作者
Elizabeth Palmer,Rani Sachdev,Rebecca Macintosh,Uirá Souto Melo,Stefan Mundlos,Sarah Righetti,Tejaswi Kandula,André E. Minoche,Clare Puttick,Velimir Gayevskiy,Luke B. Hesson,Senel Idrisoglu,Cheryl Shoubridge,Monica Hong Ngoc Thai,Ryan L. Davis,Alexander P. Drew,Hugo Sampaio,P. Ian Andrews,John A. Lawson,Michael Cardamone,David Mowat,Alison Colley,Sarah Kummerfeld,Marcel E. Dinger,Mark J. Cowley,Tony Roscioli,Ann Bye,Edwin P. Kirk
摘要
Objective
To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE). Methods
We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15). Results
Eight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked. Conclusion
WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.