Submission Details

CTR9 was first reported in relation to autosomal dominant CTR9-related neurodevelopmental disorder in 2022 (Meuwissen et al., PMID: 35499524; Suzuki et al., PMID: 35717577). CTR9 encodes a member of the polymerase-associated factor 1 (PAF1) protein complex, which associates with RNA polymerase II and a histone methyltransferase complex, and plays critical roles in transcriptional elongation and transcription-coupled histone modifications.

Seventeen unique missense variants reported in 20 probands in 6 publications (PMIDs: 25363760, 33057194, 35499524, 35717577, 35982159, 35982160) are included in this curation. Most reported variants are de novo, although one patient was reported who inherited the variant from his mildly affected father (PMID: 35499524). Two variants were identified as recurrent: p.Pro25Arg in 2 patients and p.Glu376Lys in 3 patients. Most of the curated variants lacked supportive functional evidence. The mechanism of disease is suggested to be dominant negative (PMID: 35717577), but more functional studies are needed. Patients with de novo truncating variants have also been reported in large autism or developmental disorder cohorts (PMIDs: 33057194, 35982159), but were not scored in this curation due to the unclear contribution of these variants to the neurodevelopmental phenotype. There are also reports of patients with Wilms tumor who have inherited germline CTR9 truncating variants but do not exhibit a neurodevelopmental phenotype (PMIDs: 25099282, 29292210), and myeloid malignancy patients with inherited CTR9 missense variants that demonstrate partial loss of function (PMID: 38218188); these gene-disease associations will be curated separately as they have a different phenotype and disease mechanism. CTR9 is highly constrained for both missense (Z = 4.8, gnomAD v4.1.0) and loss-of-function variants (pLI = 1).

There are a limited number of probands with detailed phenotypic features reported (PMIDs: 35499524, 35717577). Of those cases, affected individuals present with varying degrees of intellectual disability, motor and speech delay, hypotonia, and behavioral abnormalities including autism spectrum disorder. Cardiac anomalies, mild facial dysmorphism, and macrocephaly occurred less frequently.

This gene-disease relationship is also supported by biochemical function, protein interaction and a zebrafish model (PMIDs: 35713103, 15632063, 20541477, 35717577). Other genes with histone methyltransferase activity (e.g., NSD1, EHMT1, SETD2) are also associated with neurodevelopmental disorders. The PAF1 complex interacts with the RNA polymerase II subunit POLR2A and the histone methyltransferase KMT2A, both of which are involved in neurodevelopmental disorders.

In summary, there is moderate evidence supporting the relationship between CTR9 and autosomal dominant CTR9-related neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 19, 2025 (SOP Version 11).