SCAF4

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0957787

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Franklin by Genoox

Inheritance Pattern: AD

Disease ID:MONDO:0957787

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*SCAF4* encodes a Serine/Arginine-rich-related C-terminal domain-associated factor 4. It is a protein that interacts with the C-terminal domain of the largest subunit of RNA polymerase II, and together with SCAF8 is involved in correct RNA processing. *SCAF4* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 (Fliedner et al., PMID: 32730804). Individuals with variants in *SCAF4* can present with features such as mild intellectual disability (ID), seizures, behavioral abnormalities, and various skeletal and structural anomalies. Eight variants (frameshift, nonsense, missense) that have been reported in 8 probands in 3 publications (PMIDs: 32730804, 36333968,37394306) are included in this curation. Additional probands with variants in *SCAF4* and in other genes associated with neurodevelopmental phenotypes were evaluated during this curation; however, these variants were not scored due to uncertainty regarding which variant was responsible for the phenotype. These additional variants are listed in the genetic evidence section. Notably, one individual with movement and skeletal disorders, but not intellectual disability, was reported by Lin et al. to carry two *SCAF4* variants. While more evidence is available in the literature, the maximum score for genetic evidence (12 points) has been reached. The gene-disease relationship is further supported by RNA sequencing studies of patient-derived samples, which reveal broad dysregulation of gene expression, as well as studies in *drosophila* knockout models, which show abnormal synapse development, morphology, and behavior (Fliedner et al., PMID: 32730804). In summary, there is definitive evidence supporting the relationship between *SCAF4* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in the clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 7, 2025 (SOP Version 11).