SON

Inheritance Pattern: AD

Disease ID:MONDO:0014936

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014936

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014936

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014936

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014936

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0014936

Submitter: ClinGen

*SON* encodes a protein that binds RNA and promotes pre-mRNA splicing, specifically in transcripts with poor splice sites. SON plays a critical role in cell cycle progression affecting RNA splicing as a splicing cofactor (PMID: 34521999). A *de novo* frameshift variant (c.5753_5756delTTAG) in *SON* was first reported in 2015 in a 5-year-old female with developmental delay, seizures, minor dysmorphisms, macrocephaly, brain white matter abnormalities, intestinal atresia, and ventriculoseptal defect (PMID: 25590979). However, it was not until 2016 when additional *SON* variants were detected in several unrelated probands (PMID: 27256762) that a new autosomal dominant, multisystem/intellectual disability syndrome would be recognized and subsequently named ZTTK (Zhu-Tokita-Takenouchi-Kim) syndrome (PMIDs: 27256762, 27545676, 27545680). Since 2016, more than 50 probands identified with loss-of-function *SON* variants (frameshift, nonsense, missense, inframe deletion) have been reported. All reported variants are *de novo* and located within exon 3. The c.5753_5756delTTAG variant is recurrent and has been reported in 13 individuals (PMID: 34521999). While the clinical presentation is variable, all individuals have some degree of developmental delay/intellectual disability. Other common features include motor/speech delay, brain structural anomalies (like ventriculomegaly), facial dysmorphisms (such as of the ears and nasal bridge), and musculoskeletal features (like short stature). Less common features include congenital heart disease, such as ventricular septal defect, atrial septal defect, and aortic valve complications (PMIDs: 27545676, 27545680, 327057774, 34331327, 37488749). Five de novo heterozygous variants found in six probands reported in three publications (PMIDs: 27256762, 27545676, 34521999) are included in this curation. These five variants are either nonsense or frameshift, supporting a hypothesized disease mechanism of haploinsufficiency. Of note, two additional probands are available from the Brain Gene Registry (braingeneregistry.wustl.edu); one variant is the recurrent frameshift c.5753_5756delTTAG (ClinVar SCV: SCV003931201.1), but the other variant (c.384delA) is not formally documented in this curation due to technical limitations. While more evidence is available in the literature, the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by experimental evidence. A *son* knockdown zebrafish model demonstrated multiple anomalies including spinal malformations, head and eye malformations with brain edema, and other unspecified developmental abnormalities, recapitulating the phenotype of ZTTK syndrome (PMID: 27545680). In summary, there is definitive evidence to support the relationship between *SON* and autosomal dominant ZTTK syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on August 24, 2023 (SOP version 9). This curation was re-evaluated by the ClinGen Congenital Heart Disease GCEP on November 10, 2025. Additional commentary about cardiac features was added to the evidence summary, but the classification was not changed.