Research

Journal Articles

Fetal diagnosis of Mowat‐Wilson syndrome by whole exome sequencing. American Journal of Medical Genetics Part A. 179. 10.1002/ajmg.a.61295. Evans, Carey‐Anne, Pinner, Jason, Chan, Cheng, Bowyer, Lucy, Mowat, David, Buckley, Michael, Roscioli, Tony. (2019).

Mowat‐Wilson syndrome (MWS) is a complex genetic disorder associated with heterozygous variation in ZEB2. It is mainly characterized by moderate‐to‐severe intellectual disability, facial dysmorphism, epilepsy, and various malformations including Hirschsprung disease, corpus callosum anomalies, and congenital heart defects. It is rarely diagnosed prenatally and there is limited information available on the prenatal phenotype associated with MWS. Here we report the detection of a heterozygous de novo nonsense variant in ZEB2 by whole exome sequencing in a fetus with microphthalmia in addition to cardiac defects and typical MWS facial dysmorphism. As the prenatal phenotypic spectrum of MWS expands, the routine addition of fetal genomic testing particularly in the presence of multiple malformations will increase both the sensitivity and specificity of prenatal diagnostics.

Clinically Responsive Genomic Analysis Pipelines: Elements to Improve Detection Rate and Efficiency 

Samantha Leigh Sundercombe, Marina Berbic, Carey-Anne Evans, Corrina Cliffe, George Elakis, Suzanna E.L. Temple, Arthavan Selvanathan, Lisa Ewans, Nila Quayum, Cheng-Yee Nixon, Kerith-Rae Dias, Sarah Lang, Anna Richards, Shuxiang Goh, Meredith Wilson, David Mowat, Rani Sachdev, Sarah Sandaradura, Maie Walsh, Michelle A. Farrar, Rebecca Walsh, Janice Fletcher, Edwin P. Kirk, Guus M. Teunisse, Deborah Schofield, Michael Francis Buckley, Ying Zhu, and Tony Roscioli

 

Massively parallel sequencing has markedly improved mendelian diagnostic rates. This study assessed the effects of custom alterations to a diagnostic genomic bioinformatic pipeline in response to clinical need and derived practice recommendations relative to diagnostic rates and efficiency. The Genomic Annota- tion and Interpretation Application (GAIA) bioinformatics pipeline was designed to detect panel, exome, and genome sample integrity and prioritize gene variants in mendelian disorders. Reanalysis of selected negative cases was performed after improvements to the pipeline. GAIA improvements and their effect on sensitivity are described, including addition of a PubMed search for gene-disease associations not in the Online Mendelian Inheritance of Man database, inclusion of a process for calling low-quality variants (known as QPatch), and gene symbol nomenclature consistency checking. The new pipeline increased the diagnostic rate and reduced staff costs, resulting in a saving of US$844.34 per additional diagnosis. Recommendations for genomic analysis pipeline requirements are summarized. Clinically responsive bioinformatics pipeline improvements increase diagnostic sensitivity and increase cost-effectiveness. (J Mol Diagn 2021, 23: 894e905; https://doi.org/10.1016/j.jmoldx.2021.04.007)