Chromosomal inversions as a hidden disease-modifying factor

Toshifumi Nomura,1 Shotaro Suzuki,1 Toshinari Miyauchi,1 Masae Takeda,1 Yasuyuki Fujita,1 Wataru Nishie,1 Masashi Akiyama,2 and Hiroshi Shimizu1

1Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
2Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Heterozygous chromosomal inversions suppress recombination in the inverted region. Therefore, they, in theory, could influence recombination-associated phenotypes of human diseases, but no cases verifying this hypothesis have been reported. Here we describe a 35-year-old man with severe congenital ichthyosis. Mutation analysis revealed a heterozygous splice-site mutation, c.1374-2A>G (p.Ser458ArgfsTer120), in KRT10 on 17q21.2. This mutation had already been reported in patients with ichthyosis with confetti type I (IWC-I), a prominent skin disease characterized by the frequent occurrence of ‘recombination-induced’ reversion of pathogenic mutations in keratinocytes. Intriguingly, the number of revertant skin areas in the patient was much less than that in typical IWC-I cases. G-band karyotyping revealed that he harbors a heterozygous non-pathogenic pericentric inversion, inv(17)(p13q12), whose breakpoint was subsequently refined to chromosomal positions (chr17: 36,544,407-36,735,254) by fluorescence in situ hybridization. Collectively, the only chance of reversion by somatic recombination appears to be when recombination takes place between the inversion breakpoint (17q12) and the KRT10 mutation (17q21.2). Indeed, in the examined revertant keratinocytes, the KRT10 mutation was diminished by somatic recombination starting from chromosomal positions (chr17: 36,780,184-36,805,589) on 17q12. This study provides the first evidence implicating chromosomal inversions as a potential modifier of clinical phenotypes. Furthermore, much less occurrence of revertant spots in the ‘recombination-suppressed’ patient suggests that somatic recombination is the main mechanism of revertant mosaicism in IWC-I.