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Br J Dermatol. 2019 Jun 6. doi: 10.1111/bjd.18211. [Epub ahead of print]

Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.

Author information

1
NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, U.K.
2
St John's Institute of Dermatology, King's College London, Guy's Hospital, London, U.K.
3
Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, Guy's Hospital, London, U.K.
4
Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, U.S.A.
5
Genetics, Genomics and Cancer Biology, PhD Program, Thomas Jefferson University, Philadelphia, PA, U.S.A.
6
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
7
Biotechnology Research Center, Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran.
8
School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King's College London, U.K.
9
Department of Dermatology, Nottingham University Hospitals NHS Trust, Nottingham, U.K.
10
Department of Dermatology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, U.K.
11
Department of Dermatology, Bart's Health NHS Trust, London, U.K.
12
Department of Dermatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, U.K.
13
Department of Dermatology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, U.K.
14
Manchester Centre for Genomic Medicine, Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, U.K.
15
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, U.K.
16
Department of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, U.K.
17
Department of Dermatology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, U.K.
18
Dermatology Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
19
Department of Dermatology, Sheffield Children's NHS Foundation Trust, Sheffield, U.K.
20
Department of Dermatology, South Tees Hospitals NHS Foundation Trust, Middlesbrough, U.K.
21
Department of Dermatology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, U.K.

Abstract

BACKGROUND:

Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype-phenotype correlation in some populations.

OBJECTIVES:

We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype-phenotype correlation.

METHODS:

Deep phenotyping was undertaken by history-taking and clinical examination. DNA was screened for mutations using a next-generation sequencing ichthyosis gene panel and Sanger sequencing.

RESULTS:

Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self-improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype.

CONCLUSIONS:

These data refine genotype-phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management.

PMID:
31168818
DOI:
10.1111/bjd.18211

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