Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families

다국어 초록 (Multilingual Abstract)

Autosomal recessive congenital ichthyosis (ARCI), a phenotypically heterogeneous group of non‐syndromic Mendelian disorders of keratinization, is caused by mutations in as many as 13 distinct genes. We examined a cohort of 125 consanguineous families with ARCI for underlying genetic mutations. The patients’ DNA was analyzed with a gene‐targeted next generation sequencing panel comprising 38 ichthyosis associated genes. The interpretations of results of genomic data were assisted by genome‐wide homozygosity mapping and transcriptome sequencing. Sequence data analysis identified biallelic mutations in 106 families out of a total of 125 (85%), most of them (102, 96.2%) being homozygous, reflecting consanguinity in these families. Among the 85 distinct mutations in 10 different genes, 45 (53%) were previously unreported. Phenotype‐genotype correlations allowed assignment of specific genes in the majority of the families to a specific subtype of ARCI, lamellar ichthyosis (LI) versus congenital ichthyosiform erythroderma (CIE). Interestingly, mutations in several genes could give rise to an overlapping phenotype consistent with either LI or CIE. Also, this is the third report for SDR9C7 and SULT2B1, and fourth report for CERS3 mutations. Direct comparison of our results with previously published regional cohorts highlights the global mutation landscape of ARCI, however, population specific differences were noted.
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of nonsyndromic disorders of keratinization. We characterized the mutation landscape in a cohort of 125 mostly consanguineous families by a sequencing array targeting 38 ichthyosis‐associated genes, followed by whole exome sequencing, genome‐wide homozygosity mapping and transcription profiling by RNA‐Seq. Biallelic mutations were identified in 106 families (85%), highlighting the global mutation landscape in ARCI, with clinical correlations.