Low grade mosaicism in hereditary haemorrhagic telangiectasia identified by bidirectional whole genome sequencing reads through the 100,000 Genomes Project clinical diagnostic pipeline

Jessica M Clarke, Mary Alikian, Sihao Xiao, Dalia Kasperaviciute, Ellen Thomas, Isobel Turbin, Kike Olupona, Elna Cifra, Emanuel Curetean, Teena Ferguson, Julian Redhead, Genomics England Research Consortium, Claire L Shovlin, Jessica M Clarke, Mary Alikian, Sihao Xiao, Dalia Kasperaviciute, Ellen Thomas, Isobel Turbin, Kike Olupona, Elna Cifra, Emanuel Curetean, Teena Ferguson, Julian Redhead, Genomics England Research Consortium, Claire L Shovlin

No abstract available

Keywords: molecular genetics.

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1

Variant consequences: (A) schematic of variant ENG (NM_001114753) c.1134G>A, p.(Ala378=) and (B) splice site predictions: the symbols indicate from highest to lowest, the percentage (%) reduction in splice site efficiency calculated by SpliceSiteFinder-like, MaxEntScan, NNSPLICE, GeneSplicer and HumanSplicingFinder. All five exceeded the 10% reduction considered significant, and three exceeded 30% reduction. The variant therefore meets sufficient American College of MedicalGenetics and Genomics (ACHG) / Association for Molecular Pathology (AMP) criteria to be classified as ‘likely pathogenic’: 1 strong criterion (Ps4: Genome Aggregation Database frequency 0.00003), plus ≥2 supporting criteria (PP3: predicted by five splicing programmes to reduce splice site efficiency; PP4: highly specific patient phenotype; and PP5: listed as pathogenic on two reputable sources7 9).

Figure 2

Variant detection: (A) of the 35 reads at Chr9:127 824 304 (arrowed), 28 (80%) were wild type and 7 (20%) were the variant sequence; (B) of the 18 forward strand reads, 16 (88.9%) were wild type, 2 (11.1%) were variant. Of the 17 reverse strand reads, 12 (70.6%) were wild type and 5 (29.4%) were variant. (C) The clean Sanger sequencing trace at the locus demonstrating wild-type (black) and variant (green) sequences. The wild-type peak was quantified as 793 RFUs, compared with the variant peak of 121 RFUs representing 15.3% of the total. RFU, relative fluorescence unit.