Perrault syndrome: genes and variants

Genes linked to Perrault syndrome

• HSD17B4: Peroxisomal multifunctional enzyme type 2

  A peroxisomal multifunctional enzyme that carries out two steps in fatty-acid beta-oxidation. It processes straight-chain and branched fatty acids as well as bile-acid intermediates, and loss of the protein causes D-bifunctional protein deficiency.

  28 disease-causing and 194 uncertain variants in HSD17B4 are linked to Perrault syndrome.

• FBN1: Fibrillin-1

  Its fibrillin-1 microfibrils provide mechanical support to elastic tissues and regulate local availability of growth factors such as TGF-beta. Pathogenic variants cause Marfan syndrome and related fibrillinopathies affecting the aorta, skeleton, eyes, skin, and lungs.

  1 disease-causing and 0 uncertain variants in FBN1 are linked to Perrault syndrome.

• CLDN14: Claudin-14

  1 disease-causing and 0 uncertain variants in CLDN14 are linked to Perrault syndrome.

Known disease-causing variants in Perrault syndrome

Uncertain variants in Perrault syndrome that look disease-causing

Which prediction tools work for Perrault syndrome

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

• CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 98 out of 100
• ESM1b (LLR): 97 out of 100
• PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• SIFT: 85 out of 100
• phyloP: 67 out of 100

Same protein, different disease

• Bifunctional peroxisomal enzyme deficiency is also caused by HSD17B4 variants; they fall partly in the same places as the Perrault syndrome variants (33 disease-causing).
• Marfan syndrome is also caused by FBN1 variants; they fall mostly in different places as the Perrault syndrome variants (434 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by FBN1 variants; they fall mostly in different places as the Perrault syndrome variants (406 disease-causing).
• Isolated thoracic aortic aneurysm is also caused by FBN1 variants; they fall mostly in different places as the Perrault syndrome variants (12 disease-causing).
• Marfan syndrome/loeys-dietz syndrome/familial thoracic aortic aneurysms and dissections is also caused by FBN1 variants; they fall mostly in different places as the Perrault syndrome variants (10 disease-causing).
• Acromicric dysplasia is also caused by FBN1 variants; they fall mostly in different places as the Perrault syndrome variants (6 disease-causing).

Diseases related to Perrault syndrome

• Familial thoracic aortic aneurysm and aortic dissection, also linked to FBN1
• Marfan syndrome, also linked to FBN1
• Autosomal recessive nonsyndromic hearing loss 4, also linked to CLDN14
• Bifunctional peroxisomal enzyme deficiency, also linked to HSD17B4
• Hearing loss, also linked to CLDN14
• Connective tissue disorder, also linked to FBN1
• Familial aortopathy, also linked to FBN1
• Isolated thoracic aortic aneurysm, also linked to FBN1
• Marfan syndrome/loeys-dietz syndrome/familial thoracic aortic aneurysms and dissections, also linked to FBN1
• Deafness, also linked to CLDN14
• Ectopia lentis 1, isolated, autosomal dominant, also linked to FBN1
• Acromicric dysplasia, also linked to FBN1

Frequently asked questions

Which genes are linked to Perrault syndrome?

In CATVariant, Perrault syndrome is linked to 3 analyzed proteins: HSD17B4 (Peroxisomal multifunctional enzyme type 2), FBN1 (Fibrillin-1) and CLDN14 (Claudin-14).

How many genetic variants are linked to Perrault syndrome?

261 variants: 30 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 194 are of uncertain significance or have conflicting reports.

Which uncertain variants in Perrault syndrome look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example HSD17B4 A196V, HSD17B4 N98S and HSD17B4 L405F. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Perrault syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 29 disease-causing and 23 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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