Skeletal dysplasia

Gene: LRP4

Green List (high evidence)

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, with skeletal features such as bone overgrowth, phalangeal synostosis, shortened and disorganized metacarpals. There are also two individuals reported to date with skeletal and/or limb disorders, heterozygous for 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.

Created: 7 Oct 2026, 1:08 p.m. | Last Modified: 7 Oct 2026, 1:08 p.m.

Panel Version: 10.13

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.

Created: 7 Oct 2026, 12:58 p.m. | Last Modified: 7 Oct 2026, 12:58 p.m.

Panel Version: 10.13

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cenani-Lenz syndactyly syndrome, OMIM:212780; Cenani-Lenz syndactyly syndrome, MONDO:0008931; Sclerosteosis 2, OMIM:614305; sclerosteosis 2, MONDO:0013679

Publications

• 21471202
• 26751728
• 30077757
• 34857885
• 35052419
• 38013226
• https://doi.org/10.1186/s43042-025-00783-837563890

Green List (high evidence)

Other sclerosing bone disorders gp of SD, polydactyly-syndactyly-triphalangism SD gp. Several cases; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Cenani-Lenz syndactyly syndrome 212780; Sclerosteosis 2 614305

I don't know

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: LRP4; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Comment when marking as ready: Numerous variants reported in Cenani-Lenz syndactyly syndrome 212780, at least two variants reported in Sclerosteosis 2 614305

Created: 12 Jul 2016, 9:53 a.m.

Comment on phenotypes: Variants also reported in Myasthenic syndrome, congenital, 17 616304

Created: 12 Jul 2016, 9:52 a.m.

Green List (high evidence)

Tier 2

Created: 17 Jun 2016, 8:05 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
?Myasthenic syndrome, congenital, 17 616304; Cenani-Lenz syndactyly syndrome 212780; Sclerosteosis 2 614305

Variants in this GENE are reported as part of current diagnostic practice