Utilising clinical exome sequencing in patients with rare genetic disease and regions of homozygosity detected by SNP microarray


Patients from consanguineous backgrounds are at increased risk of having very rare, recessive genetic disorders making them susceptible to a diagnostic odyssey where it can take many years to achieve a genetic diagnosis. There is a need to update genetic testing methods in the National Health Service (NHS) to support patients with rare genetic diseases while taking into account the time and budget constraints imposed on the NHS. Research question: Can SNP microarray and clinical exome sequencing in a clinical diagnostic laboratory expedite a genetic diagnosis for patients with suspected rare genetic disorders who have consanguineous parents and form the basis of a cost-effective testing service? Overarching hypothesis: By highlighting cases most at risk of having homozygous pathogenic variants, prioritising gene agnostic testing and tailoring the analysis to the situation the chance of finding the causative variant would improve. 11 families with known consanguinity, and/or regions of homozygosity identified by SNP microarray, and an undiagnosed suspected genetic disorder were recruited to this study. Testing was performed using the Clinical Exome Solution (CES) from SOPHiA GENETICS and variant filtering prioritised rare homozygous variants. In addition a detailed cost and practicality analysis assessed future potential for the service in the NHS. Five pathogenic variants were identified in the CUL7, DHTKD1, SRD5A3, TRAPPC9 and UNC80 genes. These variants allowed a genetic diagnosis to be given to four families consisting of 3M syndrome, congenital disorder of glycosylation type 1Q, autosomal recessive mental retardation type 13 and infantile hypotonia, infantile with psychomotor retardation and characteristic facies type 2; an overall diagnostic yield of approximately 36%. In service the method was estimated to cost approximately £387.35 per patient sample making it a relatively cost-effective method that if taken up by other NHS laboratories could significantly improve patient outcomes and reduce the overall time and cost of the diagnostic odyssey for this patient group.