Worth disease: genes and variants

Genes linked to Worth disease

• LRP5: Low-density lipoprotein receptor-related protein 5

  It transduces canonical Wnt signals that strongly regulate bone formation and also contributes to retinal vascular development. Loss-of-function variants cause osteoporosis-pseudoglioma syndrome, while activating variants cause high-bone-mass disorders.

  9 disease-causing and 152 uncertain variants in LRP5 are linked to Worth disease.

Where Worth disease variants cluster

• LRP5 LDL-receptor class B 4 (positions 207–247): 3 of 9 disease-causing changes, 13.1× more than its size predicts.
• LRP5 Beta-propeller 2 (positions 341–602): 3 of 9 disease-causing changes, 2.0× more than its size predicts.

Known disease-causing variants in Worth disease

Which prediction tools work for Worth disease

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 96 out of 100
• CADD: 94 out of 100
• phyloP: 87 out of 100

Same protein, different disease

• Exudative vitreoretinopathy 4 is also caused by LRP5 variants; they fall mostly in different places as the Worth disease variants (17 disease-causing).
• Osteoporosis with pseudoglioma is also caused by LRP5 variants; they fall mostly in different places as the Worth disease variants (9 disease-causing).
• Autosomal dominant osteopetrosis 1 is also caused by LRP5 variants; they fall mostly in different places as the Worth disease variants (6 disease-causing).
• Polycystic liver disease 4 with or without kidney cysts is also caused by LRP5 variants; they fall mostly in different places as the Worth disease variants (6 disease-causing).

Diseases related to Worth disease

• Osteogenesis imperfecta, also linked to LRP5
• Exudative vitreoretinopathy 4, also linked to LRP5
• Osteoporosis with pseudoglioma, also linked to LRP5
• Osteoporosis, also linked to LRP5
• Autosomal dominant osteopetrosis 1, also linked to LRP5
• Polycystic liver disease 4 with or without kidney cysts, also linked to LRP5
• Bone mineral density quantitative trait locus 1, also linked to LRP5
• Postmenopausal osteoporosis, also linked to LRP5
• Skeletal dysplasia, also linked to LRP5
• Autosomal dominant polycystic liver disease, also linked to LRP5
• Familial exudative vitreoretinopathy, also linked to LRP5

Frequently asked questions

Which genes are linked to Worth disease?

In CATVariant, Worth disease is linked to 1 analyzed protein: LRP5 (Low-density lipoprotein receptor-related protein 5).

How many genetic variants are linked to Worth disease?

162 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 152 are of uncertain significance or have conflicting reports.

Which uncertain variants in Worth disease look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Worth disease?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 8 disease-causing and 14 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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