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Limb disorders v1.137 SOX9 Eleanor Williams commented on gene: SOX9: The region upstream of SOX9 where duplications are assoicated with increased expression of KCNJ2 has been submitted to Clingen for review.
Limb disorders v1.127 SOX9 Eleanor Williams changed review comment from: 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.


Other publications.
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.

Summary:
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.; to: 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.


Other publications report SNVs and deletions of SOX9 in association with Campomelic dysplasia

Summary:
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.
Limb disorders v1.56 SOX9 Eleanor Williams commented on gene: SOX9: 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.


Other publications.
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.

Summary:
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.
Limb disorders v1.24 SOX9 Andrew Wilkie reviewed gene: SOX9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb disorders v1.7 SOX9 Louise Daugherty Tag duplication was removed from gene: SOX9.
Tag gene-duplication tag was added to gene: SOX9.
Limb disorders v0.275 SOX9 Eleanor Williams Marked gene: SOX9 as ready
Limb disorders v0.275 SOX9 Eleanor Williams Gene: sox9 has been classified as Red List (Low Evidence).
Limb disorders v0.271 SOX9 Eleanor Williams 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
Limb disorders v0.270 SOX9 Louise Daugherty reviewed gene: SOX9: Rating: RED; Mode of pathogenicity: ; Publications: 19639023, 24704791; Phenotypes: Brachydactyly-anonychia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v0.146 SOX9 Eleanor Williams commented on gene: SOX9
Limb disorders SOX9 Rachel Jones reviewed SOX9
Limb disorders SOX9 Ellen McDonagh Added gene to panel