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 availableKeywords: molecular genetics.
Conflict of interest statement
Competing interests: None declared.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7691802/bin/jmedgenet-2019-106794f01.jpg)
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](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7691802/bin/jmedgenet-2019-106794f02.jpg)
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.
References
- NHS England 2019/2020 National Genomic Test Directory, 2019. Available: [Accessed 26 Feb 2020].
- Martincorena I. Somatic mutation and clonal expansions in human tissues. Genome Med 2019;11:35 10.1186/s13073-019-0648-4
- Tørring PM, Kjeldsen AD, Ousager LB, Brusgaard K. ENG mutational mosaicism in a family with hereditary hemorrhagic telangiectasia. Mol Genet Genomic Med 2018;6:121–5. 10.1002/mgg3.361
- McDonald J, Wooderchak‐Donahue WL, Henderson K, Paul E, Morris A, Bayrak‐Toydemir P. Tissue‐specific mosaicism in hereditary hemorrhagic telangiectasia: implications for genetic testing in families. Am J Med Genet A 2018;176:1618–21. 10.1002/ajmg.a.38695
- Shovlin CL, Buscarini E, Kjeldsen AD, Mager HJ, Sabba C, Droege F, Geisthoff U, Ugolini S, Dupuis-Girod S. European Reference Network For Rare Vascular Diseases (VASCERN) Outcome Measures For Hereditary Haemorrhagic Telangiectasia (HHT). Orphanet J Rare Dis 2018;13:136 10.1186/s13023-018-0850-2
- University of Utah HHT Mutation Database, hosted by the ARUP Laboratories. Available: [Accessed 26 Feb 2020].
- Turbin IG, Brownlow S, Shovlin CL. Directing HHT patients to the 100,000 genomes project. Angiogenesis 2018;21 10.1007/s10456-017-9584-3
- Genomics England The 100,000 Genomes Project. Available: [Accessed 26 Feb 2020].
- National Center for Biotechnology Information ClinVar NM_000118.3(ENG):c.1134G>A (p.Ala378=). Available: [Accessed 26 Feb 2020].
- Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of medical genetics and genomics and the association for molecular pathology. Genet Med 2015;17:405–23. 10.1038/gim.2015.30
Source: PubMed