Summary 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. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype–phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.

Summary Ichthyosis is a disorder in which the skin is very thick and scaly. It is usually caused by a genetic mistake (mutation). “Autosomal recessive” ichthyosis occurs when parents who are healthy carriers both pass on a mutant gene to their child, so the child inherits a double dose of the mutation and cannot make normal skin. Scientists have already discovered mutations in 13 genes that cause ichthyosis. This study looks at whether the type of mutation (genotype) tells us anything about the type of ichthyosis (phenotype). The doctors examined 146 ichthyosis patients, average age 17 years, from 124 families, recruited from 13 English hospitals. They extracted DNA from blood or saliva. They found mutations in 83% of patients; the other 17% presumably have mutations not detectable by current techniques or in different genes. There were mutations in 10 different ichthyosis genes, mostly a gene called TGM1. To some extent different genotypes corresponded to different phenotypes. TGM1 ichthyosis usually has large, brown scales while ALOX12B mutations cause fine white scaling. ABCA12 mutations cause more severe ichthyosis, including the very serious harlequin type with distorted fingers; by contrast patients with milder ichthyosis usually had TGM1 or ALOX12B mutations. Nearly half of the babies with ALOX12B mutations were born with the top of their ear folded over. Some TGM1 patients had abnormally red skin while others with exactly the same mutation did not. In conclusion, this large study provides a lot of new information about ichthyosis, but genotype only partly predicts phenotype. This is a summary of the study: Genotype–phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis