Compound heterozygous mutations involving splicing mutations cause Rothmund–Thomson syndrome in two Chinese families

Abstract. Objective:. Biallelic mutations in the RecQ like helicase (RECQL) 4 gene, a guardian of the genome, cause Rothmund–Thomson syndrome type II (RTS-II). Two Chinese girls with mild-phenotype RTS-II mainly restricted to their skin are herein described. Methods:. Blood specimens from two families with mild-phenotype RTS-II were collected. DNA isolation, RNA isolation and complementary DNA synthesis, and next-generation sequencing using a multi-gene panel were applied to verify the underlying pathogenic variants in the causative RECQL4 gene. Results:. We analyzed two patients with mild phenotypes. One patient had an unreported paternal c.2885+1G>A alteration in intervening sequence 16 and the previously reported maternal exon 14 c.2272C>T (p.R758X), both resulting in premature termination codons. The other patient carried two novel alterations, c.2886-1G>A and c.2752G>T (p.E918X). Complementary DNA sequencing showed that different splice-site mutations within the same intron could lead to completely different splicing modes. Conclusion:. We identified three novel pathogenic RECQL4 variants in two patients with RTS, thus expanding the mutational spectrum of RTS-II. We also explored their pathogenic effect by transcripts analysis to address genotype–phenotype correlations.