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.
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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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