Compound Heterozygous Mutations Involving Splicing Mutations Cause Rothmund-Thomson Syndrome in Two Chinese Families

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 causativeRECQL4 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 pathogenicRECQL4 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.