Limb disorders

Gene: PAX3

Green List (high evidence)

Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with biallelic PAX3 variants and Waardenburg syndrome type 3 / Klein syndrome. This syndrome includes limb deformities not present in patients with monoallelic PAX3 variants. Hence, the MOI should remain as BIALLELIC, autosomal or pseudoautosomal.

Created: 24 Aug 2026, 9:53 a.m. | Last Modified: 24 Aug 2026, 10:22 a.m.

Panel Version: 9.1

ADDITIONAL CASES SINCE 2019:

PMID: 35607853 Salah et al., 2022 - biallelic case
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PMID: 41141997 Chen et al., 2025 - het deletion
Report of a proband with a deletion affecting PAX3. A detailed ultrasound examination at 14 weeks of gestation revealed no fetal anomalies. She presented with telecanthus but no pigmentary skin anomalies at birth. She developed jaundice and neonatal infection - not consistent with WS diagnosis. Isolated congenital spina bifida was noted in a previous pregnancy, terminated at 20 weeks. CMA analysis showed a 543-kb deletion in the 2q36.1 region [arr(GRCh38) 2q36.1(222,250,171_222,792,701) × 1], encompassing PAX3, FARSB, MOGAT1, and SGPP2 genes - PAX3 gene determined to explain this family's phenotypes. Deletion was confirmed to be paternally inherited.
The father (I:1) displayed characteristic WS facial features (DC, synophrys, a white forelock, and a broad nasal root) but had normal hearing, intellectual ability, and growth.

PMID: 41159045 Zafiri et al., 2025 - het missense variant
Report of a 33yo male patient with WS type 1: white forelock, skin depigmentation (white patches on the abdoment), severe neurosensory hearing loss. A c.209G>A (p.Cys70Tyr) variant was detected in the PAX3 gene in heterozygosity. Father and brother were het for the same change, but had normal hearing, with only a white forelock noted in the brother.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).

Created: 24 Aug 2026, 9:49 a.m. | Last Modified: 24 Aug 2026, 10:21 a.m.

Panel Version: 9.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Waardenburg syndrome, type 1, OMIM:193500; Waardenburg syndrome type 1, MONDO:0008670; Waardenburg syndrome, type 3, OMIM:148820; Waardenburg syndrome type 3, MONDO:0007862; Klein-Waardenburg syndrome

Publications

• 7726174
• 12949970
• 26443304
• 35607853
• 41141997
• 41159045

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

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