM100, ZNF711 and FAM13C 16 . These molecular changes were proposed to impair complex function and lead to cohesinopathies associated with the clinical phenotypes seen in the eleven reported individuals with CHOPS and in Cornelia de Lange syndrome (CdLS; OMIM #122470) 16, 17 .…”