Autosomal Recessive Congenital Ichthyosis Research Articles

Compound heterozygous ABCA12 variants identified in a Chinese patient with congenital ichthyosiform erythroderma: Advancing genotype-phenotype correlations and literature review.

Ichthyosis is a common keratotic skin disease with high clinical, etiological and genetic heterogeneity. There are four types of non-syndromic hereditary ichthyoses, among which autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of recessive Mendelian disorders. ARCI present with different phenotypes and ABCA12 pathogenic variants have been shown to cause complex ARCI phenotypes, including harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A sporadic male patient, clinically diagnosed with CIE, was enrolled in this study. Exome sequencing was combined with Sanger sequencing to confirm the diagnosis and identify the pathogenic variants. In silico predictions were made using multiple software programs, and the identified variants were interpreted using the ACMG guidelines. A review of all literature reported ABCA12 variants was performed to explore genotype-phenotype correlations. Compound heterozygous ABCA12 variants [c.5381+1G>A and c.5485G>C (p.Asp1829His)] (NM_173076) were identified. The two variants were not detected in the public database. c.5381+1G>A is predicted to affect ABCA12 mRNA splicing and Asp1829 is highly conserved among various species. In silico analysis suggested that these two variants were responsible for the phenotype of the patient. Genotype-phenotype correlation analysis showed that biallelic truncation variants and/or exon/amino acid deletions in ABCA12 are the most common causes of HI. Biallelic missense variants are most common in LI and CIE. The compound heterozygous ABCA12 variants caused the CIE phenotype observed in the patient. The spectrum of ABCA12 pathogenic variants were broaden. Genotype-phenotype correlation analysis provided detailed evidence which can be used in future prenatal diagnosis and can inform the need for genetic counselling for patients with ABCA12-related ARCIs.

Cross-sectional study on autosomal recessive congenital ichthyoses: association of genotype with disease severity, phenotypic and ultrastructural features in 74 Italian patients.

Autosomal recessive congenital ichthyoses (ARCI) 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. 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. 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: 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 one 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. 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.

The role of genetic polymorphisms in the sulfation of pregnenolone by human cytosolic sulfotransferase SULT2B1a

Pregnenolone is a key intermediate in the biosynthesis of many steroid hormones and neuroprotective steroids. Sulfotransferase family cytosolic 2B member 1 (SULT2B1a) has been reported to be highly selective to sulfate pregnenolone. This study aimed to clarify the effect of missense single nucleotide polymorphisms (SNPs) of the human SULT2B1 gene on the sulfating activity of coded SULT2B1a allozymes toward Pregnenolone. To investigate the effects of single nucleotide polymorphisms of the SULT2B1 gene on the sulfation of pregnenolone by SULT2B1a allozymes, 13 recombinant SULT2B1a allozymes were generated, expressed, and purified using established procedures. Human SULT2B1a SNPs were identified by a comprehensive database search. 13 SULT2B1a nonsynonymous missense coding SNPs (cSNPs) were selected, and site-directed mutagenesis was used to generate the corresponding cDNAs, packaged in pGEX-2TK expression vector, encoding these 13 SULT2B1a allozymes, which were bacterially expressed in BL21 E. coli cells and purified by glutathione-Sepharose affinity chromatography. Purified SULT2B1a allozymes were analyzed for sulfating activities towards pregnenolone. In comparison with the wild-type SULT2B1a, of the 13 allozymes, 11 showed reduced activity toward pregnenolone at 0.1 µM. Specifically, P134L and R259Q allozymes, reported to be involved in autosomal-recessive congenital ichthyosis, displayed low activity (1–10%) toward pregnenolone. The findings of this study may demonstrate the impact of genetic polymorphism on the sulfation of pregnenolone in individuals with different SULT2B1 genotypes.

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).

Genetic inheritance in tandem: Non-syndromic autosomal recessive congenital ichthyosis with beta-thalassaemia: A rare coincidence

Ichthyosis belongs to the group of Mendelian disorders of cornification. Congenital ichthyosis is inherited as an autosomal recessive trait, so it is also known as autosomal recessive congenital ichthyosis (ARCI). ARCI is classified into two types: syndromic and non-syndromic ARCI. Non-syndromic ARCIs include lamellar ichthyosis, congenital ichthyosiform erythroderma and Harlequin ichthyosis. Syndromic-ARCI is associated with multisystemic involvement, which includes Netherton syndrome, Chanarin-Dorfman disease and others. Other systemic diseases associated with ichthyosis include Gaucher disease type II and hypothyroidism. Chanarin-Dorfman and Gaucher disease-II are additionally associated with hepatosplenomegaly (HSM) and anaemia. We describe a child of congenital ichthyosis with HSM and anaemia thought to be syndromic-ARCI, but diagnosed for beta-thalassaemia (b-thal) concurrently. An infant presented with peeling skin along with absent sweating since birth and recent onset paleness of the body. Examination revealed Ichthyosis (Lamellar-variant), severe pallor and HSM, raising the possibility of Chanarin-Dorfman syndrome and Gaucher’s disease. The investigation revealed an Erlenmeyer flask deformity of the knee, but no Gaucher’s cells were found in the bone marrow. In the absence of lipid vacuoles leaden leukocytes (Jordan’s anomaly), Chanarin-Dorfman disease was also ruled out. Haemoglobin (Hb) high-performance liquid chromatography revealed β-thal major, and both parents were traits, giving us the diagnosis, which was further confirmed by the next-generation gene sequencing for clinical exomes. This report was to highlight non-syndromic ARCI involving the CYP4F22 gene variant, which is a rare finding, and the association of such ichthyosis with β-thal major was an unexpected result. Genetic counselling was provided to the parents in light of the autosomal recessive nature of both diseases. Genes of congenital ichthyosis and β-thal were unrelated, but simultaneous expressions of two autosomal-recessive diseases together are it merely by chance or a new entity.

Tofacitinib ameliorates skin inflammation in a case of severe autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder manifesting aberrant skin scaling and increased transepidermal water loss (TEWL). Current treatments for ARCI are limited and sub-optimal. We studied a 27-year-old man with ARCI resulting from a homozygous missense variant in TGM1 (transglutaminase 1). RNA-sequencing of lesional skin revealed aberrant JAK-STAT signalling, providing a rationale for innovative treatment with a Janus kinase inhibitor. We prescribed oral tofacitinib (11 mg daily) for 26 weeks. Rapid improvements in erythema and fissuring manifested within the first month. Sustained reductions in 5-D itch scale and Dermatology Life Quality Index (DLQI) scores were also observed. TEWL decreased for the first 10 weeks but increased thereafter. Tofacitinib down-regulated inflammatory genes and pathways, while enhancing skin barrier markers. Moreover, TGM1 distribution was normalized although enzymatic activity remained deficient. This study suggests that oral tofacitinib may be a useful therapy to consider in patients with ARCI.

Clinico-Epidemiologic Profile of Non-Syndromic Congenital Ichthyosis – A Retrospective Chart Review of 107 Patients

Background: Congenital ichthyoses are a rare Mendelian group of disorders affecting the integument with a heterogeneous clinical presentation amongst which scaling is a constant feature. There is scanty epidemiologic data regarding the clinical profile and histologic patterns of inherited ichthyosis from resource-poor countries. Aims and Objectives: The study was aimed at assessing the clinic-epidemiologic characteristics associated with the different forms of non-syndromic congenital ichthyosis. Materials and Methods: This was a retrospective chart review of ichthyosis patients that presented between July 2016 and Jun 2020. Details including demographic profile, clinical characteristics along with any relevant investigations done were included. Results: During the study period of 4 years, 107 patients with congenital non-syndromic ichthyosis were seen. The most frequent diagnosis was of common ichthyoses, followed by autosomal recessive congenital ichthyosis, epidermolytic ichthyosis and erythrokeratoderma, in decreasing order. Conclusion: Important clinical findings like erythema and the type of scales as well as histological differences including an absent or reduced granular layer in ichthyosis vulgaris can help differentiate among the clinical phenotypes of inherited non-syndromic ichthyosis especially in resource-poor settings. Also, there is a high prevalence of vitamin D deficiency and hence a need for screening for the same in all patients of congenital ichthyosis including the milder phenotypes.

Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations.

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by well-demarcated erythematous patches and hyperkeratotic plaques. EKV is most often transmitted in an autosomal dominant manner. Until recently, only mutations in connexins such as GJB3 (connexin 31), GJB4 (connexin 30.3), and occasionally GJA1 (connexin 43) were known to cause EKV. In recent years, mutations in other genes have been described as rare causes of EKV, including the genes KDSR, KRT83, and TRPM4. Features of the EKV phenotype can also appear with other genodermatoses: for example, in Netherton syndrome, which hampers correct diagnosis. However, in autosomal recessive congenital ichthyosis (ARCI), an EKV phenotype has rarely been described. Here, we report on seven patients who clinically show a clear EKV phenotype, but in whom molecular genetic analysis revealed biallelic mutations in ABCA12, which is why the patients are classified in the ARCI group. Our study indicates that ARCI should be considered as a differential diagnosis in EKV.

Syndromic or non-syndromic congenital ichthyosis? A case report of two brothers with ichthyosis but microphthalmia and blindness in only one brother

We present the cases of two brothers with ichthyosis, born to consanguineous parents, with the eldest having extracutaneous manifestations in the form of microphthalmia and corneal opacities causing complete blindness. Initially, we were faced with the question of whether the phenotype in this family was due to the effects of a single pleiotropic, presumably autosomal recessive gene manifesting as a syndromic form of ichthyosis, or whether there were multiple causal genes, and the ichthyosis was non-syndromic. Ultimately, clinical follow-up of the family, combined with research-based exome sequencing established a diagnosis of NIPAL4 autosomal recessive congenital ichthyosis in both brothers, but the ocular abnormalities causing blindness in the older brother were due to coexisting autosomal recessively inherited loss of function mutations in peroxidasin, the latter finding also seen in a sister unaffected by ichthyosis.

Case Report: A newborn in western Nepal with Harlequin ichthyosis

Harlequin ichthyosis(HI) is a rare autosomal recessive congenital ichthyosis with an incidence of 1 in 300,000 live births. It is lethal in 44% of cases and the baby is usually prematurely born. These babies have thick, highly keratinized armor-like skin, which forms large diamond, trapezoid or rectangular plates separated by deep fissures. These affect the shapes of eyelids, nose, mouth and ears, and also limit movement of the arms, legs and chest. This condition is linked with a nonsense or frameshift mutation in the ABCA12 gene, which is responsible for lipid transport in the keratinocytes. This gene synthesizes a protein that transports a lipid, epidermoside, a glucosylceramide, out of stratum corneum cells in the epidermis. To our knowledge, this is the first case report on Harlequin ichthyosis from Nepal, which makes this case unique. The takeaway lesson from this case is that couples with consanguineous marriages should undergo screening of ABCA12 gene if they plan to conceive.

Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs.

Autosomal recessive congenital ichthyoses (ARCI) are a skin pathology due to genetic causes characterized by a variable degree of desquamation, accompanied by erythema. The degree of symptoms is variable, different altered genes are involved, and the symptoms drastically affect patients' quality of life. Topical treatments are a first-choice strategy due to their ease of application and cost; however, enteral administration of retinoids offers greater efficacy, although with certain limitations. Despite the treatment alternatives, ARCI will persist throughout life, disabling people. Therefore, the search for new treatments always remains necessary. Especially repositioning drugs could be a short-term alternative to new affordable treatments for patients. Taking advantage of extensive knowledge of known drugs or biologics could ensure more accessible and possibly lower-cost treatments. This review briefly and concisely addresses possible repositioning strategies with drugs and biologics for ichthyosis.

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin.

Despite exciting advances in gene editing, the efficient delivery of genetic tools to extrahepatic tissues remains challenging. This holds particularly true for the skin, which poses a highly restrictive delivery barrier. In this study, we ran a head-to-head comparison between Cas9 mRNA or ribonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) to deliver gene editing tools into epidermal layers of human skin, aiming for in situ gene editing. We observed distinct LNP composition and cell-specific effects such as an extended presence of RNP in slow-cycling epithelial cells for up to 72 h. While obtaining similar gene editing rates using Cas9 RNP and mRNA with MC3-based LNPs (10-16%), mRNA-loaded LNPs proved to be more cytotoxic. Interestingly, ionizable lipids with a pKa ∼ 7.1 yielded superior gene editing rates (55%-72%) in two-dimensional (2D) epithelial cells while no single guide RNA-dependent off-target effects were detectable. Unexpectedly, these high 2D editing efficacies did not translate to actual skin tissue where overall gene editing rates between 5%-12% were achieved after a single application and irrespective of the LNP composition. Finally, we successfully base-corrected a disease-causing mutation with an efficacy of ∼5% in autosomal recessive congenital ichthyosis patient cells, showcasing the potential of this strategy for the treatment of monogenic skin diseases. Taken together, this study demonstrates the feasibility of an in situ correction of disease-causing mutations in the skin that could provide effective treatment and potentially even a cure for rare, monogenic, and common skin diseases.

Congenital ichthyosis presentation and outcome - A case series.

The ichthyosis, also called disorders of keratinization or cornification, are heterogeneous group of disorders characterized by a generalized scaling of the skin of varying severity. The majority of ichthyosis is inherited but acquired forms can develop in the setting of malignancy, autoimmune or infectious disease, and nutritional deficiency. Autosomal recessive congenital ichthyosis, which include lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis, are rare; their overall incidence has been estimated at approximately 1 in 300,000 births. In this article, we described four cases of congenital ichthyosis, their potential complications, causes of morbidity and mortality, and discussed the management and importance of genetic testing for diagnosis as definitive diagnosis is important for long-term management and counseling of the parents.

Patients with keratinization disorders due to ABCA12 variants showing pityriasis rubra pilaris phenotypes.

Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a "congenital" phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.

High TGM1 Allelic Heterogeneity causing Lamellar ichthyosis in a small geographic area in South Mexico: Another Example of the “Réunion Paradox”

Lamellar ichthyosis (LI) is an autosomal recessive congenital ichthyosis characterized by generalized dry skin and severe scaling. It is caused by biallelic mutations in the TGM1 gene, however molecular data from non-Caucasian populations are limited. Results of genetic-molecular analysis of a group of LI pedigrees originating from two close small populations from south Mexico are presented. LI affected individuals belonging to 9 apparently unrelated families were studied. Exome sequencing or Sanger sequencing in probands from each family was carried out. Furthermore, DNA from 294 unaffected subjects from one of the communities were Sanger sequenced to determine the carrier frequency of the c.427C > T TGM1 variant. Five different TGM1 pathogenic variants, either in homozygous or in compound heterozygous state, were demonstrated in affected subjects. The two most common variants were c.427C > T (p.Arg143Cys) and c.1159+1G > T. A novel c.1645+1G > T TGM1 pathogenic allele was recognized. Carrier frequency analysis identified a total of 23 individuals heterozygous for the c.427C > T variant, predicting a prevalence of 78 carriers per 1000 inhabitants in the community. A high TGM1 allelic heterogeneity with 5 different LI-causing alleles in a limited geographic area was demonstrated. While the occurrence of homozygosity for a founder mutation is expected in small populations with high frequency of a particular autosomal recessive disorder, the occurrence of multiple pathogenic alleles has been previously described, a situation known as the Reúnion paradox. Our results expand the current knowledge of the mutational spectrum of TGM1-linked LI.

Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis.

Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.

ВРОЖДЕННЫЙ ИХТИОЗ (КОЛЛОДИЙНЫЙ ПЛОД) (КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ)

Intensive research is currently underway on the treatment of congenital ichthyosis in newborns. The paper describes a case of lamellar congenital ichthyosis, manifested by the state of a "colloidal" fetus. Congenital ichthyosis is a serious disease in which the process manifests itself at the time of birth. At the same time, the skin of the child is covered with a thin, dry, yellowish-brown layer resembling a colloid; ectropion and eclabium are often noted. After some time, cracks appear, often deep, the film turns into large scales, a clinical picture of congenital ichthyosis is formed. Lamellar ichthyosis (LI) belongs to the group of autosomal recessive congenital ichthyosis of the skin and is caused by a significant impairment of the skin barrier function due to the inability of differentiated keratinocytes to synthesize and/or secrete lipids necessary for the formation of corneocytes and the extracellular matrix of the stratum corneum. For the first time the disease was described by E. Seligman (1841) under the name "lamellar desquamation of newborns". The term "lamellar ichthyosis" was proposed by L. Gross and L. Torok (1895). The disease is genetically heterogeneous, occurs with a frequency of 1:300,000 of the population, more often in closely related marriages. They are affected with equal frequency by males and females. The described clinical case vividly illustrates the features of the course of congenital ichthyosis, the effectiveness of timely therapy using modern skin care products in a short time without the use of hormonal drugs.

The possibilities of using retinol palmitate in the systemic treatment of generalized hereditary keratinization disorders

Hereditary ichthyosis is a group of generalized hereditary keratinization disorders characterized by general dryness of the skin, peeling, hyperkeratosis and often erythroderma. These manifestations are caused by mutations in genes mainly involved in the formation of the skin barrier. Hereditary ichthyosis is divided into syndromic and non-syndromic. Nonsyndromic ichthyoses include: vulgar ichthyosis, recessive X-linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis and other forms. At present, the best result for achieving clinical remission has been established with oral retinoids: retinol palmitate, isotretinoin (1st generation of retinoids) and acitretin (2nd generation of retinoids). The ability of retinol palmitate to regulate keratinization processes, strengthen the epidermal barrier and have an antioxidant effect is used in the treatment of generalized hereditary keratinization disorders. Medium and high therapeutic doses (200010 000 IU/kg/day) are used in the treatment. The prescribed dose of retinol palmitate differs in various nosological forms of ichthyosis, and depends on the severity of the pathological process, the age and weight of the patient, which must be taken into account when prescribing therapy to obtain the best result. It should be noted that clinical manifestations mainly regress at doses that do not lead to the appearance of signs of toxicity of the drug. The methods of retinol palmitate treatment of ichthyosis and ichthyosiform erythroderma are described.

The Cornified Envelope: A Versatile Contributor to the Epidermal Barrier

The Cornified Envelope: A Versatile Contributor to the Epidermal Barrier

A novel homozygous splice site variant in CERS3 causes autosomal recessive congenital ichthyosis.

The authors have no conflicts of interest to declare. Data are available on request from the authors. Figure S1: Pedigree of family segregating autosomal recessive congenital ichthyosis haplotypes of the closely linked locus-specific microsatellite markers under each genotyped member. The cytogenetic position is represented in centimorgan (cM). Black symbols depict affected members whereas blank symbols represent normal members of the family. Table S1: Description and Pathogenicity Prediction of Identified variant (c.466-1G>A) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.