Knuckle pads, deafness AND leukonychia syndrome: genes and variants

Genes linked to Knuckle pads, deafness AND leukonychia syndrome

• GJB2: Gap junction beta-2 protein

  Its connexin 26 channels support potassium and metabolite recycling within the cochlea and communication across epithelial gap junctions. Biallelic pathogenic variants are among the most common causes of congenital nonsyndromic hearing loss, while dominant variants can cause syndromic deafness with skin disease.

  10 disease-causing and 1 uncertain variants in GJB2 are linked to Knuckle pads, deafness AND leukonychia syndrome.

Where Knuckle pads, deafness AND leukonychia syndrome variants cluster

• GJB2 Transmembrane (positions 136–156): 3 of 10 disease-causing changes, 3.2× more than its size predicts.

Known disease-causing variants in Knuckle pads, deafness AND leukonychia syndrome

Which prediction tools work for Knuckle pads, deafness AND leukonychia syndrome

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

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 93 out of 100
• CADD: 91 out of 100
• phyloP: 76 out of 100

Same protein, different disease

• Autosomal recessive nonsyndromic hearing loss 4 is also caused by GJB2 variants; they fall partly in the same places as the Knuckle pads, deafness AND leukonychia syndrome variants (38 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by GJB2 variants; they fall partly in the same places as the Knuckle pads, deafness AND leukonychia syndrome variants (28 disease-causing).
• Rare genetic deafness is also caused by GJB2 variants; they fall partly in the same places as the Knuckle pads, deafness AND leukonychia syndrome variants (25 disease-causing).
• Mutilating keratoderma is also caused by GJB2 variants; they fall partly in the same places as the Knuckle pads, deafness AND leukonychia syndrome variants (15 disease-causing).
• Ichthyosis, hystrix-like, with hearing loss is also caused by GJB2 variants; they fall mostly in different places as the Knuckle pads, deafness AND leukonychia syndrome variants (13 disease-causing).

Diseases related to Knuckle pads, deafness AND leukonychia syndrome

• Autosomal recessive nonsyndromic hearing loss 4, also linked to GJB2
• Noonan syndrome, also linked to GJB2
• Rare genetic deafness, also linked to GJB2
• Autosomal dominant nonsyndromic hearing loss, also linked to GJB2
• Nonsyndromic genetic hearing loss, also linked to GJB2
• Hearing loss, also linked to GJB2
• Monogenic hearing loss, also linked to GJB2
• Mutilating keratoderma, also linked to GJB2
• Autosomal dominant keratitis-ichthyosis-hearing loss syndrome, also linked to GJB2
• Ichthyosis, hystrix-like, with hearing loss, also linked to GJB2
• Palmoplantar keratoderma-deafness syndrome, also linked to GJB2
• Deafness, also linked to GJB2

Frequently asked questions

Which genes are linked to Knuckle pads, deafness AND leukonychia syndrome?

In CATVariant, Knuckle pads, deafness AND leukonychia syndrome is linked to 1 analyzed protein: GJB2 (Gap junction beta-2 protein).

How many genetic variants are linked to Knuckle pads, deafness AND leukonychia syndrome?

14 variants: 10 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1 are of uncertain significance or have conflicting reports.

Which uncertain variants in Knuckle pads, deafness AND leukonychia syndrome 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 Knuckle pads, deafness AND leukonychia syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 10 disease-causing and 9 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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