title: Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.
abstract: Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom; a.r.lehmann@sussex.ac.uk Hiva.Fassihi@gstt.nhs.uk.
authors.forename: Hiva
authors.initials: H
authors.lastname: Fassihi
authors.affiliation: King's College London, Kings Health Partners, Division of Genetics and Molecular Medicine, St John's Institute of Dermatology, Guy's Hospital, London SE1 9RT, United Kingdom;
authors.forename: Mieran
authors.initials: M
authors.lastname: Sethi
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, United Kingdom;
authors.forename: Heather
authors.initials: H
authors.lastname: Fawcett
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, United Kingdom;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wing
authors.affiliation: Genetics Department, Guy's Hospital, London SE1 9RT, United Kingdom;
authors.forename: Natalie
authors.initials: N
authors.lastname: Chandler
authors.affiliation: Genetics Department, Guy's Hospital, London SE1 9RT, United Kingdom;
authors.forename: Shehla
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Emma
authors.initials: E
authors.lastname: Craythorne
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Ana M S
authors.initials: AM
authors.lastname: Morley
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Rongxuan
authors.initials: R
authors.lastname: Lim
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Sally
authors.initials: S
authors.lastname: Turner
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Tanya
authors.initials: T
authors.lastname: Henshaw
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Isabel
authors.initials: I
authors.lastname: Garrood
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom; Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, United Kingdom;
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Tammy
authors.initials: T
authors.lastname: Hedderly
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Adesoji
authors.initials: A
authors.lastname: Abiona
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Harsha
authors.initials: H
authors.lastname: Naik
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Gemma
authors.initials: G
authors.lastname: Harrop
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: McGibbon
authors.affiliation: Department of Genetics, Erasmus Medical Center, 3015 CN, Rotterdam, The Netherlands;
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, 27100 Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Botta
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, 27100 Pavia, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Nardo
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, 27100 Pavia, Italy.
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
authors.affiliation: King's College London, Kings Health Partners, Division of Genetics and Molecular Medicine, St John's Institute of Dermatology, Guy's Hospital, London SE1 9RT, United Kingdom;
authors.forename: Antony R
authors.initials: AR
authors.lastname: Young
authors.affiliation: National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, United Kingdom;
authors.forename: Robert P E
authors.initials: RP
authors.lastname: Sarkany
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, United Kingdom; a.r.lehmann@sussex.ac.uk Hiva.Fassihi@gstt.nhs.uk.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D006113:United Kingdom; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D055815:Young Adult
keywords: UV radiation; neurodegeneration; nucleotide excision repair; ocular disease; skin cancer