Search

Whole-genome sequencing (WGS) has been championed within the UK National Health Service (NHS) and represents one of the approaches within the forthcoming UK National Genomic Test Directory to identify genetic variants that cause particular rare inherited diseases.1 Although diploid organisms such as man develop from a single cell, postzygotic somatic mutations occur and lead to mosaicism.2 Sufficiently early generation of a disease-causing DNA sequence variant can result in a mosaic individual who is the first member of a family to be affected by an inherited disorder.3 4 Their causative DNA sequence variant is likely to be present at less than the 50% expected for a heterozygote, and may be difficult to detect with confidence. Greater ability to detect mosaicism has been used to favour higher depth panel-based sequencing rather than WGS as, due to sequencing capacities, there are trade-offs between the number of target nucleotides sequenced and the average depth of reads at any given nucleotide. It is increasingly recognised that hereditary haemorrhagic telangiectasia (HHT5) is a condition where the first affected member of the family may be a mosaic.3 4 HHT is transmitted as an autosomal dominant trait via a single pathogenic DNA sequence variant, usually in ENG , ACVRL1 or SMAD4 .5 There are hundreds of different pathogenic variants in these genes in different HHT families, all resulting in similar clinical features.6 HHT is diagnosed clinically by the presence of at least three Curacao Criteria: recurrent nosebleeds, mucocutaneous telangiectasia, visceral involvement such as pulmonary, hepatic, gastrointestinal or cerebral arteriovenous malformations (AVMs), and an affected first-degree relative.5 A high index of suspicion for HHT is warranted, particularly in cases where more than one AVM is present or where multiple generations display these features. As we have shown, however, high proportions of …