A feasibility study for rapid Whole-Exome Sequencing for paediatric genetic disorders in Hong Kong

Abstract

Traditionally genetic tests have long turn-around-time (TAT) and are unhelpful in acute patient care. Our objective is to test the feasibility of rapid WES in Hong Kong. Methods We recruit patients suspected to have a genetic disorder and (i) are critically ill; or (ii) a timely diagnosis may affect decision in management. We use a trio-based WES approach. First, we analyse genetic variants within one of the 13 gene panels based on clinical information, then the Mendeliome (4,278 OMIM genes) if negative. We aim to complete this stage of analysis within 14 working days. We will proceed to the exome-wide analysis with no time constraints if the first-tier testing is negative. Results and Conclusion This is an on-going study. So far, we have made 2 molecular diagnoses out of 10 cases. The first patient (M/4y) presented with Juvenile Myelomonocytic Leukemia (JMML). A de-novo mutation in NF1, p.R1947X, was identified as heterozygote in buccal mucosa and as homozygote in blood. This resulted in a diagnosis of NF1 and the “2nd hit” mutation leading to JMML. The second patient (F/9d) had prenatally detected bilateral echogenic kidneys. We identified 2 disease-causing mutation in PKHD1 (p.D703N and p.A3057fs), and substantiated the diagnosis of AR polycystic kidney disease. In both, the TAT was 5 days. Our preliminary results support the feasibility of a timely and accurate genetic diagnosis by WES.