Updated mutational spectrum and genotype-phenotype correlations in ichthyosis patients with ABCA12 pathogenic variants.

Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).

Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients.

BACKGROUND: Autosomal recessive congenital ichthyoses (ARCIs) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes. The aim of our study was to assess disease severity, phenotypic, and ultrastructural features and to evaluate their association with genetic findings in ARCI patients. METHODS: Clinical signs and symptoms, and disease severity were scored in a single-center series of patients with a genetic diagnosis of ARCI. Skin ultrastructural findings were reviewed. RESULTS: Seventy-four consecutive patients (mean age 11.0 years, range 0.1-48.8) affected with lamellar ichthyosis (50/74, 67.5%), congenital ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74, 2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled. Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%). Twenty-five previously undescribed mutations in the different ARCI causative genes, as well as two microduplications in TGM1, and two microdeletions in CYP4F22 and NIPAL4 were identified. The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients. Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick, and brownish scales with TGM1 mutations. Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients. Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients. CONCLUSION: Our study expands the phenotypic and genetic characterization of ARCI by the description of statistically significant associations between disease severity, specific clinical signs, and different mutated genes. Finally, we highlighted the presence of psoriasis-like lesions in NIPAL4-ARCI patients as a novel phenotypic feature with diagnostic and possible therapeutic implications.

Prenatal ultrasound detection of collodion membrane in association with an autosomal recessive congenital ichthyosis due to transglutaminase 1 deficiency.

We describe a case of collodion baby diagnosed prenatally by ultrasound. Classic signs (ectropion, flattened nose, and eclabion) were detected on routine ultrasound at 21 weeks of gestation. At birth, the presence of collodion membrane was confirmed and subsequently, the diagnosis of an autosomal recessive congenital ichthyosis due to compound heterozygosity of the TGM1 gene was made.

Lamellar ichthyosis with a novel NIPAL4 variant showing dramatic response to high-dose vitamin D therapy.

Therapeutic options are limited in cases of autosomal recessive congenital ichthyosis with inadequate response to topical agents. Acitretin is the current standard of care in these patients, but its use is limited by cumulative toxicity when prolonged therapy is needed in children. There is evidence to suggest that high doses of vitamin D can normalize keratinization and suppress inflammatory cytokines. Here, we report a patient with lamellar ichthyosis with a novel mutation in the Nipa-like Domain-Containing 4 (NIPAL4) gene. High dose short-term vitamin D therapy was administered with a dramatic and sustained clinical response.

Autosomal recessive congenital ichthyosis due to novel CYP4F22 mutation presenting with a collodion membrane and ocular manifestations.

Autosomal recessive congenital ichthyoses (ARCI) are a range of genetic disorders of keratinization. The rare CYP4F22 gene mutation can present with or without collodion membrane at birth and leads to the development of mild ichthyosis phenotype. We report a case of a novel pathogenic CYP4F22 genetic mutation presenting with collodion membrane and ocular manifestations. Ocular manifestations have recently been reported in a patient with ARCI with known CYP4F22 mutation, which further supports a possible correlation between the CYP4F22 mutation and this distinct phenotype.

French national protocol for the management of congenital ichthyosis.

Congenital ichthyoses (CI) comprise a heterogeneous group of monogenic genetic skin diseases characterized by diffuse scaling, often associated with skin inflammation. Diagnosis of the individual form of ichthyosis is complex and is guided by clinical expertise. CI usually has a major impact on quality of life (QOL) and thus requires lifelong treatment. To date, there are no curative therapies, although various symptomatic treatment options exist. The present protocol for the management of CI has been drawn up in accordance with the recommendations published in 2012 by the French National Authority for Health, based on a literature review, with the help and validation of members of the French network for rare skin diseases (FIMARAD). It provides a summary of evidence and expert-based recommendations and is intended to help clinicians with the management of these rare and often complex diseases.

Recombinant PNPLA1 catalyzes the synthesis of acylceramides and acyl acids with selective incorporation of linoleic acid.

Loss-of-function mutations in patatin-like phospholipase domain-containing protein 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, and altered PNPLA1 activity is implicated in the pathogenesis of atopic dermatitis and other common skin diseases. To examine the hypothesis that PNPLA1 catalyzes the synthesis of acylceramides and acyl acids, we expressed and partially purified a soluble, truncated form of PNPLA1 in Escherichia coli, (PNPLA1trun) along with the related protein PNPLA2 (ATGL, adipose triglyceride lipase) and coactivator CGI-58. Liposomal substrates were incubated with recombinant enzymes for 0.5-24 h and products analyzed by HPLC-UV and LC-MS. Using trilinolein or dilinolein substrates, PNPLA1trun, like ATGLtrun, catalyzed lipolysis and acyltransferase reactions with 2-30% conversion into linoleic acid, monolinolein, and trilinolein. CGI-58 enhanced ATGL-catalyzed lipolysis as previously reported, but transacylase activity was not enhanced with ATGL or PNPLA1. In matching the proposed activity in vivo, PNPLA1 catalyzed acyl transfer from trilinolein and dilinolein donors to omega-hydroxy ceramide, omega-hydroxy glucosylceramide, and omega-hydroxy acid acceptors to form acylceramide, glucosyl-acylceramide, and acyl acid, respectively, albeit with only ∼0.05% conversion of the substrates. Notably, in experiments comparing dilinolein vs. diolein acyl donors, PNPLA1 transferred linoleate with 3:1 selectivity over oleate into acylceramide. These results support the role for PNPLA1 in the synthesis of acylceramides and acyl acids in epidermis and suggest that the enrichment of these lipids with linoleic acid could result from the substrate selectivity of PNPLA1.

Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

Phase IIb randomized CONTROL study demonstrates a novel topical isotretinoin formulation, TMB-001, is safe and effective in participants with either recessive X-linked or autosomal recessive lamellar congenital ichthyosis.

BACKGROUND: In two severe congenital ichthyosis subtypes, autosomal recessive lamellar ichthyosis (ARCI-LI) and X-linked recessive ichthyosis (XLRI), cutaneous manifestations include widespread scaling. Approved topical treatment options are limited to emollients and keratolytics. AIM: This analysis from the randomized phase IIb CONTROL study assessed whether the efficacy and safety of TMB-001, a novel topical isotretinoin ointment formulation, differed between ARCI-LI and XLRI subtypes. METHODS: Participants ≥ 9 years with genetically confirmed XLRI or ARCI-LI and ≥ 2 (of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%/TMB-001 0.1%/vehicle, twice daily for 12 weeks. The proportion of participants with ≥ 50% reduction vs. baseline in VIIS scaling (VIIS 50; primary endpoint) and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score vs. baseline (key secondary endpoint) were evaluated. Adverse events (AEs) were monitored. RESULTS: Among enrolled participants (TMB-001 0.05%, n = 11; 0.1%, n = 10; and vehicle, n = 12), 52% had ARCI-LI and 48% XLRI subtypes. Mean age was 33.6 and 35.4 years for participants with ARCI-LI and XLRI, respectively. Overall, 33%, 50% and 17% of participants with ARCI-LI and 100%, 33% and 75% of participants with XLRI achieved VIIS 50 in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.24 for 0.05% vs. vehicle, intent-to-treat population). Improvement of ≥ 2-grade IGA score was observed in 33%, 50% and 0% of participants with ARCI-LI and 83%, 33% and 25% of participants with XLRI in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.03 for 0.05% vs. vehicle, intention-to-treat population). Most AEs were application-site reactions. CONCLUSION: Regardless of congenital ichthyosis subtype, TMB-001 demonstrated greater proportions of participants achieving VIIS 50 and ≥ 2-grade IGA improvement vs. vehicle.

SDR9C7 missense variant in a Chihuahua with non-epidermolytic ichthyosis.

Ichthyoses represent a heterogeneous group of cornification disorders that are associated with skin barrier defects. We investigated a 9-month-old Chihuahua showing excessive scale formation. Clinical and histopathological examinations revealed non-epidermolytic ichthyosis and a genetic defect was suspected. We therefore sequenced the genome of the affected dog and compared the data with 564 genetically diverse control genomes. Filtering for private variants identified a homozygous missense variant in SDR9C7, c.454C>T or p.(Arg152Trp). SDR9C7 is a known candidate gene for ichthyosis in humans and encodes the short-chain dehydrogenase/reductase family 9C member 7. The enzyme is involved in the production of a functional corneocyte lipid envelope (CLE), a crucial component of the epidermal barrier. Pathogenic variants in SDR9C7 have been described in human patients with autosomal recessive ichthyosis. We assume that the identified missense variant in the affected Chihuahua of this study impairs the normal enzymatic activity of SDR9C7 and thus prevents the formation of a functioning CLE, resulting in a defective skin barrier. To the best of our knowledge, this is the first report of a spontaneous SDR9C7 variant in domestic animals.

Acral lamellar ichthyosis with amino acid substitution in the C-terminus of keratin 2.

BACKGROUND: Most cases of hereditary ichthyoses present with generalized scaling and skin dryness. However, in some cases skin involvement is restricted to particular body regions as in acral lamellar ichthyosis. OBJECTIVES: We report on the genetic basis of acral ichthyosis in two families presenting with a similar phenotype. METHODS: Genetic testing was performed by targeted next generation sequencing and whole-exome sequencing. For identity-by-descent analysis, the parents were genotyped and data analysis was performed with the Chromosome Analysis Suite Software. RT-PCR with RNA extracted from skin samples was used to analyse the effect of variants on splicing. RESULTS: Genetic testing identified a few heterozygous variants, but only the variant in KRT2 c.1912 T > C, p.Phe638Leu segregated with the disease and remained the strongest candidate. Pairwise identity-by-descent analysis revealed no indication of family relationship. Phenylalanine 638 is the second last amino acid upstream of the termination codon in the tail of K2, and substitution to leucine is predicted as probably damaging. Assessment of the variant is difficult, in part due to the lack of crystal structures of this region. CONCLUSIONS: Altogether, we show that a type of autosomal dominant acral ichthyosis is most probably caused by an amino acid substitution in the C-terminus of keratin 2.

Dysfunction of Oskyddad causes Harlequin-type ichthyosis-like defects in Drosophila melanogaster.

Prevention of desiccation is a constant challenge for terrestrial organisms. Land insects have an extracellular coat, the cuticle, that plays a major role in protection against exaggerated water loss. Here, we report that the ABC transporter Oskyddad (Osy)-a human ABCA12 paralog-contributes to the waterproof barrier function of the cuticle in the fruit fly Drosophila melanogaster. We show that the reduction or elimination of Osy function provokes rapid desiccation. Osy is also involved in defining the inward barrier against xenobiotics penetration. Consistently, the amounts of cuticular hydrocarbons that are involved in cuticle impermeability decrease markedly when Osy activity is reduced. GFP-tagged Osy localises to membrane nano-protrusions within the cuticle, likely pore canals. This suggests that Osy is mediating the transport of cuticular hydrocarbons (CHC) through the pore canals to the cuticle surface. The envelope, which is the outermost cuticle layer constituting the main barrier, is unaffected in osy mutant larvae. This contrasts with the function of Snu, another ABC transporter needed for the construction of the cuticular inward and outward barriers, that nevertheless is implicated in CHC deposition. Hence, Osy and Snu have overlapping and independent roles to establish cuticular resistance against transpiration and xenobiotic penetration. The osy deficient phenotype parallels the phenotype of Harlequin ichthyosis caused by mutations in the human abca12 gene. Thus, it seems that the cellular and molecular mechanisms of lipid barrier assembly in the skin are conserved during evolution.

Acral collodion membrane associated with ichthyosis due to a heterozygous pathogenic variant of ELOVL4 gene.

A female twin presented at birth with a collodion membrane on the hands and feet. After the membrane resolved over the first months of life, she was initially diagnosed with acral self-healing collodion membrane. However, she subsequently developed brown well-defined geometric scales on the trunk and extremities, consistent with ichthyosis. Genetic testing showed a heterozygous pathogenic variant in ELOVL4, a gene associated with syndromic ichthyosis with developmental delay, seizures, and spasticity. Although acral collodion membrane is considered to be a benign variant of the more generalized collodion, usually described as "self-healing," it may be the initial presentation of more diffuse ichthyosis.

Clinical and molecular characteristics of autosomal recessive congenital ichthyosis in Thailand.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a heterogenous group of rare keratinization disorders. To date, more than 13 causative genes have been identified. However, data on clinical and molecular characteristics including genotype-phenotype correlation are lacking in Thailand. OBJECTIVE: We collected cases diagnosed with non-syndromic ARCI and syndromic recessive congenital ichthyosis at the Institute of Dermatology from 2011 to 2021 and performed genetic testing with next-generation sequencing and assessed clinical details. METHODS: Baseline demographic data, birth history, family history, skin manifestations at birth, current cutaneous manifestations, comorbidities, and response to treatments were assessed. DNA was screened for mutations using targeted gene sequencing of 45 genes related to congenital ichthyosis. RESULTS: A total of 33 patients were analyzed with an average age of 23.8 ± 13.9 years. Congenital ichthyosiform erythroderma (CIE) was most common (60.6%), followed by lamellar ichthyosis (18.2%), self-improving congenital ichthyosis (6.1%), Netherton syndrome (6.1%), ichthyosis prematurity syndrome (3%), Sjögren-Larsson syndrome (3%) and bathing suit ichthyosis (3%). Eight genes were found with pathogenic variants in our cohort as follows: ABCA12 42.4% (14/33), NIPAL4 24.2% (8/33), TGM1 15.2% (5/33), SPINK5 6.1% (2/33), ALDH3A2 3% (1/33), SLC27A4 3% (1/33), CYP4F22 3% (1/33), and ST14 3% (1/33). Clinically, 79% of patients with ABCA12 pathogenic variants in this study had CIE, 79% of w had novel biallelic pathogenic compound heterozygous variants, whereas 21% had homozygous missense variants. CONCLUSIONS: This is the first study to describe clinical and molecular findings of ARCI in a cohort from Thailand. Our findings demonstrate the clinical spectrum of the diseases and expand the molecular findings in a Southeast Asian population.

Ichthyosis, cataracts, and motor delay in an infant: A case of Chanarin-Dorfman syndrome.

Chanarin-Dorfman syndrome (CDS) is a rare, autosomal recessive disorder of impaired triacylglycerol catabolism leading to cytoplasmic deposition of triglycerides in various cell types. We describe the case of an 8-month-old boy with cataracts, strabismus, motor delays, and an ichthyosiform rash since birth. Genetic testing revealed a pathogenic variant of the ABHD5 gene, suggestive of CDS, and further workup demonstrated hepatic steatosis and myopathy. His ichthyosis improved with initiation of a diet low in very long-chain fatty acids and medium-chain fatty acid supplementation.

Partial Loss of Function ABCA12 Mutations Generate Reduced Deposition of Glucosyl-Ceramide, Leading to Patchy Ichthyosis and Erythrodermia Resembling Erythrokeratodermia Variabilis et Progressiva (EKVP).

Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.

Identification and In Silico Analysis of a Homozygous Nonsense Variant in TGM1 Gene Segregating with Congenital Ichthyosis in a Consanguineous Family.

Background and Objectives: Lamellar ichthyosis is a rare skin disease characterized by large, dark brown plate-like scales on the entire body surface with minimum or no erythema. This phenotype is frequently associated with a mutation in the TGM1 gene, encoding the enzyme transglutaminase 1 which plays a catalytic role in the formation of the cornified cell envelop. The present study aimed to carry out clinical and genetic characterization of the autosomal recessive lamellar ichthyosis family from Balochistan. Materials and Methods: A consanguineous family with lamellar ichthyosis was enrolled from Balochistan, Pakistan. PCR amplification of all the exons and splice site junctions of the TGM1 gene followed by Sanger sequencing was performed on the genomic DNA. The identified variant was checked by In silico prediction tools to evaluate the effect of the variant on protein. Results: Sanger sequencing identified a homozygous nonsense variant c.131G >A (p.Trp44*) in the TGM1 gene that segregated in the autosomal recessive mode of inheritance in the family. The identified variant results in premature termination of transcribed mRNA and is predicted to cause a truncated or absent translation product transglutaminase-1 (TGase-1) accompanied by loss of catalytic activity, causing a severe clinical phenotype of lamellar ichthyosis in the patients. Conclusions: Here, we report a consanguineous lamellar ichthyosis family with a homozygous nonsense variant in the TGM1 gene. The variant is predicted as pathogenic by different In silico prediction tools.

Ophthalmic findings in patients with autosomal recessive lamellar ichthyosis due to TGM1 mutations in an isolated population.

PURPOSE: To describe the ocular clinical characteristics of a group of Mexican patients with lamellar ichthyosis (LI) arising from TGM1 pathogenic variants. METHODS: Ophthalmological exploration, pedigree analysis and genetic screening were performed in patients with an established clinical diagnosis of lamellar ichthyosis from families located in a small community in the Southeast of Mexico. RESULTS: Nine patients with LI in five families were identified. There were six affected females. All patients (9/9) demonstrated eye lid abnormalities with eight patients showing lid margin abnormalities. Madarosis was present in only three individuals and corneal scarring was documented in two. All nine individuals carried biallelic TGM1 variants, either homozygously or as compound heterozygous. CONCLUSION: Ocular anomalies are common in individuals with TGM1-related LI. The occurrence of a variety of private or rare mutations hampers the identification of a genotype-phenotype correlation for ocular anomalies in this disorder.

Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies.

Self-healing collodion baby (SHCB), also called "self-improving collodion baby", is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

Distinct skin microbiome community structures in congenital ichthyosis.

BACKGROUND: The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored. OBJECTIVES: To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes. METHODS: Body site-matched skin surface samples were collected from the scalp, upper arm and upper buttocks of 16 healthy control participants and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis. RESULTS: Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. Cutibacterium acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. Malassezia globosa was reduced at all body sites, whereas M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. Malassezia slooffiae, by contrast, was strikingly increased at all body sites in participants with congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing the skin of patients with CIE, LI and epidermolytic ichthyosis subtypes. CONCLUSIONS: The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis. What is already known about this topic? The skin microbiome of congenital ichthyoses is largely unexplored. Microbes play an important role in pathogenesis, as infections are common. The relative abundances of staphylococci and corynebacteria is increased in the cutaneous microbiome of patients with Netherton syndrome, but extension of these abundances to all congenital ichthyoses is unexplored. What does this study add? A common skin microbiome signature was observed across congenital ichthyoses. Distinct microbiome features were associated with ichthyosis subtypes. Changes in microbiome may contribute to T helper 17 cell immune polarization. What is the translational message? These data provide the basis for comparison of the microbiome with lipidomic and transcriptomic alterations in these forms of ichthyosis and consideration of correcting the dysbiosis as a therapeutic intervention.