ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 14.6 | DOI: 10.1530/ey.18.14.6

Nature 2020; 583: 96–102

The authors applied whole-genome sequencing (WGS) in 9,802 patients with a rare disease in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. WGS identified the genetic diagnosis in 1138/7065 extensively phenotyped participants. They identified 95 genes in which mutations were very likely to be the cause of a rare Mendelian disease.

The large majority of children born with rare diseases undergo a long journey until diagnosis, from the gradually emerging manifestation of the disease phenotype, through multiple health referrals and convoluted, repeated and invasive investigations. On average, it takes more than 2 years to reach a diagnosis. This paper describes a major milestone towards the use of genomics in routine clinical practice, especially in those patients who have a higher likelihood of a genetic disorder. They describe a number of cases for whom WGS findings informed treatment decisions (with a strong bias towards haematological disorders reflecting the interests of the investigators), including specific treatments for thrombocytopenia and early-onset dystonia. Other diagnoses informed prediction of high risk of disease progression, or stratification of patients into higher or lower risk of malignancy. Furthermore, they demonstrate the added value of WGS above gene centric sequencing (whole-exome sequencing), by identifying causal variants in gene-regulatory regions in the non-coding genome.

We look forward to the widespread use of genomics in paediatric endocrinology and diabetes, to shorten time to diagnosis and to direct personalised treatments and disease monitoring. Towards this aim there are still many challenges, discussed in this paper, ranging from laboratory protocols and quality control, development of fast and accurate data processing and statistical methodology, patient information and consent with potential ethical issues for the wider family, and complementary studies of WGS in large populations to ascertain the contribution of mutations to the extreme tails of normal phenotypic distributions.

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