ExperimentName: Targeted disruption of Lrp5 in mice

NonHumanModel: Mus musculus

GeneAlteration: Model animals were subjected to targeted disruption of Lrp5 by inserting an IRES-LacZ-Neomycin cassette to replace the region encoding the extracellar domain, starting at amino acid 373.

ModelPhenotype: HP:0004349 (Reduced bone mineral density), HP:0410280 (Pediatric onset), decreased osteoblast proliferation, HP:0007968 (Remnants of the hyaloid vascular system), failure of macrophage-mediated endothelial cell apoptosis

HumanPhenotype: HP:0000939 (Osteoporosis), HP:0011463 (Childhood onset), HP:0000541 (Retinal detachment), HP:0007968 (Remnants of the hyaloid vascular system), HP:0008046 (Abnormal retinal vascular morphology), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0020110 (Bone fracture), HP:0000938 (Osteopenia), HP:0000926 (Platyspondyly)

ModelEvidence: Model animals subjected to targeted disruption of Lrp5 resembled human patients in that they exhibited reduced bone mineral density in the post-natal stage (Figs. S2, 3A), decreased osteoblast proliferation (Fig. 4), delayed ossification (Fig. 5), and remnants of the hyaloid vascular system due to failure of macrophage-mediated endothelial cell apoptosis (Fig. 8).

ModelVariant: The model features disruption of the wild-type Lrp5 gene, but not a mutation equivalent to a human variant.

PMID: 11956231

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 25711638

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 25920554

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

Selection B - Gene function is consistent with phenotype.

Title: LRP5 is a canonical Wnt signaling pathway co-receptor.

GOterm: GO:0060070 (canonical Wnt signaling pathway)

FunctionalEvidence: Exogenous LRP5 expression in NIH3T3 cells increases the activity of the canonical Wnt signaling transcription factor LEF1 only when combined with exogenous expression of the Wnt-1 ligand in a separate population of cells grown in co-culture (Figure 1). This function is related to the phenotype in that canonical Wnt signaling is known to mediate bone formation.

FunctionalHPO: HP:0004349 (reduced bone mineral density), osteoporosis (HP:0000939), HP:0020110 (bone fracture)

PMID: 11336703

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

Case#: Narumi_2010_patient_3, male, age 10 years at report, national origin listed as Japanese

CasePresentingHPOs: HP:0000939 (Osteoporosis), HP:0011463 (Childhood onset), HP:0000572 (Visual loss), HP:0000639 (Nystagmus), HP:0000541 (Retinal detachment), HP:0004327 (Abnormal vitreous humor morphology, vascular remnants), HP:0008046 (Abnormal retinal vascular morphology), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0020110 (Bone fracture), HP:0001388 (Joint laxity), HP:0001252 (Hypotonia), HP:0007083 (Hyperactive patellar reflex), HP:0000938 (Osteopenia), HP:0000926 (Platyspondyly)

CaseHPOFreeText: The patient has been diagnosed with osteoporosis-pseudoglioma syndrome. In one eye, peripheral retinal vessel was insufficiently developed and optic disc traction was observed. Complete blindness occurred at age 3 due to deterioration of abnormal vascular growth in one eye.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No deformity of long bones was observed.

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 locus.

CaseMethod1: Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1145C>T (p.Pro382Leu) and NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) variants in the compound heterozygous state.

ClinVar: 40288, 40290

gnomAD: The NM_002335.4(LR5P5):c.1145C>T (p.Pro382Leu) variant is found in gnomAD v2.1.1 at a frequency of 0.000008800 (1/113634) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68153913-C-T The NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LR5P5):c.1145C>T (p.Pro382Leu) is a missense variant that does not have evidence of impact on the protein product, although it has been observed in the compound heterozygous state in an apparently unrelated proband from this same study. NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) is a nonsense variant in exon 23 of 23 and is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 5% of the protein product.

CaseAddInfo: The patient has 2 apparently unaffected parents, one of whom carries the p.Arg1534Ter variant (mother), and one of whom carries the p.Pro382Leu variant (father)

CasePMIDs: N/A

Case#: Narumi_2010_patient_4, male, age 7 years at report, national origin listed as Japanese

CasePresentingHPOs: HP:0000555 (Leukocoria, bilateral), HP:0000541 (Retinal detachment), HP:0007968 (Remnants of the hyaloid vascular system), HP:0000529 (Progressive visual loss), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0002757 (Recurrent fractures), HP:0000938 (Osteopenia), HP:0000926 (Platyspondyly), HP:0000774 (Narrow chest), HP:0000883 (Thin ribs), HP:0003100 (Slender long bone), HP:0004322 (Short stature), HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The patient has been diagnosed with osteoporosis-pseudoglioma syndrome. Minor breathing problems were observed at birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 locus and the surrounding genomic region.

CaseMethod1: Oligonucleotide tiling microarray analyses in the 600-kb region around LRP5.

CaseMethod2: Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to oligonucleotide tiling microarray analyses in the 600-kb region around LRP5, and Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1584+1G>A and NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variants in the compound heterozygous state.

ClinVar: 40291, 40292

gnomAD: The NM_002335.4(LRP5):c.1584+1G>A and NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variants were not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1584+1G>A is a canonical splice site variant that triggers the inclusion of 63 aberrant base pairs between exons 7 and 8 (Figure 3A). NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del is a 7.2-kb microdeletion that removes the final two exons of LRP5, disrupting the C-terminal 7% of the protein product.

CaseAddInfo: The patient has 2 apparently unaffected parents, one of whom carries the NM_002335.4(LRP5):c.1584+1G>A variant (mother) and one of whom carries the NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variant (father). Both parents and a carrier sister had significantly decreased bone mineral density, and the father had multiple reported long bone fractures.

CasePMIDs: N/A

PMID: 20034086

Case#: Gong_2001_Proband_2, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant in the homozygous state.

ClinVar: 6269

gnomAD: The NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) is a nonsense variant in exon 6 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~74% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_4, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) variant in the homozygous state.

ClinVar: 6271

gnomAD: The NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) is a nonsense variant in exon 10 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~56% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_5, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant in the homozygous state.

ClinVar: 6272

gnomAD: The NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) is a nonsense variant in exon 12 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~47% of the protein product. It appears to be stable at the protein level but is not secreted in the exogenous expression system, consistent with loss-of-function rather than dominant negative effect.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_3, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant in the homozygous state.

ClinVar: 6270

gnomAD: The NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1468del (p.Asp490fs) is a frameshift variant in exon 7 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~70% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Selection A- Gene is expressed in tissues relevant to disease:

ExperimentName: Lrp5 expression in mouse embryonic osteoblasts coincides with bone formation / ossification.

TissueExpression: UBERON:0003129 (skull)

ExpressionEvidence: In situ hybridization first detects Lrp5 expression in the mouse clavicle at embryonic day 14, when membranous ossification is occurring (Fig. 3A) and when other markers of skeletal differentiation are present. Lrp5 is also seen at embryonic day 16.5 in osteoblasts along the endosteal surface of the developing humerus, but not in growth plates (Fig. 3B). Finally, osteoblasts in the developing calvaria (skull) exhibit Lrp5 expression as well (Fig. 3C). All three observations support a role for LRP5 in bone formation, which is consistent with the phenotype of osteoporosis in patients with biallelic loss-of-function.

Case#: Gong_2001_Proband_6, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.3804del (p.Glu1270fs) variant in the homozygous state.

ClinVar: 6273

gnomAD: The NM_002335.4(LRP5):c.3804del (p.Glu1270fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.3804del (p.Glu1270fs) is a frameshift variant in exon 18 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~21% of the protein product. It appears to be stable at the protein level but is not secreted in the exogenous expression system, consistent with loss-of-function rather than dominant negative effect.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_1, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) variant in the homozygous state.

ClinVar: 6268

gnomAD: The NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) is a nonsense variant in exon 1 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~99% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

ExperimentName: LRP5 inhibition using a dominant negative construct blocks bone accrual in mouse calvarial explant culture.

NonPatientCell: CL:0001035 (bone cell, specifically mouse calvarial explant cultures)

GeneFunction: GO:0098868 (bone growth)

GeneAlteration: Calvarial explant cultures from mice were treated with conditioned media from cells exogenously secreting either wild-type LRP5 or dominant negative LRP5deltaTM.

FunctionalEvidence: Bone accrual / thickness decreases significantly at multiple points in mouse calvarial (skull) explants treated with LRP5deltaTM relative to LRP5-WT (Figure 7).

FAVariants: LRP5 function was attenuated using an artificial dominant negative mutant while a human variant was not introduced into the LRP5 gene.

PMID: 11719191

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 15908424

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

ExperimentName: LRP5 interacts with SOST

InteractingGene: SOST (HGNC:13771)

InteractionType: Physical

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of an exogenously expressed IgG-SOST fusion protein from conditioned medium pulled down the Myc-tagged soluble portion of LRP5 (and LRP6, but not control targets) (Fig. 3A). Subsequent experiments identified SOST as an LRP5/6 antagonist that attenuates canonical Wnt signaling through these receptors (Figure 4).

Case#: Qin_2005_Patient_7, gender not reported, age 1 year at report, national origin reported as Japanese

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density), HP:0008052 (Retinal fold), HP:0000541 (Retinal detachment)

CaseHPOFreeText: The patient has been diagnosed with FEVR. Retinal folds and later complete retinal detachment were present in both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 and FZD4 loci.

CaseMethod1: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci.

Variant: The patient harbors the NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) and NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) variants in the compound heterozygous state.

ClinVar: 2137179

CAID: CA224268235

gnomAD: The NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) variant was not found in gnomAD v2.1.1. The NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) variant was found in gnomAD v2.1.1 at a frequency of 0.00001759 (2/113686) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68170970-C-T?dataset=gnomad_r2_1

VariantEvidence: NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) and NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) are missense variants in exons 8 and 9, respectively, out of 23. Neither has evidence of an impact on the gene product.

CaseAddInfo: The proband's parents are carriers for p.Phe617Cys (maternal) and p.Thr535Met (paternal). The father was apparently unaffected in terms of retinal change and reduced bone mass. The mother was subclinically affected unilaterally with localized retinal avascularization with tortuosity of the retinal vessels and reduced bone density.

CasePMIDs: N/A

Case#: Qin_2005_patient_8, female, age 14 years at report, national origin reported as Japanese

CasePresentingHPOs: HP:0001103 (Abnormal macular morphology), HP:0004349 (Reduced bone mineral density), HP:0003621 (Juvenile onset)

CaseHPOFreeText: The patient has been diagnosed with simplex FEVR, with bilateral dragged macula.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 and FZD4 loci.

CaseMethod1: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci.

Variant: The patient harbors the NM_002335.4(LRP5):c.804_813del (p.Gly269fs) and NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) variants in the compound heterozygous state.

ClinVar: 6295, 6294

gnomAD: The NM_002335.4(LRP5):c.804_813del (p.Gly269fs) variant was not found in gnomAD v2.1.1. The NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) variant was found in gnomAD v2.1.1 at a frequency of 0.00002644 (3/113484) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68174018-G-A

VariantEvidence: NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) is a missense variant in exon 9 that does not have experimental evidence of an impact on the protein product. NM_002335.4(LRP5):c.804_813del (p.Gly269fs) is a frameshift variant in exon 4 of 23 that is predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 83% of the protein product.

CaseAddInfo: The patient has no family history of FEVR in her parents and brother, although bone mineral density was reduced in both parents. The mother is a carrier for p.Gly610Arg, while the father and brother are heterozygous for p.G268fsX272.

CasePMIDs: N/A

PMID: 15981244

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 15346351

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

FamilyLabel: Jiao_2004_Three_Families

Family#PresentingHPOs: N/A

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with familial exudative vitreoretinopathy segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Although bone density measurements are not available, at least two of the affected individuals lack bone fractures in the first three decades of life, distinguishing their phenotype from osteoporosis-pseudoglioma syndrome.

CountryOrigin: The three families are reportedly of European descent.

Ethnicity: Not specifically described

Race: The three families are reportedly of European descent.

Family#PreviousTesting: Candidate-locus-directed linkage analysis focused on chromosome 11q, with maximum LOD score of 3.6 associated with the D11S987 microsatellite marker linked to a 311-Mb region.

Family#Method1: Genome-wide linkage analysis

Family#Method2: Sanger sequencing of the candidate gene LRP5

Family#GenotypingMethod: Candidate-locus-directed linkage analysis was initially performed on all three families, focused on chromosome 11q, with maximum LOD score of 3.6 associated with the D11S987 microsatellite marker linked to a 311-Mb region. Sanger sequencing of the candidate gene LRP5 locus was subsequently performed.

Affected: 6 genotyped

Unaffected: 0 genotyped (although 6 unaffected individuals are genotyped but ineligible because they are from previous generations that lack affected members.

Segregations: 3 segregations are shown by the three pedigrees in Figure 1.

PublishedLOD: 3.6

eLOD: N/A

AddSegregationInfo: While none of the families would individually be eligible for inclusion in segregation evidence using an estimated LOD score, the published LOD score is sufficient for their inclusion.

ProbandLabel: Jiao_2004_Family_68001_Proband, Jiao_2004_Family_68002_Proband, Jiao_2004_Family_68003_Proband

Variant: The affected family members harbor one of the following three variants in homozygous state; NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly), NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys), or NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln)

ClinVar: 6290, 6291, 6289

gnomAD: NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly) was not found in gnomAD v2.1.1. NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys) is present in gnomAD v2.1.1. at a frequency of 0.00001760 (2/113626) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68204455-G-A?dataset=gnomad_r2_1 NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln) was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly) is a missense variant in exon 10 of 23 that does not have experimental evidence of impact on the protein product. NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys) is a missense variant in exon 19 of 23 that does not have experimental evidence of impact on the protein product. NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln) is a missense variant in exon 8 of 23 that does not have experimental evidence of impact on the protein product.

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

PMID: 27228167

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

Case#: Zhang_2016_Pedigree_C_Proband_C001, male, 32 years old at time of report, national origin reported to be Indian.

CasePresentingHPOs: HP:0007770 (Hypoplasia of the retina), HP:0007685 (Peripheral retinal avascularization), HP:0030666 (Retinal neovascularization)

CaseHPOFreeText: The proband has been diagnosed with familial exudative vitreoretinopathy (FEVR).

CaseNotHPOs: N/A

CaseNotHPOFreeText: Premature birth, maternal drug intake during pregnancy, or other ocular disease associated with osteopenia / osteoporosis

CasePreviousTesting: Whole exome sequencing was performed, ruling out variations in the NDP, FZD4, TSPAN12, and ZNF408 loci.

CaseMethod1: Whole exome sequencing

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Whole exome sequencing was performed, ruling out variations in the NDP, FZD4, TSPAN12, and ZNF408 loci. This was followed by Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) variant in the homozygous state.

ClinVar: 1477058

gnomAD: The NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) variant was found in gnomAD v2.1.1 at a maximum allele frequency of 0.000008796 (1/113688) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68174060-C-T

VariantEvidence: NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) is a missense variant in exon 9 out of 23 that has evidence of a functional impact on the protein product. The variant was expressed in STF cells harboring a luciferase reporter construct, showing a reduced (hypomorphic) ability to induce luciferase reporter activity compared with wild-type control LRP5. (Figure 3).

CaseAddInfo: The proband shares the homozygous genotype with his affected mother, although the father's genotype is not available. The asymptomatic uncle and aunt are heterozygous.

CasePMIDs: N/A

PMID: 8659519

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

FamilyLabel: Gong_1996_Three_Families

Family#PresentingHPOs: N/A

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The three families are reportedly of Finnish, South African, and Italian descent, respectively.

Ethnicity: Not specifically described

Race: Not specifically described

Family#PreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1).

Family#Method1: Genome-wide linkage analysis

Family#Method2: Further linkage analysis with additional markers around a strong candidate marker

Family#GenotypingMethod: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (Fig. 1). Further linkage testing with additional markers around a strong candidate marker yielded a LOD score of 5.99 for Dl1S987. The region consisted of a 13-cM genetic interval on chromosome 11q12-13.

Affected: 7 genotyped

Unaffected: 5 genotyped

Segregations: 5 segregations are shown by the three pedigrees in Figure 1.

PublishedLOD: 5.99 (for the Dl1S987 marker)

eLOD: N/A

AddSegregationInfo: While only one of the families would individually be eligible for inclusion in segregation evidence using an estimated LOD score, the published LOD score is sufficient for their inclusion.

ProbandLabel: N/A (Probands have been incorporated into the later Gong 2001 publication and will be scored in connection to that article.)

Variant: The affected family members harbor three different variants, each in the homozygous state.

ClinVar: N/A

gnomAD: N/A

VariantEvidence: N/A

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

Case#: Streeten_2010_patient_A1, male, age 8 years at report, ethnicity reported as Conservative Mennonite from Pennsylvania

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0200026 (Ocular pain), HP:0004322 (Short stature), HP:0000541 (Retinal detachment), HP:0002757 (Recurrent fractures), HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The patient has been diagnosed with osteoporosis-pseudoglioma syndrome, and had positive responses to bisphosphonates such as pamidronate.

CaseNotHPOs: HP:0001249 (Intellectual disability), HP:0007832 (Pigmentation of the sclera), HP:0011729 (Abnormality of joint mobility)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 locus.

CaseMethod1: Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1275G>A (p.Trp425Ter) variant in the homozygous state.

ClinVar: 1459979

gnomAD: The NM_002335.4(LRP5):c.1275G>A (p.Trp425Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1275G>A (p.Trp425Ter) is a nonsense variant in exon 6 of 23 that is predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 74% of the protein product.

CaseAddInfo: The patient is part of a large multi-generation extended family with multiple affected homozygous and compound heterozygous members (Figure 1).

CasePMIDs: N/A

PMID: 18602879

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 12579474

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 33531964

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

Does model have relevance to bone density or retinal function?

PMID: 16252235

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 15024691

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 21407258

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID:34743040

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.