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.

Keywords: Skin permeability barrier; congenital ichthyosis; erythema; genotype/phenotype correlation; homozygosity mapping; skin scaling.

Figure 1

Clinical features of patients with ARCI, categorized by mutant genes. (a–c) TGM1 affected patients showed generalized severe, dark colored scales, and palmoplantar hyperkeratosis, apparently independent of type of mutation or treatment. (d) Patient diagnosed with SII, with no visible skin alterations at 6 years of age. (e–f) Patients with NIPAL4 splice site (e) and missense (f) mutations presented a variable range of symptoms like milder to moderate scaling more prominent in the upper body half but no palmar hyperkeratosis. (g–h) Patients with ABCA12 mutations with fine to medium‐sized whitish scaling and erythema (SA‐02), and with slightly milder phenotype and white scales (PK01). (i) Patients from families PK04 and PK03 with generalized whitish scaling, quite visible on the hands, diagnosed with ALOXE3 nonsense mutations. (j) Affected individuals from another branch of family PK03, initially also diagnosed with ARCI. Upon reinvestigation, they showed more localized severe scaling on the hands and feet as well as nail and teeth (not shown) anomalies consistent with a diagnosis of Papillon–Lefèvre syndrome caused by CTSC mutation

Figure 2

Family pedigrees and sequences of unknown mutations identified in this study. Pedigrees show index patients used for homozygosity mapping marked with a black outlined arrow (↑) and all samples confirmed by Sanger sequencing marked with a star (*). All parents of patients have a consanguinity relation. At least one parent is included in the displayed sequences to demonstrate co‐segregation. Red arrows indicate the positions of nucleotide substitutions or deletions. In the reference sequences, uppercase letters indicate exon nucleotides and lowercase letters intronic bases. (a) Examples of two Saudi Arabian pedigrees with patients with a homozygous intronic deletion in intron 1 of NIPAL4. (b) A homozygous missense mutation c.1340A>C was detected in exon 9 of TGM1 in SA‐04. (c) Patient SA‐05 was identified with a homozygous mutation in the acceptor splice site of TGM1 intron 4. (d) A previously unknown missense mutation in exon 9 of CYP4F22 was found in SA‐15

Figure 3

Schematic representation of genotype/phenotype correlations of ARCI found in this study. All phenotypes and genotypes were grouped according to our findings. Each index case is named and boxed according to the severity of the scaling (X axis) and its extension (Y axis). Types of mutations are indicated by the shape of the boxes, that is, squares for missense, oval for nonsense, and diamonds for splice site mutations. Scaling type was also included, with coarse scales represented by a full‐outline box and fine scales by dashed outlines. Patients with an erythematous phenotype are represented by an asterisk (*) and those treated with acitretin are underlined