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

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

OBJECTIVE: 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 (NHS) sites in England, with 65% of subjects aged <16 years at enrolment. Pathogenic bi-allelic 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 over-folded ear at birth, was noted with 43% of 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 co-morbidities, as well as the gene pathologies therein. Collectively, data from these subjects provide a valuable resource for further clinical assessment, improving clinical care, and the possibility of future stratified management.