CYP4F22 – Lamellar Ichthyosis

Autosomal recessive congenital ichthyosis comprises a group of cornification disorders marked by generalized scaling and thickening of the skin. The CYP4F22 gene encodes a fatty acid ω-hydroxylase essential for skin barrier formation. Bi-allelic pathogenic variants in CYP4F22 are associated with lamellar ichthyosis, a Mendelian disorder characterized by large, plate-like scales on the epidermis.

In a consanguineous Tunisian family, whole-exome sequencing identified a novel homozygous missense variant c.728G>T (p.Arg243Leu) segregating with lamellar ichthyosis in three affected siblings, with two additional affected relatives confirmed to be homozygous for the variant (PMID:31020658). This variant was predicted pathogenic by SIFT, PolyPhen, and MutationTaster, and no unrelated controls carried the allele.

In a Turkish cohort of twelve lamellar ichthyosis patients, one individual harbored a homozygous truncating mutation c.976C>T (p.Arg326Ter) in CYP4F22, linking loss-of-function alleles to the ichthyosis phenotype in an independent family (PMID:24397709). The study also documented ocular surface complications, underscoring the broader clinical spectrum associated with CYP4F22 mutations.

Functional assessment in a Chinese neonate with autosomal recessive congenital ichthyosis revealed compound heterozygous variants c.844C>T (p.Arg282Trp) and c.1189C>T (p.Arg397Cys) in CYP4F22 (PMID:35014717). In vitro expression demonstrated significantly reduced CYP4F22 protein levels for both mutants, which could be rescued by trichostatin A treatment, confirming a direct impact on enzyme stability and suggesting potential therapeutic avenues.

Collectively, these data support a haploinsufficiency mechanism whereby missense and truncating variants disrupt fatty acid ω-hydroxylation, impairing lipid barrier integrity without evidence of gain-of-function or dominant-negative effects. No studies have reported conflicting genotype–phenotype correlations for CYP4F22 in lamellar ichthyosis.

In summary, three unrelated probands with bi-allelic CYP4F22 variants, segregation in a consanguineous family, and concordant functional data establish a Moderate strength association between CYP4F22 and lamellar ichthyosis. Key Take-home: CYP4F22 should be included in diagnostic gene panels for autosomal recessive ichthyosis to enable molecular diagnosis and facilitate genetic counseling.

References

• International journal of dermatology • 2019 • A Tunisian family with a novel mutation in the gene CYP4F22 for lamellar ichthyosis and co-occurrence of hearing loss in a child due to mutation in the SLC26A4 gene. PMID:31020658
• Ophthalmic genetics • 2015 • Genotype and Anterior Segment Phenotype in a Cohort of Turkish Patients with Lamellar Ichthyosis. PMID:24397709
• The Journal of dermatology • 2022 • Whole-exome sequencing identified a novel pathogenic mutation of the CYP4F22 gene in a Chinese patient with autosomal recessive congenital ichthyosis and in vitro study of the mutant CYP4F22 protein. PMID:35014717

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