Identification of clinically useful predictive genetic variants in pachyonychia congenita

Samuelov, Liat; Sarig, Ofer; Adir, Noam; Pavlovsky, Mor; Smith, Frances J.D.; Schwartz, Janice; Hansen, D.; Sprecher, Eli

doi:10.1111/ced.14569

Cited by 9 publications

(5 citation statements)

References 25 publications

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“…The c.275A>G (p.N92S) KRT17 mutation, which results in a combined phenotype of both PC and HS, as described above, is the most common PC ‐ associated KRT17 mutation 13,24 and is responsible for 40% of cases of KRT17 ‐associated PC. Given the fact that abnormal NOTCH signalling has been found to contribute to the pathogenesis of both familial and sporadic HS, 25,26 we ascertained the effect of the PC‐causing KRT17 variant c.275A>G on NOTCH signalling.…”

Section: Resultsmentioning

confidence: 96%

“…No mutations were identified in genes previously reported to be associated with HS, including PSEN, PSENEN and NCSTN (not shown). [1][2][3][4][5] Abnormal NOTCH signalling associated with a pachyonychia congenita-causing KRT17 variant The c.275A>G (p.N92S) KRT17 mutation, which results in a combined phenotype of both PC and HS, as described above, is the most common PC-associated KRT17 mutation 13,24 and is responsible for 40% of cases of KRT17-associated PC. Given the fact that abnormal NOTCH signalling has been found to contribute to the pathogenesis of both familial and sporadic HS, 25,26 we ascertained the effect of the PC-causing KRT17 variant c.275A>G on NOTCH signalling.…”

Section: Resultsmentioning

confidence: 99%

“…Using direct sequencing, we identified a previously reported heterozygous missense mutation in KRT17 , 13 c.275A>G, in all affected family members for whom DNA was available. The mutation is predicted to result in the substitution of asparagine with serine (p.N92S) 24 . The mutation was not identified in DNA obtained from an unaffected family member for whom DNA was available (I‐2, Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…The mutation is predicted to result in the substitution of asparagine with serine (p.N92S). 24 The mutation was not identified in DNA obtained from an unaffected family member for whom DNA was available (I-2, Figure 1a). No mutations were identified in genes previously reported to be associated with HS, including PSEN, PSENEN and NCSTN (not shown).…”

Section: Resultsmentioning

confidence: 99%

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Coexistence of pachyonychia congenita and hidradenitis suppurativa: more than a coincidence

Pavlovsky

Peled

Sarig

et al. 2022

British Journal of Dermatology

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Background The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. Objectives To determine the genetic defect underlying the coexistence of PC and HS in a large kindred, to delineate a pathophysiological signalling defect jointly leading to both phenotypes, and to estimate the prevalence of HS in PC. Methods We used direct sequencing and a NOTCH luciferase reporter assay to characterize the pathophysiological basis of the familial coexistence of HS and PC. A questionnaire was distributed to patients with PC registered with the International Pachyonychia Congenita Research Registry (IPCRR) to assess the prevalence of HS among patients with PC. Results Direct sequencing of DNA samples obtained from family members displaying both PC and HS demonstrated a missense variant (c.275A>G) in KRT17, encoding keratin 17. Abnormal NOTCH signalling has been suggested to contribute to HS pathogenesis. Accordingly, the KRT17 c.275A>G variant resulted in a significant decrease in NOTCH activity. To ascertain the clinical importance of the association of HS with PC, we distributed a questionnaire to all patients with PC registered with the IPCRR. Seventy-two of 278 responders reported HSassociated clinical features (25Á9%). Disease-causing mutations in KRT17 were most prevalent among patients with a dual phenotype of PC and HS (43%). Conclusions The coexistence of HS and KRT17-associated PC is more common than previously thought. Impaired NOTCH signalling as a result of KRT17 mutations may predispose patients with PC to HS.What is already known about this topic?• The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. • However, the pathomechanism underlying this association and its true prevalence are unknown.What does this study add?• A dual phenotype consisting of PC and HS was found to be associated with a pathogenic variant in KRT17. • This variant was found to affect NOTCH signalling, which has been previously implicated in HS pathogenesis.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Coexistence of pachyonychia congenita and hidradenitis suppurativa: more than a coincidence

Pavlovsky

Peled

Sarig

et al. 2022

British Journal of Dermatology

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“…The full-length amino acid sequence of the human CLDN1 protein (NP_069924.1) was obtained from NCBI (https://www.ncbi.nlm.nih. gov) and used for three-dimensional structure prediction as previously described (Samuelov et al, 2021).…”

Section: Protein Modelingmentioning

confidence: 99%

Autosomal recessive congenital ichthyosis caused by a pathogenic missense variant in CLDN1

Mohamad

Samuelov

Assaf

et al. 2022

American J of Med Genetics Pt A

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Autosomal recessive congenital ichthyosis (ARCI) refers to a large and genetically heterogenous group of non‐syndromic disorders of cornification featuring diffuse scaling. Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) syndrome is a rare autosomal recessive syndromic form of ichthyosis. The disease usually results from premature termination codon‐causing pathogenic variants in CLDN1 encoding CLAUDIN‐1 (CLDN1). We used whole exome sequencing (WES), Sanger sequencing, 3D protein modeling, Western blotting, and immunofluorescence confocal microscopy to delineate the genetic basis of ichthyosis in two siblings with ichthyosis but no other ectodermal abnormalities. One of the two siblings underwent liver transplantation in early childhood due to biliary atresia. Both patients were found to carry a homozygous missense pathogenic variant, c.242G>A (p.Arg81His), in CLDN1. The variant resulted in decreased CLDN1 expression in patient skin. 3D protein modeling predicted that p.Arg81His induces deleterious conformational changes. Accordingly, HaCaT cells transfected with a construct expressing the mutant CLDN1 cDNA featured decreased levels and mislocation of CLDN1 as compared with cells expressing the wildtype cDNA. In conclusion, we describe the first pathogenic missense variant in CLDN1 shown to result in ARCI.

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Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma

Gram,

Brusgaard,

Lei

et al. 2024

JAMA Dermatol

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ImportancePalmoplantar keratoderma poses diagnostic challenges due to its clinical and genetic heterogeneity, and knowledge on the value of systematic genetic testing on clinically well-described patient cohorts is sparse.ObjectiveTo improve knowledge of the clinical and genetic spectrum of patients with palmoplantar keratoderma.Design, Setting, and ParticipantsThis cohort study prospectively recruited patients and affected family members with palmoplantar keratoderma between September 1, 2016, and December 31, 2022. Patients were recruited from private practitioners in dermatology and dermatology departments in Denmark. Study participants were patients 18 years or older either newly diagnosed with palmoplantar keratoderma or being followed up for the disease at referral centers.Main Outcomes and MeasuresPhenotypes and clinical subtypes were classified. Genetic testing was performed by whole-exome or genome sequencing using an in silico panel containing genes related to palmoplantar keratoderma, or by Sanger sequencing for specific variants. Descriptive analysis, such as proportions and frequency, were used to describe clinical characteristics, distribution of disease-causing variants, and genotype-phenotype associations.ResultsThis study included 142 study participants from 76 families (90 [63%] female; median [range] age, 52 [18-92] years). Clinical subtypes included 42 punctate (55%), 26 diffuse (34%), 5 focal (7%), and 3 striate (4%). A genetic diagnosis was found in 63 of 76 families (83%), including 27 disease-causing variants within 13 different genes: AAGAB (n = 39), DSG1 (n = 8), KRT1 (n = 3), DSP (n = 2), KRT9 (n = 2), AQP5 (n = 2), KRT16 (n = 1), SERPINA12 (n = 1), ABCA12 (n = 1), COL7A1 (n = 1), CARD14 (n = 1), DST (n = 1), and LORICRIN (n = 1). All participants with AAGAB variants presented with punctate palmoplantar keratoderma, showing a clear genotype-phenotype correlation. The other subtypes (diffuse, focal, and striate) proved more challenging to clinically subclassify, and disease-causing variants were identified in 12 genes, contributing to more complex genotype-phenotype patterns. Patients with palmoplantar keratoderma due to DSP variants were found, which is important to identify because of an associated risk of cardiomyopathy.Conclusion and RelevanceThis study provides novel insights into the clinical and genetic spectrum of patients with palmoplantar keratoderma. It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes. The established and well-described cohort lays the foundation for future research in palmoplantar keratoderma.

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Identification of clinically useful predictive genetic variants in pachyonychia congenita

Cited by 9 publications

References 25 publications

Coexistence of pachyonychia congenita and hidradenitis suppurativa: more than a coincidence

Coexistence of pachyonychia congenita and hidradenitis suppurativa: more than a coincidence

Autosomal recessive congenital ichthyosis caused by a pathogenic missense variant in CLDN1

Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma

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