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| Limb disorders v9.8 | LRP4 | Ida Ertmanska commented on gene: LRP4: Comment on mode of inheritance: There are numerous individuals reported in literature with biallelic LRP4 variants, presenting with either Sclerosteosis 2 or Cenani-Lenz syndactyly syndrome, both of which affect distal limbs (polydactyly, phalangeal synostosis, syndactyly, oligodactyly). There are also two individuals reported to date with limb disorders and heterozygous missense LRP4 variants - one of which was detected by targeted sequencing of LRP4 (other genes like SOST are known to cause a similar phenotype). In addition, heterozygous carriers of LRP4 missense variants in recessive pedigrees are always unaffected. Based on available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.8 | LRP4 | Ida Ertmanska Phenotypes for gene: LRP4 were changed from Cenani-Lenz syndactyly syndrome, OMIM:212780; CLSS; Cenani syndactyly; Cenani-Lenz syndactyly; Syndactyly type 7; Polydactyly to Cenani-Lenz syndactyly syndrome, OMIM:212780; Cenani-Lenz syndactyly syndrome, MONDO:0008931; Sclerosteosis 2, OMIM:614305; sclerosteosis 2, MONDO:0013679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.7 | LRP4 | Ida Ertmanska Publications for gene: LRP4 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.6 | LRP4 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: LRP4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
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| Limb disorders v9.6 | LRP4 | Ida Ertmanska edited their review of gene: LRP4: Changed publications to: 21471202, 26751728, 30077757, 34857885, 35052419, 38013226, https://doi.org/10.1186/s43042-025-00783-837563890 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
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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. 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. |
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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. 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.; 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 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. |
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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. 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. 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.; 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 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. |
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| Limb disorders v9.6 | LRP4 | Ida Ertmanska reviewed gene: LRP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21471202, 37563890; Phenotypes: Cenani-Lenz syndactyly syndrome, OMIM:212780, Sclerosteosis 2, OMIM:614305; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v2.79 | LRP4 | Arina Puzriakova commented on gene: LRP4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v2.74 | LRP4 | Eleanor Williams commented on gene: LRP4: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v2.73 | LRP4 | Eleanor Williams Mode of inheritance for gene LRP4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v2.72 | LRP4 | Eleanor Williams Phenotypes for gene: LRP4 were changed from Cenani-Lenz syndactyly syndrome, 212780; CLSS; Cenani syndactyly; Cenani-Lenz syndactyly; Syndactyly type 7; Polydactyly to Cenani-Lenz syndactyly syndrome, OMIM:212780; CLSS; Cenani syndactyly; Cenani-Lenz syndactyly; Syndactyly type 7; Polydactyly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v0.143 | LRP4 | Eleanor Williams commented on gene: LRP4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders | LRP4 | Louise Daugherty classified LRP4 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders | LRP4 | Louise Daugherty edited their review of LRP4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders | LRP4 | Louise Daugherty commented on LRP4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders | LRP4 | Louise Daugherty Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||