ClinGen Dosage Sensitivity Curation Page

SOX9 upstream enhancer region

  • Curation Status: Complete
  • id: ISCA-46303
  • Date last evaluated: 2021-06-07
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 1


Location Information

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Evidence for haploinsufficiency phenotype
PubMed ID Description
19234473 In 2009, Benko, et al. used high-density-tiling-path comparative genomic hybridization array on 5 families and 12 individuals with Pierre Robin Syndrome (PRS). One family had a deletion in the noncoding 5? elements of SOX9 in the proband and 2 segregations. 2 other individuals separate from the families had de novo deletions that were confirmed with parental testing.
26663529 In 2015, Castori et al. used PCR on a 3-generational family with a heterogeneous phenotype from PRS to acampomelic campomelic dysplasia (ACD). A deletion at 17q24.2 spanning from 68,046,281 to 69,123,428 pm (GRCh37/hg19) and including the entire coding region of KCNJ16 and the regulatory elements of KCNJ2, HCNE-F2, was found in the proband and 4 family members.
24934569 In 2014, Gordon et al. used comparative genomic hybridization and qPCR on 20 patients with non-syndromic PRS. One family had a proband and 2 family members with a 280kb deletion upstream of the SOX9 transcription start sight. Another family had a 6kb deletion upstream of the SOX9 gene with one segregation.

Haploinsufficiency phenotype comments:

Pierre Robin Syndrome is caused by dysregulation of SOX9 and KCNJ2 due to deletion of the upstream region between SOX9 and KCNJ2 (PMID: 17551083). Genomic coordinates for this region were determined by utilizing the largest region found in reported deletions (PMID: 32583964). Note the exact minimum and maximum deleted region sufficient to cause Pierre Robin Syndrome phenotype is unknown. Additional evidence includes: PMID: 23532965 In 2013, Amarillo et al. used chromosomal microarray (CMA) on a family with PRS. The proband and mother had a 623kb microdeletion upstream of 5? SOX9.

Evidence for triplosensitivity phenotype
PubMed ID Description
32583964 In 2020, Liu, et al. used whole-exome sequencing (WES) and microarray-based comparative genomic hybridization on a family with brachydactyly-anonychia. The proband and 2 individuals in the family have a duplication involving regulatory elements of SOX9, and coding regions of KCNJ2 and KCNJ16. All family members underwent a physical and radiographic examination.
19639023 In 2009, Kurth, et al. used qPCR in four unrelated families with brachydactyly-anonychia. Family 1 had the proband and 2 segregations of a duplication of the noncoding elements of 5? SOX9. The original duplication was de novo and was confirmed with parental testing. Family 3 had a de novo duplication confirmed with parental testing. Family 2 had the proband and one segregation of the duplication and family 4 had one individual with the duplication and no parental testing. The minimal critical region of the duplication of noncoding elements 5? of SOX9 is Chr17:65642665-66847686.

Triplosensitivity phenotype comment:

A duplication in this upstream SOX9 region puts KCNJ2 under SOX9 enhancer regulation, causing limb malformation. (PMID: 27706140). Genomic coordinates for this region were determined by utilizing the coordinates of the variant that encompassed all other reported variants as of September 2020 found in reported duplications (PMID: 32583964). Note the exact minimum and maximum duplicated region sufficient to cause Cooks Syndrome is unknown.