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CHOPS syndrome is a clinically recognizable multisystem disorder characterized by cognitive impairment, coarse facial features, congenital heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia. It overlaps phenotypically with Cornelia de Lange syndrome but is distinguished by obesity, pulmonary disease, and osteopenia. The disorder is caused by heterozygous missense variants in AFF4 that cluster within a highly conserved 14–amino acid ALF homology domain, underlining its critical role in human development. AFF4 encodes a core component of the super elongation complex (SEC), which regulates RNA polymerase II pause release during transcription. To date, 11 unrelated individuals with CHOPS syndrome have been described, expanding the initial cohort of three reported cases to a total of eleven affected probands (PMID:31058441). These observations confirm AFF4 as the causative gene for CHOPS syndrome.
All reported AFF4 variants are de novo missense changes in the ALF homology domain without evidence of inheritance from affected relatives. No familial segregation of affected relatives has been observed, supporting autosomal dominant disease transmission with full penetrance in heterozygotes. No loss-of-function, splice, structural, or deep-intronic variants have been implicated to date, and there are no recurrent or founder alleles reported.
The phenotypic spectrum among the 11 patients includes universal short stature and obesity, synophrys, highly arched eyebrows, long eyelashes, and coarse facial features. Approximately 70% of individuals exhibit congenital heart defects and pulmonary involvement, and skeletal findings such as osteopenia, vertebral anomalies, and hypoplastic long bones are common (PMID:31058441). Cognitive impairment of variable severity is consistently noted.
Three novel missense variants—c.764C>T (p.Ala255Val), c.773G>A (p.Arg258Gln), and c.778A>G (p.Met260Val)—all lie within the ALF homology domain of AFF4 and have been shown to be deleterious by in silico modeling and conservation analyses (PMID:31058441). No experimental assays of these specific variants have been published to date.
Functional studies of AFF4 in other contexts demonstrate its nuclear localization sequences and essential role in recruiting P-TEFb for transcriptional elongation, but no direct functional characterization of CHOPS-associated variants has been reported. Thus, experimental evidence for pathogenicity in CHOPS syndrome remains limited.
Gene–Disease AssociationModerateEleven unrelated probands with de novo missense variants in AFF4 clustering in a conserved ALF homology domain and consistent multisystem phenotype; no segregation or functional validation beyond case descriptions Genetic EvidenceModerateCase series of 11 unrelated individuals with heterozygous missense variants meeting criteria in a critical domain of AFF4 Functional EvidenceLimitedNo direct functional studies of CHOPS-associated variants; existing data demonstrate AFF4 role in transcriptional elongation but lack CHOPS‐specific models or rescue assays |