ClinGen Dosage Sensitivity Curation Page


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Select assembly: (NC_000021.8) (NC_000021.9)
Evidence for haploinsufficiency phenotype
PubMed ID Description
25590979 Zhu et al. (2015). This group analyzed 119 trios by WES. Heterzygous de novo frameshift mutation (4-bp deletion) was identified in a 5-year-old girl with with intellectual disability, seizures, dysmorphic features, white matter abnormalities, intestinal atresia, and VSD.
27256762 Takenouchi et al (2016) this study describe a 13 year old male with the same de novo frameshift mutation (as seen in Zhu 2015 study) within exon 3 that is predicted to result in haploinsufficiency. This patient had intellectual disability, congenital heart disease, distinctive facial features, long slender extremities, and hyperextensible joints.
27545680 Kim et al (2016) describe 20 individuals with loss of function mutations in SON. Common phenotypic features include "ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations". Trios study by WES reveals that 17/20 had frameshift indels (including the patient (patient 3) reported by Zhu et al. (2015)), 1/20 had nonsense mutation, 1/20 had in-frame deletion, and 1/20 had whole gene deletion including 5 other genes: GART, SON, DONSON, CRYZL1, ITSN1 and ATP5O. So 17 cases can be considered as additional de novo LOF variants identified in this study.

Haploinsufficiency phenotype comments:

PMID: 27545676 Tokita et al (2016) performed WES on over 6,000 subjects and identified de novo truncating mutations in SON in 6 individuals with Intellectual Disability, Congenital Malformations, and Failure to Thrive. In total, there are over 20 individuals with ZTTK syndrome carrying a de novo LOF variant of SON gene. ZTTK (ZHU-TOKITA-TAKENOUCHI-KIM SYNDROME) syndrome is the name given to individuals with SON gene mutation or deletion. The syndrome is characterized by "delayed psychomotor development and intellectual disability. Affected individuals have characteristic dysmorphic facial features, hypotonia, poor feeding, poor overall growth, and eye or visual abnormalities. Most patients also have musculoskeletal abnormalities, and some have congenital defects of the heart and urogenital system. Brain imaging usually shows developmental abnormalities such as gyral changes, cortical and/or cerebellar atrophy, and thin corpus callosum".

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity