Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan

Abstract

Background Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogeneous skin disease, associated with defects in the skin permeability barrier. Several but not all genes with underlying mutations have been identified, but a clear correlation between genetic causes and clinical picture has not been described to date. Methods Our study included 19 families from Saudi Arabia, Yemen, and Pakistan. All patients were born to consanguineous parents and diagnosed with ARCI. Mutations were analyzed by homozygosity mapping and direct sequencing. Results We have detected mutations in all families in five different genes: TGM1 , ABCA12 , CYP4F22 , NIPAL4 , and ALOXE3 . Five likely pathogenic variants were unknown so far, a splice site and a missense variant in TGM1 , a splice site variant in NIPAL4 , and missense variants in ABCA12 and CYP4F22 . We attributed TGM1 and ABCA12 mutations to the most severe forms of lamellar and erythematous ichthyoses, respectively, regardless of treatment. Other mutations highlighted the presence of a phenotypic spectrum in ARCI. Conclusion Our results contribute to expanding the mutational spectrum of ARCI and revealed new insights into genotype/phenotype correlations. The findings are instrumental for a faster and more precise diagnosis, a better understanding of the pathophysiology, and the definition of targets for more specific therapies for ARCI.

Quality of life and clinical characteristics of self‐improving congenital ichthyosis within the disease spectrum of autosomal‐recessive congenital ichthyosis

“…SICI is one phenotypic variant of ARCI implying a good prognosis that becomes evident in the first year of life. About 10%–25% newborns with collodion suffer from SICI 2,4,16,17 …”

Biallelic mutations in FLG, TGM1, and STS genes segregated with different types of ichthyoses in eight families of Pakistani origin

“…TGM1 variants are the most notable cause of ARCI phenotypes worldwide 21 . Genes other than TGM1 causing autosomal recessive congenital ichthyosis in Pakistani population comprise, ABCA12 , CTSC (OMIM:602365), 26 NIPAL4 , ALOXE3 , 27 SULT2B1 , 19 and PNPLA1 4 …”

Molecular Genetic Study of Congenital Ichthyosiform Erythroderma (CIE) Reveals a Novel Likely Pathogenic Variant in an Iranian Pedigree

“…Autosomal recessive congenital ichthyosis belongs to a diverse group of non-syndromic keratinization disorders (7,17). The most prevalent molecular causes of ARCI are mutations (mainly missense) in the TGM1 gene encoding the transglutaminase-1 enzyme (8).…”

“…Genetically, ARCI is a heterogeneous disease and results from mutations in 14 genes, including TGM1, ABCA12, NIPAL4, lipo-oxygenase genes (ALOX12B and ALOXE3), LIPN, CYP4F22, ST14, CASP14, SDR9C7, SULT2B1, CERS3, SLC7A4, and PNPLA1 (5)(6)(7). However, the genotype-phenotype correlation in ARCI is weak.…”

“…However, the genotype-phenotype correlation in ARCI is weak. For example, LI phenotype, frequently but not exclusively, is caused by mutations in the TGM1 gene, but the same mutations can also lead to CIE (3,6,7). In this context, several studies have reported that more than 55% of ARCI cases are resulted from germline mutations in the TGM1 gene that encodes transglutaminase-1, a cell membrane-bound epidermal enzyme with a pivotal role in the structure and function of the skin barrier through participating in cell envelope formation (8,9).…”