Trisomic rescue causing reduction to homozygosity for a novel ABCA12 mutation in harlequin ichthyosis

• Published in: Clinical genetics Vol. 76; no. 4; pp. 392 - 397
• Main Authors: Castiglia, D, Castori, M, Pisaneschi, E, Sommi, M, Covaciu, C, Zambruno, G, Fischer, J, Magnani, C
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2009; Wiley-Blackwell
• Subjects: ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Birth defects; Chromosomes; Chromosomes, Human, Pair 2 - genetics; confined placental mosaicism; Dermatology; Fatal Outcome; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic disorders; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes - genetics; harlequin fetus; Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue; Humans; Ichthyosis, Lamellar - genetics; isodisomy; Karyotyping; Medical genetics; Medical sciences; Microsatellite Repeats - genetics; Molecular and cellular biology; Mutation; nonsense mutation; Trisomy - genetics; Uniparental Disomy - genetics; UPD; Human; Dyskeratosis; Rescue; Skin disease; Nonsense mutation; Hyperkeratosis; UPD; Harlequin fetus; Homozygosity; Ichthyosis; Genetic disease; Isodisomy; Reduction; Placenta; confined placental mosaicism; Genetics; Mosaicism
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2009.01198.x

Harlequin ichthyosis (HI) is the most severe and often lethal form of congenital ichthyosis, characterized by abnormal desquamation and extreme skin thickening and hardening over the entire body. It is caused by recessive loss‐of‐function mutations in the ABCA12 gene located on chromosome 2q34. Here, we report a sporadic HI patient born prematurely due to severe growth delay and oligohydramnios. The diagnosis was confirmed by ABCA12 molecular analysis, which disclosed the novel homozygous mutation p.R287X. Microsatellite analysis and parental segregation study showed that the disease resulted from complete paternal isodisomy. In addition, chorionic villus karyotyping revealed a non‐mosaic chromosome 2 trisomy, while postnatal peripheral blood karyotype resulted normal female. Thus, these findings indicate that trisomic rescue is one step of the mutational cascade leading to reduction to homozygosity for the ABCA12 mutation in the embryo. Our case is the first reported HI patient in whom the disease is due to uniparental isodisomy.