Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short‐rib thoracic dystrophies

A.M. McInerney‐Leo, J.E. Harris, P.J. Leo, M.S. Marshall, B. Gardiner, E. Kinning, H.Y. Leong, F. McKenzie, W.P. Ong, J. Vodopiutz, C. Wicking, M.A. Brown, A. Zankl, E.L. Duncan

Short-rib thoracic dystrophies (SRTDs) are congenital disorders due to defects in primary cilium function. SRTDs are recessively inherited with mutations identified in thirteen genes to date (398 exons). Conventional mutation detection (usually by iterative Sanger sequencing) is thus inefficient and expensive, and often not undertaken clinically. Whole exome massive parallel sequencing (WES) has been used to identify new genes for SRTD (WDR34, WDR60 and IFT172); however, the clinical utility of WES has not been established. WES was performed in eleven individuals with SRTDs. Compound heterozygous or homozygous mutations were identified in six known SRTD genes in ten individuals (IFT172, DYNC2H1, TTC21B, WDR60, WDR34 and NEK1), giving overall sensitivity of 90.9%. WES data from 993 unaffected individuals sequenced using similar technology demonstrated two individuals with rare (minor allele frequency <0.005) compound heterozygous variants of unknown significance in SRTD genes (specificity >99%). Costs for consumables, laboratory processing and bioinformatic analysis were <AU$850 per person. WES is sensitive, specific, efficient and cost-effective for mutation screening as well as gene discovery in SRTDs and should be considered a first-line methodology for mutation identification in affected individuals.