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

• Published in: Molecular genetics & genomic medicine Vol. 7; no. 3; pp. e539 - n/a
• Main Authors: Lima Cunha, Dulce, Alakloby, Omar Mohammed, Gruber, Robert, Kakar, Naseebullah, Ahmad, Jamil, Alawbathani, Salem, Plank, Roswitha, Eckl, Katja, Krabichler, Birgit, Altmüller, Janine, Nürnberg, Peter, Zschocke, Johannes, Borck, Guntram, Schmuth, Matthias, Alabdulkareem, Adnan S., Abdulaziz Alnutaifi, Kholood, Hennies, Hans Christian
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-03-2019; John Wiley and Sons Inc
• Subjects: Adolescent; ATP-Binding Cassette Transporters - genetics; Child; congenital ichthyosis; Correlation; Cytochrome P-450 Enzyme System - genetics; erythema; Female; Gene mapping; Genes; Genes, Recessive; Genotype; genotype/phenotype correlation; Genotypes; Homozygosity; homozygosity mapping; Humans; Ichthyosiform Erythroderma, Congenital - epidemiology; Ichthyosiform Erythroderma, Congenital - genetics; Ichthyosis; Lipoxygenase - genetics; Male; Mapping; Mutation; Mutation Rate; Original; Pakistan; Parents; Patients; Permeability; Phenotype; Phenotypes; Receptors, Cell Surface - genetics; Saudi Arabia; Skin diseases; Skin permeability barrier; skin scaling; Transglutaminases - genetics; Young Adult; Saudi Arabia; Pakistan; congenital ichthyosis; genotype/phenotype correlation; skin scaling; erythema; Skin permeability barrier; homozygosity mapping
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.539

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.
Autosomal recessive congenital ichthyosis (ARCI) is a phenotypically and genetically heterogeneous skin disease, associated with defects in the skin permeability barrier. Here, we have detected mutations in the genes TGM1, ABCA12, CYP4F22, NIPAL4, and ALOXE3 in 19 consanguineous families from Saudi Arabia, Yemen, and Pakistan. Our results revealed new insights into genotype/phenotype correlations and contribute to expanding the mutational spectrum of ARCI.