Lihi Atzmony1, Habib M Khan1, Young H Lim1,2,3, Amy S Paller4, Jonathan L Levinsohn1,2,3, Kristen E Holland5, Fatima Nadeem Mirza1, Emily Yin1, Christine J Ko1,2, Jonathan S Leventhal1, Keith A Choate1,2,3. 1. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut. 2. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. 3. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut. 4. Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 5. Department of Dermatology, Medical College of Wisconsin, Milwaukee.
Abstract
Importance: Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. Objective: To identify genetic mutations associated with linear porokeratosis. Design, Setting, and Participants: Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. Interventions or Exposures: Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. Main Outcomes and Measures: Germline and somatic genomic characteristics of participants with linear porokeratosis. Results: Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). Conclusions and Relevance: Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.
Importance: Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. Objective: To identify genetic mutations associated with linear porokeratosis. Design, Setting, and Participants: Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. Interventions or Exposures: Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. Main Outcomes and Measures: Germline and somatic genomic characteristics of participants with linear porokeratosis. Results: Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). Conclusions and Relevance: Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.
Authors: Geraldine A Van der Auwera; Mauricio O Carneiro; Christopher Hartl; Ryan Poplin; Guillermo Del Angel; Ami Levy-Moonshine; Tadeusz Jordan; Khalid Shakir; David Roazen; Joel Thibault; Eric Banks; Kiran V Garimella; David Altshuler; Stacey Gabriel; Mark A DePristo Journal: Curr Protoc Bioinformatics Date: 2013
Authors: Niklas Krumm; Peter H Sudmant; Arthur Ko; Brian J O'Roak; Maika Malig; Bradley P Coe; Aaron R Quinlan; Deborah A Nickerson; Evan E Eichler Journal: Genome Res Date: 2012-05-14 Impact factor: 9.043
Authors: Lihi Atzmony; Young H Lim; Claire Hamilton; Jonathan S Leventhal; Annette Wagner; Amy S Paller; Keith A Choate Journal: J Am Acad Dermatol Date: 2019-08-23 Impact factor: 11.527
Authors: Sabine Jägle; Hazem A Juratli; Geoffroy Hickman; Kira Süssmuth; Maria C Boente; Julia Kopp; Peter Kirchmeier; Andreas Zimmer; Rudolf Happle; Emmanuelle Bourrat; Henning Hamm; Judith Fischer Journal: Acta Derm Venereol Date: 2021-02-16 Impact factor: 3.875