Activity
| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
27 actions
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.4 | PAX3 | Ida Ertmanska Phenotypes for gene: PAX3 were changed from Waardenburg syndrome, type 3, 148820 to 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.3 | PAX3 | Ida Ertmanska Publications for gene: PAX3 were set to 6340503; 12949970; 7726174; 26443304; 8447316; 11683776; 30173992; 35607853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.2 | PAX3 | Ida Ertmanska edited their review of gene: PAX3: Changed publications to: 7726174, 12949970, 26443304, 35607853, 41141997, 41159045 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.2 | PAX3 | Ida Ertmanska Publications for gene: PAX3 were set to 6340503; 12949970; 7726174; 26443304; 8447316; 11683776; 30173992 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 | Ida Ertmanska changed review comment from: 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.; to: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 |
Ida Ertmanska changed review comment from: 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 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. 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).; to: 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). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 |
Ida Ertmanska changed review comment from: PMID: 7726174 Zlotogora et al. 1995 Report of 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: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het). PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 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. 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).; to: 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 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. 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). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 | Ida Ertmanska edited their review of gene: PAX3: Changed publications to: 7726174, 12949970, 26443304, 35607853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 |
Ida Ertmanska changed review comment from: PMID: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het). PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 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. 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).; to: PMID: 7726174 Zlotogora et al. 1995 Report of 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: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het). PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 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. 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). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 | Ida Ertmanska commented on gene: PAX3: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 | Ida Ertmanska edited their review of gene: PAX3: Changed rating: GREEN; Changed publications to: 12949970 26443304, 35607853; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 |
Ida Ertmanska changed review comment from: PMID: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for p.Y90H PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 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. 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).; to: PMID: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het). PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 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. 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). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 | Ida Ertmanska reviewed gene: PAX3: Rating: ; Mode of pathogenicity: None; Publications: 26443304, 35607853; 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; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.137 | EPHA4 |
Eleanor Williams changed review comment from: EPHA4 not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 25959774 - Lupiáñez et al 2015 - studied limb abnormalities in 3 sets of families: Group 1 - 3 unrelated families with a dominantly inherited novel type of brachydactyly, characterized by short digits predominantly on the preaxial (radial) side resulting in stub thumbs, short index fingers and a cutaneous web between the first and second fingers. aCGH revealed heterozygous deletions of 1.75–1.9 Mb on chromosome 2q35–36 in all three affected families. All three deletions include the EPHA4 gene along with a large portion of its surrounding TAD and extend into the non-coding part of the adjacent PAX3 TAD (topologically associated domain), thereby removing the predicted boundary between the EPHA4 and PAX3 TADs. Mutant mice with a deletion corresponding to the human disease alleles recapitulated the phenotype observed in patients. Group 2 - 2 unrelated families with F-syndrome, a limb malformation syndrome characterized by severe and complex syndactyly, often involving the first and second fingers, and polydactyly of the feet. By whole genome sequencing they detected a ~1.1 Mb heterozygous inversion in family F1 and a ~1.4 Mb heterozygous duplication, arranged in direct tandem orientation, in family F2. The telomeric breakpoints were located 1.4 Mb away from the EPHA4 gene within the gene desert in the case of the inversion, and 1.2 Mb in the case of the duplication. Heterozygous as well as homozygous newborn mice generated via tetraploid aggregation died shortly after birth of unknown cause and did not show overt limb phenotypes or other morphological defects Group 3 - a family that carries a heterozygous ~900 kb duplication in chromosomal region 2q35 that results in severe polysyndactyly and craniofacial abnormalities. The phenotype is reminiscent of the doublefoot (Dbf) mouse mutant, which also features massive polysyndactyly and was shown to be caused by a ~600 kb deletion affecting the same region (Babbs et al., 2008) Using 4C-seq they show that In wild-type distal limbs, there was minimal interaction of Pax3, Wnt6 and Ihh with non-coding sequences in the Epha4 TAD. In contrast, all three genes showed substantial interaction with the Epha4 TAD in the mutants. Similar results were found using patient fibroblasts. Genomic re-arrangements in the Epha4 TAD can result in limb abnormalities. It maybe best to represent these as regions of gain or loss in PanelApp; to: EPHA4 not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 25959774 - Lupiáñez et al 2015 - studied limb abnormalities in 3 sets of families: Group 1 - 3 unrelated families with a dominantly inherited novel type of brachydactyly, characterized by short digits predominantly on the preaxial (radial) side resulting in stub thumbs, short index fingers and a cutaneous web between the first and second fingers. aCGH revealed heterozygous deletions of 1.75–1.9 Mb on chromosome 2q35–36 in all three affected families. All three deletions include the EPHA4 gene along with a large portion of its surrounding TAD and extend into the non-coding part of the adjacent PAX3 TAD (topologically associated domain), thereby removing the predicted boundary between the EPHA4 and PAX3 TADs. Mutant mice with a deletion corresponding to the human disease alleles recapitulated the phenotype observed in patients. They detected a significant upregulation of Pax3 in DelB/+ limbs in mice, and DelB/+ (brachydactyly-like deletion) mice showed strong misexpression of Pax3 in the distal anterior part of the autopod, in a pattern resembling endogenous Epha4 expression. Group 2 - 2 unrelated families with F-syndrome, a limb malformation syndrome characterized by severe and complex syndactyly, often involving the first and second fingers, and polydactyly of the feet. By whole genome sequencing they detected a ~1.1 Mb heterozygous inversion in family F1 and a ~1.4 Mb heterozygous duplication, arranged in direct tandem orientation, in family F2. The telomeric breakpoints were located 1.4 Mb away from the EPHA4 gene within the gene desert in the case of the inversion, and 1.2 Mb in the case of the duplication. Heterozygous as well as homozygous newborn mice generated via tetraploid aggregation died shortly after birth of unknown cause and did not show overt limb phenotypes or other morphological defects Group 3 - a family that carries a heterozygous ~900 kb duplication in chromosomal region 2q35 that results in severe polysyndactyly and craniofacial abnormalities. The phenotype is reminiscent of the doublefoot (Dbf) mouse mutant, which also features massive polysyndactyly and was shown to be caused by a ~600 kb deletion affecting the same region (Babbs et al., 2008) Using 4C-seq they show that In wild-type distal limbs, there was minimal interaction of Pax3, Wnt6 and Ihh with non-coding sequences in the Epha4 TAD. In contrast, all three genes showed substantial interaction with the Epha4 TAD in the mutants. Similar results were found using patient fibroblasts. Genomic re-arrangements in the Epha4 TAD can result in limb abnormalities. It maybe best to represent these as regions of gain or loss in PanelApp |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.116 | PAX3 | Eleanor Williams Classified gene: PAX3 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.116 | PAX3 | Eleanor Williams Added comment: Comment on list classification: At least two, possibly three, cases and a mouse model. Rating agreed with Genomics England clinical team. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.116 | PAX3 | Eleanor Williams Gene: pax3 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.115 | PAX3 | Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic cases show stronger evidence of limb phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.115 | PAX3 | Eleanor Williams 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.56 | EPHA4 |
Eleanor Williams commented on gene: EPHA4: EPHA4 not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 25959774 - Lupiáñez et al 2015 - studied limb abnormalities in 3 sets of families: Group 1 - 3 unrelated families with a dominantly inherited novel type of brachydactyly, characterized by short digits predominantly on the preaxial (radial) side resulting in stub thumbs, short index fingers and a cutaneous web between the first and second fingers. aCGH revealed heterozygous deletions of 1.75–1.9 Mb on chromosome 2q35–36 in all three affected families. All three deletions include the EPHA4 gene along with a large portion of its surrounding TAD and extend into the non-coding part of the adjacent PAX3 TAD (topologically associated domain), thereby removing the predicted boundary between the EPHA4 and PAX3 TADs. Mutant mice with a deletion corresponding to the human disease alleles recapitulated the phenotype observed in patients. Group 2 - 2 unrelated families with F-syndrome, a limb malformation syndrome characterized by severe and complex syndactyly, often involving the first and second fingers, and polydactyly of the feet. By whole genome sequencing they detected a ~1.1 Mb heterozygous inversion in family F1 and a ~1.4 Mb heterozygous duplication, arranged in direct tandem orientation, in family F2. The telomeric breakpoints were located 1.4 Mb away from the EPHA4 gene within the gene desert in the case of the inversion, and 1.2 Mb in the case of the duplication. Heterozygous as well as homozygous newborn mice generated via tetraploid aggregation died shortly after birth of unknown cause and did not show overt limb phenotypes or other morphological defects Group 3 - a family that carries a heterozygous ~900 kb duplication in chromosomal region 2q35 that results in severe polysyndactyly and craniofacial abnormalities. The phenotype is reminiscent of the doublefoot (Dbf) mouse mutant, which also features massive polysyndactyly and was shown to be caused by a ~600 kb deletion affecting the same region (Babbs et al., 2008) Using 4C-seq they show that In wild-type distal limbs, there was minimal interaction of Pax3, Wnt6 and Ihh with non-coding sequences in the Epha4 TAD. In contrast, all three genes showed substantial interaction with the Epha4 TAD in the mutants. Similar results were found using patient fibroblasts. Genomic re-arrangements in the Epha4 TAD can result in limb abnormalities. It maybe best to represent these as regions of gain or loss in PanelApp |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.27 | PAX3 | Eleanor Williams Publications for gene: PAX3 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.26 | PAX3 | Eleanor Williams Phenotypes for gene: PAX3 were changed from to Waardenburg syndrome, type 3, 148820 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.25 | PAX3 | Eleanor Williams 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.24 | PAX3 |
Eleanor Williams changed review comment from: 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: PMID: 7726174- Zlotogora et al. 1995 - 1 family - 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. 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: 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: 30173992 - Saberi et al 2018 - 1 family - Iranian family with 10 affected members with WS type 1 or type 3. A 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.; to: 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.24 | PAX3 |
Eleanor Williams commented on gene: PAX3: 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: PMID: 7726174- Zlotogora et al. 1995 - 1 family - 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. 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: 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: 30173992 - Saberi et al 2018 - 1 family - Iranian family with 10 affected members with WS type 1 or type 3. A 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.24 | PAX3 | Andrew Wilkie reviewed gene: PAX3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.12 | PAX3 |
Eleanor Williams 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 Added comment: Gene suggested for the panel by Andrew Wilkie, Oxford University Hospitals NHS Foundation Trust Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||