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Limb disorders

Gene: PAX3

Green List (high evidence)

PAX3 (paired box 3)
EnsemblGeneIds (GRCh38): ENSG00000135903
EnsemblGeneIds (GRCh37): ENSG00000135903
OMIM: 606597, Gene2Phenotype
PAX3 is in 14 panels

2 reviews

Andrew Wilkie (University of Oxford)

I don't know

Klein-Waardenburg syndrome
Created: 1 Aug 2019, 5:10 p.m. | Last Modified: 1 Aug 2019, 5:10 p.m.
Panel Version: 1.24

Eleanor Williams (Genomics England Curator)

I don't know

Comment on list classification: At least two, possibly three, cases and a mouse model. Rating agreed with Genomics England clinical team.
Created: 25 Nov 2019, 11:54 p.m. | Last Modified: 25 Nov 2019, 11:54 p.m.
Panel Version: 1.116
Comment on mode of inheritance: Biallelic cases show stronger evidence of limb phenotype.
Created: 25 Nov 2019, 11:54 p.m. | Last Modified: 25 Nov 2019, 11:54 p.m.
Panel Version: 1.115
Associated with Waardenburg syndrome, type 3 (148820) and Craniofacial-deafness-hand syndrome (122880) in OMIM. It is also associated with Waardenburg syndrome type 1 (193500) which presents with a milder phenotype.

Waardenburg syndrome, type 3:

Homozygous cases:

PMID: - not available - Bottani et al., 1999 - 1 case originally reported in Klein et al 1983 (PMID: 6340503) of compound heterozygous mutations in PAX3 involving a recurrent missense mutation in the homeodomain and a new one in the paired domain in an individual with WS3. (Full publications not accessed).

PMID: 12949970 - Wollnik et al. 2003 - 1 family - a consanguineous Turkish family with a daughter in which a homozygous variant in the PAX3 gene resulted in a Y90H substitution. Both parents were heterozygous for the variant. The daughter was determined to have type 3 Waardenburg syndrome. The limb phenotype includes flexion deformities of wrists and fingers with ulnar deviation, decreased palmar creases, and minimal webs between fingers were noted.

PMID: 7726174- Zlotogora et al. 1995 - 1 case - a large kindred with Waardenburg syndrome type 1 and a heterozygous mutation S84F in PAX3 gene. 1 child, born of consanguineous parents, had a severe phenotype consistent with WS type 3. This child was homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Severe changes were present in the
upper limbs, with rigidity of the larger joints -including shoulders, elbows, and wrists-as well as of the smaller
joints of the fingers. Muscle wasting was severe in the pectoral region, the shoulders, and upper limbs. Axillary
webs were present on both sides. There was a slight degree of contracture of the knees, and there was calcaneovalgus deformation of the feet.

PMID: 26443304 - Mousty et al 2015 - 1 case - parents were first‐cousin relatives from a gypsy community in the south of France which both presented with a typical WS1 profile. Ultrasound examination of the fetus revealed cystic hygroma, holoprosencephaly, a lack of active movements, extremity abnormalities (short long bones associated with bilateral club hand and club foot), and significant spinal curvature. Both parents were found to have the same heterozygous mutation in exon 6 of PAX3, namely c.807C>G (p.Asn269Lys). Sequencing of fetal DNA found the mutation in the homozygous state. Functional studies showed an almost total loss of function of PAX3 co‐activation with SOX10 when it came to the mutant.

Heterozygous cases:

PMID: 8447316 - Hoth et al. 1993 - 1 family - report the identification of a heterozygous variant leading to a N47H substitution in PAX3 (exon 2) in affected members of a family with Waardenburg syndrome type 3. In addition to hearing loss and dystopia canthorum, affected members of this family have both third-fifth-finger bilateral camptodactyly with proximal insertion of the thumbs and other limb abnormalities. The family were previously reported by Milunsky et al. (1992), Goodman et al. (1982) and Sheffer and Zlotogora (1992).

PMID: 11683776 - Tekin et al. 2001 - describe a mother and son with typical clinical findings of WS type 3 segregating with a heterozygous 13-bp deletion in the paired domain in exon 3 of the PAX3 gene. However, the limb phenotype is restricted to slight flexion contractures of the fingers, especially involving the ulnar ray in the mother, and bilateral flexion contractures of the fingers especially of the lateral three digits in the son.

PMID: 30173992 - Saberi et al 2018 - 1 family - Iranian family with 10 affected members with WS type 1 or type 3. A heterozygous donor splice site variant (c.586 + 2 T > C) was found in intron 4 of PAX3 that was predicted to be deleterious and co-segregated in the pedigree. It was not found in asymptomatic members. Of the 6 family members for which clinical features are available, 3 showed camptodactyly along with other features such as Hypertelorism, Dystopia Canthorum, and Broad/high nasal root. Hearing loss was not observed.
Created: 6 Aug 2019, 1:42 p.m. | Last Modified: 6 Aug 2019, 2:32 p.m.
Panel Version: 1.24
Gene suggested for the panel by Andrew Wilkie, Oxford University Hospitals NHS Foundation Trust
Sources: Expert list
Created: 1 Aug 2019, 2:05 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

History Filter Activity

25 Nov 2019, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: pax3 has been classified as Green List (High Evidence).

25 Nov 2019, Gel status: 1

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: PAX3 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal

6 Aug 2019, Gel status: 1

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: PAX3 were set to

6 Aug 2019, Gel status: 1

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: PAX3 were changed from to Waardenburg syndrome, type 3, 148820

6 Aug 2019, Gel status: 1

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: PAX3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

1 Aug 2019, Gel status: 1

Created, Added New Source, Set mode of inheritance

Eleanor Williams (Genomics England Curator)

gene: PAX3 was added gene: PAX3 was added to Limb disorders. Sources: Expert list Mode of inheritance for gene: PAX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Review for gene: PAX3 was set to AMBER