Download files
Abstract
Whole genome sequencing (WGS) is a powerful tool for diagnosis of Mendelian disorders. This study is aimed at evaluating the utility of WGS for molecular diagnosis of a multiethnic Intellectual Disability(ID) cohort.
Individuals were recruited through the Clinical Genetics department of a tertiary hospital in New South Wales, Australia, over three years. All patients had varying degrees of syndromic or non-syndromic ID; some had neurological syndromes. WGS was undertaken using singleton, duo or trio approach after assessment of clinical features, family history and screening genetic investigations. Next Generation Sequencing (NGS) technology was utilised for sequencing and analysing genomic data at Genome.One, a NATA accredited WGS laboratory in Australia. Analysis included sequence variation and copy number limited to exonic and flanking splice site regions of known Mendelian disease-causing genes. Families where no diagnosis was made on initial analysis, were reanalysed two years later.
A total of 46 probands from 43 families underwent WGS. There were 8/43 (18%) consanguineous families. A final diagnosis was made in 22/43 (51%) families. A variant providing a partial explanation of the phenotype was found in 3/43(6.9%) families. Actionable incidental findings were reported in 3/43 families. No copy number variants were identified. The RAS-MAPK pathway and microtubule related proteins emerged as predominant causative pathways within this phenotypically diverse cohort.
Reanalysis revealed candidate variants in 6/14 families reanalysed representing a potential increased yield of 14%.
In summary, application of WGS for investigation of an unselected ID cohort demonstrated a significant diagnostic yield. A clinical and genomic data review two years after the initial analysis was an achievable and worthwhile exercise, increasing the diagnostic yield to 65%.