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Limb disorders v9.6 LRP4 Ida Ertmanska changed review comment from: MONOALLELIC CASES:
PMID: 37563890 Khan et al., 2023
Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. Heterozygous variants were prioritised based on the pedigree.

PMID: 21471202 Leupin et al., 2011
Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing.
P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2.
P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant.

BIALLELIC CASES:
https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs.
PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant
PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each
PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous.
PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp
PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents

LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.; to: MONOALLELIC CASES:
PMID: 37563890 Khan et al., 2023
Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. Heterozygous variants were prioritised based on the pedigree.

PMID: 21471202 Leupin et al., 2011
Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing.
P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2.
P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant.

BIALLELIC CASES:
https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs.
PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant
PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each
PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous.
PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp; sequenced 35 genes including SOST
PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents

LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.
Limb disorders v9.6 LRP4 Ida Ertmanska changed review comment from: MONOALLELIC CASES:
PMID: 37563890 Khan et al., 2023
Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals.

PMID: 21471202 Leupin et al., 2011
Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing.
P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2.
P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant.

BIALLELIC CASES:
https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs.
PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant
PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each
PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous.
PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp
PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents

LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.; to: MONOALLELIC CASES:
PMID: 37563890 Khan et al., 2023
Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. Heterozygous variants were prioritised based on the pedigree.

PMID: 21471202 Leupin et al., 2011
Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing.
P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2.
P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant.

BIALLELIC CASES:
https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs.
PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant
PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each
PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous.
PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp
PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents

LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.
Limb disorders v9.6 LRP4 Ida Ertmanska changed review comment from: MONOALLELIC CASES:
PMID: 37563890 Khan et al., 2023
Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals.

PMID: 21471202 Leupin et al., 2011
Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth
P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails. Complications included such as dizziness, difficulties with gait and coordination, vertigo, and spastic and ataxic gait disturbances. Several neurological complications, such as facial nerve palsy and hearing loss, were present due to bone compression of cranial nerves. X-rays revealed severe thickening of the calvaria and the cortices of the long bones. Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2.
P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant.

LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.; to: MONOALLELIC CASES:
PMID: 37563890 Khan et al., 2023
Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals.

PMID: 21471202 Leupin et al., 2011
Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing.
P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2.
P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant.

BIALLELIC CASES:
https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs.
PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant
PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each
PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous.
PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp
PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents

LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.
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 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 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 v8.8 NPR2 Ida Ertmanska gene: NPR2 was added
gene: NPR2 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: NPR2.
Mode of inheritance for gene: NPR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NPR2 were set to 40424589
Phenotypes for gene: NPR2 were set to Short stature with nonspecific skeletal abnormalities, OMIM:616255
Review for gene: NPR2 was set to GREEN
Added comment: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 had brachydactyly; clinodactyly and syndactyly were also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).
Sources: Literature
Limb disorders v8.8 NPR2 Ida Ertmanska gene: NPR2 was added
gene: NPR2 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: NPR2.
Mode of inheritance for gene: NPR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NPR2 were set to 40424589
Phenotypes for gene: NPR2 were set to Short stature with nonspecific skeletal abnormalities, OMIM:616255
Review for gene: NPR2 was set to GREEN
Added comment: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 had brachydactyly; clinodactyly and syndactyly were also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).
Sources: Literature
Limb disorders v8.8 NPR2 Ida Ertmanska gene: NPR2 was added
gene: NPR2 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: NPR2.
Mode of inheritance for gene: NPR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NPR2 were set to 40424589
Phenotypes for gene: NPR2 were set to Short stature with nonspecific skeletal abnormalities, OMIM:616255
Review for gene: NPR2 was set to GREEN
gene: NPR2 was marked as current diagnostic
Added comment: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 had brachydactyly; clinodactyly and syndactyly were also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).
Sources: Literature
Limb disorders v7.32 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Limb disorders v7.29 SCNM1 Ida Ertmanska changed review comment from: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature; to: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.

SCNM1 is associated with AR Orofaciodigital syndrome XIX, OMIM:620107 in OMIM (accessed 14th Apr 2026).
Sources: Literature
Limb disorders v7.28 SCNM1 Ida Ertmanska gene: SCNM1 was added
gene: SCNM1 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: SCNM1.
Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCNM1 were set to 36084634; 41291844
Phenotypes for gene: SCNM1 were set to Orofaciodigital syndrome XIX, OMIM:620107; orofaciodigital syndrome 19, MONDO:0859310
Review for gene: SCNM1 was set to GREEN
Added comment: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature
Limb disorders v5.6 MAPKAPK5 Achchuthan Shanmugasundram Phenotypes for gene: MAPKAPK5 were changed from Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism; Synpolydactyly to Neurocardiofaciodigital syndrome, OMIM:619869
Limb disorders v2.81 HEATR3 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. HEATR3 has been rated as Green as the affected members of 3/4 families identified had brachydactyly and other features of hands and/or feet.
Limb disorders v2.69 SMO Eleanor Williams Tag for-review was removed from gene: SMO.
Limb disorders v2.67 SMO Eleanor Williams commented on gene: SMO: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Limb disorders v2.66 SMO Eleanor Williams Source Expert list was added to SMO.
Mode of inheritance for gene SMO was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb disorders v2.65 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Limb disorders v2.64 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Limb disorders. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Limb disorders v2.40 MAPKAPK5 Arina Puzriakova gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 33442026
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism; Synpolydactyly
Review for gene: MAPKAPK5 was set to AMBER
Added comment: MAPKAPK5 is not yet associated with any phenotype in OMIM (last edited on 06/04/2016) but has a 'probable' disease confidence rating for 'MAPKAPK5-associated syndrome with synpolydactyly' in Gene2Phenotype.

- PMID: 33442026 (2021) - 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.

Rating Amber, awaiting further cases.
Sources: Literature
Limb disorders v2.29 SMO Eleanor Williams Tag for-review tag was added to gene: SMO.
Limb disorders v2.29 SMO Eleanor Williams Added comment: Comment on mode of inheritance: Leaving MOI has monoallelic just now, but with recommendation for updating to BOTH monoallelic and biallelic at the next review, due to additional biallelic cases now reported.
Limb disorders v2.29 SMO Eleanor Williams Mode of inheritance for gene: SMO was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.28 SMO Eleanor Williams Phenotypes for gene: SMO were changed from Polydactyly; Curry-Jones syndrome, somatic mosaic, MIM:601500; Cutaneous syndactyly; Preaxial polydactyly to Curry-Jones syndrome, somatic mosaic, OMIM:601500; postaxial polydactyly MONDO:0020927; Microcephaly HP:0000252; congenital heart disease MONDO:0005453; Hirschsprung disease MONDO:0018309
Limb disorders v2.27 SMO Eleanor Williams Publications for gene: SMO were set to 27236920
Limb disorders v2.26 SMO Eleanor Williams reviewed gene: SMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 32413283; Phenotypes: postaxial polydactyly MONDO:0020927, Microcephaly HP:0000252, congenital heart disease MONDO:0005453, Hirschsprung disease MONDO:0018309; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v2.5 SMO Zornitza Stark reviewed gene: SMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 32413283; Phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v1.137 WDPCP Eleanor Williams changed review comment from: PMID: 28289185 - Bruel et al 2017 - report 1 case (patient 10) with compound heterozygous variants in WDPCP and an Oral-facial-digital syndrome phenotype which includes Post-axial polydactyly of the hands and syndactyly of the feet.

PMID: 27158779 - Toriyama et al 2016 - report 1 case of a 5-year-old male presenting with facial dysmorphism, tongue hamartoma, high arched palate, tooth abnormalities, and postaxial polydactyly. He was found to be compound heterozygous for two mutations in WDPCP, a frameshift and a missense variant predicted to alter splicing. Each parent had one of the variants. Functional studies in Xenopus MCCs and found that the frame-shift allele resulted in total loss of protein, while the point mutation led to a consistent but more modest defect in protein stability They also observed Y-shaped metacarpals and defects in tongue and palate morphology in Wdpcp mouse mutants

PMID: 25427950 - Saari et al 2015 - report 1 case of a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas. By whole exome sequencing they found she is a compound heterozygote for a frame shift mutation and a likely pathogenic sequence variant in WDPCP. The parents and two siblings were heterozygous carriers.

PMID: Kim et al 2010 - report 1 cases of a proband with a clinical diagnosis of BBS and a homozygous Fritz mutation that segregated with the disorder. Both parents and an unaffected sib were heterozygous carriers. No details

3 cases with oralfacial digitial syndrome type phenotypes and one with a clinical diagnosis of BBS.; to: PMID: 28289185 - Bruel et al 2017 - report 1 case (patient 10) with compound heterozygous variants (a missense variant and 2bp deletion leading to a frameshift) in WDPCP and an Oral-facial-digital syndrome phenotype which includes Post-axial polydactyly of the hands and syndactyly of the feet.

PMID: 27158779 - Toriyama et al 2016 - report 1 case of a 5-year-old male presenting with facial dysmorphism, tongue hamartoma, high arched palate, tooth abnormalities, and postaxial polydactyly. He was found to be compound heterozygous for two mutations in WDPCP, a frameshift and a missense variant predicted to alter splicing. Each parent had one of the variants. Functional studies in Xenopus MCCs and found that the frame-shift allele resulted in total loss of protein, while the point mutation led to a consistent but more modest defect in protein stability They also observed Y-shaped metacarpals and defects in tongue and palate morphology in Wdpcp mouse mutants

PMID: 25427950 - Saari et al 2015 - report 1 case of a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas. By whole exome sequencing they found she is a compound heterozygote for a frame shift mutation and a likely pathogenic sequence variant in WDPCP. The parents and two siblings were heterozygous carriers.

PMID: Kim et al 2010 - report 1 cases of a proband with a clinical diagnosis of BBS and a homozygous Fritz mutation that segregated with the disorder. Both parents and an unaffected sib were heterozygous carriers. No details

3 cases with oralfacial digitial syndrome type phenotypes and one with a clinical diagnosis of BBS.
Limb disorders v1.129 WDPCP Eleanor Williams commented on gene: WDPCP: PMID: 28289185 - Bruel et al 2017 - report 1 case (patient 10) with compound heterozygous variants in WDPCP and an Oral-facial-digital syndrome phenotype which includes Post-axial polydactyly of the hands and syndactyly of the feet.

PMID: 27158779 - Toriyama et al 2016 - report 1 case of a 5-year-old male presenting with facial dysmorphism, tongue hamartoma, high arched palate, tooth abnormalities, and postaxial polydactyly. He was found to be compound heterozygous for two mutations in WDPCP, a frameshift and a missense variant predicted to alter splicing. Each parent had one of the variants. Functional studies in Xenopus MCCs and found that the frame-shift allele resulted in total loss of protein, while the point mutation led to a consistent but more modest defect in protein stability They also observed Y-shaped metacarpals and defects in tongue and palate morphology in Wdpcp mouse mutants

PMID: 25427950 - Saari et al 2015 - report 1 case of a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas. By whole exome sequencing they found she is a compound heterozygote for a frame shift mutation and a likely pathogenic sequence variant in WDPCP. The parents and two siblings were heterozygous carriers.

PMID: Kim et al 2010 - report 1 cases of a proband with a clinical diagnosis of BBS and a homozygous Fritz mutation that segregated with the disorder. Both parents and an unaffected sib were heterozygous carriers. No details

3 cases with oralfacial digitial syndrome type phenotypes and one with a clinical diagnosis of BBS.
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 v1.39 SUFU Eleanor Williams commented on gene: SUFU: Associated with Joubert syndrome 32 (#617757) in OMIM and Joubert Syndrome with Cranio-facial and Skeletal Defects in Gene2Phenotype (probable).

PMID: 28965847 - Mori et al 2017 - 2 cases. They report four children from two unrelated consanguineous families (from Italy and Egypt) carrying homozygous missense variants (c.1217T>C,p.Ile406Thr and c.1218C>G,p.Ile406Met) in SUFU. The children presented with congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and 3 had postaxial polydactyly.
In family 1, the two affected siblings also had a homozygous missense variant in CDHR1 but is expressed only in the outer nuclear layer of the retina and pathogenic variants of this gene are known to cause an autosomal-recessive form of cone-rod dystrophy with onset in the late second decade of life (older than the probands).
Functional studies on fibroblasts and cell lines showed that the mutant proteins were less stable and more rapidly degraded than SUFU WT and had impaired ability to bind GLI3 and promote its cleavage into the repressor form GLI3R, while they maintained unaltered ability to bind GLI1. These findings suggest that both variants are hypomorphic alleles, resulting only in a partial loss of the normal gene function.
Limb disorders v1.38 TRAF7 Eleanor Williams Phenotypes for gene: TRAF7 were changed from to Cardiac, facial, and digital anomalies with developmental delay, 618164; Developmental Delay, Congenital Anomalies, and Dysmorphic Features
Limb disorders v1.37 TRAF7 Eleanor Williams changed review comment from: Associated with Cardiac, facial, and digital anomalies with developmental delay (#618164) in OMIM and Developmental Delay, Congenital Anomalies, and Dysmorphic Features in Gene2Phenotype.

PMID: 29961569 - Tokita et al. 2018 - 7 cases. They report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. There was substantial phenotypic overlap between individuals, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features as key features. 6 individuals had de novo variants (absence of paternal DNA in one patient did not allow confirmation of a de novo variant), with four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant in 4 individuals. The variants affect evolutionarily conserved amino acids and are located in key functional domains.

All 7 subjects had limb and digital anomalies to a variable degree, including variant palmar/digital crease patterns (n = 6) and overlapping toes (n = 5) and clinodactyly (n=3). One subject (Subject 3) had more extensive involvement of the musculoskeletal system including scoliosis with degenerative joint disease, an asymmetric sternum, bilateral avascular necrosis of the hip, tibial malformation, valgus deformity of the ankles, flexion contractures of the hands, and subluxation of multiple joints in the hands and feet.; to: Associated with Cardiac, facial, and digital anomalies with developmental delay (#618164) in OMIM and Developmental Delay, Congenital Anomalies, and Dysmorphic Features in Gene2Phenotype.

PMID: 29961569 - Tokita et al. 2018 - 7 cases. They report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. There was substantial phenotypic overlap between individuals, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features as key features. 6 individuals had de novo variants (absence of paternal DNA in one patient did not allow confirmation of a de novo variant), with four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant in 4 individuals. The variants affect evolutionarily conserved amino acids and are located in key functional domains.
All 7 subjects had limb and digital anomalies to a variable degree, including variant palmar/digital crease patterns (n = 6) and overlapping toes (n = 5) and clinodactyly (n=3). One subject (Subject 3) had more extensive involvement of the musculoskeletal system including scoliosis with degenerative joint disease, an asymmetric sternum, bilateral avascular necrosis of the hip, tibial malformation, valgus deformity of the ankles, flexion contractures of the hands, and subluxation of multiple joints in the hands and feet.
Limb disorders v1.37 TRAF7 Eleanor Williams changed review comment from: Associated with Cardiac, facial, and digital anomalies with developmental delay (#618164) in OMIM and Developmental Delay, Congenital Anomalies, and Dysmorphic Features in Gene2Phenotype.; to: Associated with Cardiac, facial, and digital anomalies with developmental delay (#618164) in OMIM and Developmental Delay, Congenital Anomalies, and Dysmorphic Features in Gene2Phenotype.

PMID: 29961569 - Tokita et al. 2018 - 7 cases. They report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. There was substantial phenotypic overlap between individuals, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features as key features. 6 individuals had de novo variants (absence of paternal DNA in one patient did not allow confirmation of a de novo variant), with four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant in 4 individuals. The variants affect evolutionarily conserved amino acids and are located in key functional domains.

All 7 subjects had limb and digital anomalies to a variable degree, including variant palmar/digital crease patterns (n = 6) and overlapping toes (n = 5) and clinodactyly (n=3). One subject (Subject 3) had more extensive involvement of the musculoskeletal system including scoliosis with degenerative joint disease, an asymmetric sternum, bilateral avascular necrosis of the hip, tibial malformation, valgus deformity of the ankles, flexion contractures of the hands, and subluxation of multiple joints in the hands and feet.
Limb disorders v1.35 TRAF7 Eleanor Williams commented on gene: TRAF7: Associated with Cardiac, facial, and digital anomalies with developmental delay (#618164) in OMIM and Developmental Delay, Congenital Anomalies, and Dysmorphic Features in Gene2Phenotype.
Limb disorders v1.35 NCAPG2 Eleanor Williams changed review comment from: Associated with Khan-Khan-Katsanis syndrome (#618460) in OMIM.

PMID: 30609410 - Khan et al. 2019 - 2 unrelated cases with homozygous or compound heterozygous variants in NCAPG2.
Family 1 - female with bilateral postaxial polydactyly on the feet, moderate intellectual disability, ocular anomalies, sensorineural hearing impairment, sleep apnea, and a short stature. Renal anomalies were also observed although these resolved over time. She was found to have compound-heterozygous missense NCAPG2 mutations, c.1825A>G (p.Lys609Glu) and c.2078C>T (p.Thr693Met); three healthy siblings are either wild-type (WT) or heterozygous for the mutations (mut).
Family 2 - proband was a twin with multiple congenital anomalies at birth; these included microcephaly, facial dysmorphisms, digit abnormalities (postaxial absent toes and clinodactyly of the 5th finger), ocular phenotypes (Peters anomaly, bilateral glaucoma, and buphthalmos of the left eye), contractures, neonatal hypertonia, and a sacral dimple. A homozygous missense variant was found in the proband c.2548A>C [p.Thr850Pro]. Both parents are heterozygous for this variant.
Functional studies with skin fibroblasts from the proband in family 1, showed abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells. In a ncapg2 zebrafish model, morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants.; to: Associated with Khan-Khan-Katsanis syndrome (#618460) in OMIM.

PMID: 30609410 - Khan et al. 2019 - 2 unrelated cases with homozygous or compound heterozygous variants in NCAPG2.
Family 1 - female with bilateral postaxial polydactyly on the feet, moderate intellectual disability, ocular anomalies, sensorineural hearing impairment, sleep apnea, and a short stature. Hydronephrosiss was also observed although this improved over time. She was found to have compound-heterozygous missense NCAPG2 mutations, c.1825A>G (p.Lys609Glu) and c.2078C>T (p.Thr693Met); three healthy siblings are either wild-type (WT) or heterozygous for the mutations (mut). Also of note was a heterozygous NPHP1 deletion, a common contributor to nephronophthisis.
Family 2 - proband was a twin with multiple congenital anomalies at birth; these included microcephaly, facial dysmorphisms, digit abnormalities (postaxial absent toes and clinodactyly of the 5th finger), ocular phenotypes (Peters anomaly, bilateral glaucoma, and buphthalmos of the left eye), contractures, neonatal hypertonia, and a sacral dimple. A homozygous missense variant was found in the proband c.2548A>C [p.Thr850Pro]. Both parents are heterozygous for this variant.
Functional studies with skin fibroblasts from the proband in family 1, showed abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells. In a ncapg2 zebrafish model, morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants.
Limb disorders v1.35 NCAPG2 Eleanor Williams commented on gene: NCAPG2: Associated with Khan-Khan-Katsanis syndrome (#618460) in OMIM.

PMID: 30609410 - Khan et al. 2019 - 2 unrelated cases with homozygous or compound heterozygous variants in NCAPG2.
Family 1 - female with bilateral postaxial polydactyly on the feet, moderate intellectual disability, ocular anomalies, sensorineural hearing impairment, sleep apnea, and a short stature. Renal anomalies were also observed although these resolved over time. She was found to have compound-heterozygous missense NCAPG2 mutations, c.1825A>G (p.Lys609Glu) and c.2078C>T (p.Thr693Met); three healthy siblings are either wild-type (WT) or heterozygous for the mutations (mut).
Family 2 - proband was a twin with multiple congenital anomalies at birth; these included microcephaly, facial dysmorphisms, digit abnormalities (postaxial absent toes and clinodactyly of the 5th finger), ocular phenotypes (Peters anomaly, bilateral glaucoma, and buphthalmos of the left eye), contractures, neonatal hypertonia, and a sacral dimple. A homozygous missense variant was found in the proband c.2548A>C [p.Thr850Pro]. Both parents are heterozygous for this variant.
Functional studies with skin fibroblasts from the proband in family 1, showed abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells. In a ncapg2 zebrafish model, morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants.
Limb disorders v1.30 FZD2 Eleanor Williams commented on gene: FZD2: Associated with Omodysplasia 2 (#164745) in OMIM.

Omodysplasia 2:

PMID: 25759469 - Saal et al. 2015 - 1 case - a mother and daughter with omodysplasia were found to have a FZD2 mutation (c.1644G>A, p.Trp548*). The variant was found to have occurred de novo in the mother. The altered protein is still produced in vitro, but is shown to have reduced ability to interact with its downstream target DISHEVELLED. The mother had multiple anomalies, including bilateral cleft lip and cleft palate, short upper extremities, dysmorphic facial features and hypoplastic labia and clitoris. Skeletal X rays of the daughter showed hypoplasia of T11 vertebral body and bilateral dislocation of the radius with short humeri. At 6 years musculoskeletal examination showed primarily rhizomelic shortening of the upper extremities and a mild shortening of the forearms with limited forearm supination/pronation. There was mild fifth finger clinodactyly with no brachydactyly.

Robinow syndrome:

PMID: 29276006 - White et al 2018 - 4 families with at least one individual clinical diagnosed with Robinow or Robinow-like phenotypes and with variants in FZD2 were identified . All showed limb phenotypes including mesomelic limb shortening (3 families, mild in one case), brachdactyly (3 families), proximaly implanted thumbs (1 family), Medelung deformity (1 family).
Limb disorders v0.256 SMO Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'Other' in order to capture variants within this gene in our current tiering pipeline.
Limb disorders v0.256 SMO Rebecca Foulger Mode of inheritance for gene: SMO was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v0.236 SMO Rebecca Foulger Classified gene: SMO as Green List (high evidence)
Limb disorders v0.236 SMO Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green: sufficient unrelated cases of syndactyly and/or preaxial polydactyly in Curry-Jones patients for inclusion on panel.
Limb disorders v0.236 SMO Rebecca Foulger Gene: smo has been classified as Green List (High Evidence).
Limb disorders v0.235 SMO Rebecca Foulger Added comment: Comment on mode of inheritance: Somatic mosaic.
Limb disorders v0.235 SMO Rebecca Foulger Mode of inheritance for gene: SMO was changed from to Other
Limb disorders v0.234 SMO Rebecca Foulger commented on gene: SMO: Added 'somatic' tag.
Limb disorders v0.234 SMO Rebecca Foulger Tag somatic tag was added to gene: SMO.
Limb disorders v0.233 TFAP2B Rebecca Foulger commented on gene: TFAP2B: Confirmed DD-G2P gene for Char syndrome (MIM:169100). Char syndrome is characterized by the triad of patent ductus arteriosus (PDA), facial dysmorphism and hand anomalies including aplasia or hypoplasia of the middle phalanges of the fifth fingers or fifth finger clinodactyly. However, hand anomalies are not reported in all patients. Variants in TFAP2B can also cause PDA without facial dysmorphism or hand anomalies (MIM:617035).
Limb disorders v0.176 SMO Rebecca Foulger commented on gene: SMO: PMID:27236920 (Twigg et al, 2016) analysed 10 unrelated patients with Curry-Jones syndrome including 6 previously reported patients. They identified somatic mosaicism for the identical L412F variant in SMO in 8 of the patients. The patients all showed cutaneous syndactyly and/or preaxial polydactyly.
Limb disorders v0.176 SMO Rebecca Foulger Phenotypes for gene: SMO were changed from Polydactyly to Polydactyly; Curry-Jones syndrome, somatic mosaic, MIM:601500; Cutaneous syndactyly; Preaxial polydactyly
Limb disorders v0.175 SMO Rebecca Foulger Publications for gene: SMO were set to
Limb disorders v0.174 SMO Rebecca Foulger Added comment: Comment on mode of pathogenicity: Somatic mosaicism.
Limb disorders v0.174 SMO Rebecca Foulger Mode of pathogenicity for gene: SMO was changed from None to Other
Limb disorders v0.173 SMO Rebecca Foulger commented on gene: SMO
Limb disorders v0.173 SMO Rebecca Foulger Tag mosaicism tag was added to gene: SMO.
Limb disorders v0.146 SMOC1 Eleanor Williams commented on gene: SMOC1
Limb disorders SMO Ellen McDonagh Added gene to panel
Limb disorders SMOC1 Ellen McDonagh classified SMOC1 as Green List (high evidence)