Limb disordersGene: SOX9
SOX9 and brachydactyly should be green (multiple duplications in cis associated: Kurth Nat Genet 41:862-3;2009. However these alter regulation of KCNJ2 rather than SOX9; Franke Nature 538:265-8;2016)
Created: 1 Aug 2019, 5:10 p.m. | Last Modified: 1 Aug 2019, 5:10 p.m.
Panel Version: 1.24
Agree with Red rating. Brachydactyly-anonychia is not primarily a limb-only phenotype, the gene is better represented on the Unexplained skeletal dysplasia panel due campomelic dysplasia, or acampomelic dysplasia, with short ribs and bowed long bones being the predominant phenotype. PMID: 19639023 reported duplications of noncoding elements 5' of SOX9 were associated with brachydactyly-anonychia.
Created: 7 Nov 2018, 1:26 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Associated with Campomelic dysplasia (114290) in OMIM and CAMPOMELIC DYSPLASIA and PIERRE ROBIN SEQUENCE in Gene2Phenotype (both confirmed).
Publications relating to the duplications in the region between KCNJ2 and SOX9:
PMID: 19639023 - Kurth et al 2009 - investigated four families with symmetric brachydactyly of the hands and feet as well as hyponychia or anonychia. All affected were of normal height and had no other skeletal abnormality. They identified overlapping duplications in a ∼2 Mb interval on chromosome 17q24.3. Comparison of the four duplications revealed a minimal critical region of ∼1.2 Mb encompassing a large gene desert between KCNJ2 and SOX9. In situ hybridizations in mouse embryos, showed that Sox9 was strongly expressed in the distal mesenchymal condensations at embryonic day (E) 12.5 that will later develop into the terminal phalanges and, at a later time point (E17.5), in the anlagen of the developing claw.
PMID: 27706140 - Franke et al 2016 - used chromosome conformation capture methods to look at topologically associated domains in patient cells and mouse models where the regulatory region next to SOX9 is duplicated. They generated mice with a duplicated region associated with Cooks syndrome as reported by Kurth et al 2009 (which they call Dup-C). cHi-C of E12.5 Dup-C limb buds showed a new chromatin domain corresponding to the duplicated region.
RNA sequencing expression analysis of Dup-C limb buds at E12.5 and E17.5 confirmed the upregulation of Kcnj2, whereas other genes around the locus stayed unchanged, in particular Sox9, but also Kcnj16. Thus, the inclusion of Kcnj2 in the neo-TAD resulted in its activation by regulatory elements that originally belonged to the Sox9 TAD.
PMID: 21373255 - Corbani et al 2011 - reported patient with SOX9 missense mutation and mild form of campomelic dysplasia. Features include short stature, dysmorphic facial features, limitation of supination and pronation of the forearms, dysplastic nails, and bone abnormalities consisting especially of cone-shaped epiphyses of the middle phalanx of the 2nd fingers, brachydactyly and clinodactyly of the middle phalanx of both 5th fingers, short 4th metacarpals, radial and femoral head subluxation, hypoplastic scapulae, humeral and ulnar epiphyseal abnormalities, unossified symphysis pubis, and a significant delay in bone age.
PMID: 24704791 - Takenouchi et al 2014 - report patient with many features of the type 2 collagen disorder including micrognathia, cleft palate, flat midface, and visual and hearing impairment, and a retarded enchondral ossification of the appendicular skeleton during the infantile period. The patient had in addition severe developmental delay. A de novo heterozygous missense mutation, c.239T>G p.Val80Gly, in exon 1 of SOX9 was found.
Evidence that duplication of a region upstream of SOX9 can result in a brachydactyly phenotype. This appears to be as a result of increased expression of KCNJ2. It maybe most appropriate to add this upstream region as a CNV.
Created: 8 Aug 2019, 4:17 p.m. | Last Modified: 8 Aug 2019, 4:17 p.m.
Panel Version: 1.56
Genomics England clinical team notes - Agree with red rating. Some patients with milder phenotypes resulting from SOX9 mutations.
Created: 9 Sep 2018, 7:56 p.m.
SOX9 mutations usually cause campomelic dysplasia, or acampomelic dysplasia, with short ribs and bowed long bones. SOX 9 is already on skeletal dysplasia and clefting panels in green.
However there are some papers that have identified patients with milder phenotypes
PMID: 24704791 - patient with Pierre-Robin and talipes, some facial dysmorphic features, severe deafness, compatible with a Collagen disorder plus a degree of intellectual disability
PMID: 21373255 - patient with features of a skeletal dysplasia (including short stature), intellectual disability, mild hearing loss, micrognathia and a high palate. Same paper gives clinical summary of other surviving patients with mild campomelic dysplasia/SOX9 mutations. 90% have a skeletal dysplasia (short stature/short limbs, 50% with bowing of the long bones) and 84% intellectual disability, 50% with hearing impairment.
Should remain red on limb panel for now as not primarily a limb-only phenotype. I will review other panels gene is red/amber in on this basis though.
Created: 24 Apr 2018, 2:58 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tag duplication was removed from gene: SOX9. Tag gene-duplication tag was added to gene: SOX9.
Rachel Jones: SOX9 mutations usually cause c
Gene: sox9 has been classified as Red List (Low Evidence).
Source Expert Review Red was added to SOX9. Mode of inheritance for gene SOX9 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Added phenotypes Brachydactyly-anonychia for gene: SOX9 Publications for gene SOX9 were changed from 19639023 to 24704791; 19639023
SOX9 was added to Limb disorders panel. Sources: Literature
SOX9 was created by Ellen McDonagh