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

Abstract

Short-rib thoracic dystrophies (SRTDs) are congenital disorders due to defects in primary cilium function. SRTDs are recessively inherited with mutations identified in 14 genes to date (comprising 398 exons). Conventional mutation detection (usually by iterative Sanger sequencing) is inefficient and expensive, and often not undertaken. Whole exome massive parallel sequencing has been used to identify new genes for SRTD (WDR34, WDR60 and IFT172); however, the clinical utility of whole exome sequencing (WES) has not been established. WES was performed in 11 individuals with SRTDs. Compound heterozygous or homozygous mutations were identified in six confirmed SRTD genes in 10 individuals (IFT172, DYNC2H1, TTC21B, WDR60, WDR34 and NEK1), giving overall sensitivity of 90.9%. WES data from 993 unaffected individuals sequenced using similar technology showed 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 sample. WES is sensitive, specific, efficient and cost-effective for mutation screening as well as gene discovery in SRTDs and can be considered a first-line methodology for mutation identification in affected individuals.

Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature

“…3,[31][32][33][34][35][36][37][38][39][40][41][42] Seven studies presented data on the costs of WES or WGS testing pathways, [24][25][26][27][43][44][45] and eight studies presented data on clinically relevant outcome measures for these tests. 5,6,[8][9][10][46][47][48] Of the eight full economic evaluations, two were CUAs 22,23 and six were CEAs, published between 2014 and 2017 in Australia (2), the United States (1), the UK (1), the Netherlands (1), and Canada (1).…”

“…While all 13 publications reported cost estimates for WES or WGS, only 3 stated the methods and sources underlying these estimates. 35,37,42 Of the seven studies that presented data on the costs of WES or WGS testing pathways, four evaluated WGS. Chrystoja and Diamandis 24 reviewed the potential of WGS and summarized cost data extracted from previously published scientific studies and commercial sources.…”

“…[19][20][21][26][27][28]36,37,45 Many publications did not state which components were included in the cost estimate. The costs for reagents ranged from £291 ($420) 35 to £1,171 ($1,685). 31 Cost estimates varied little over time.…”

Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short‐rib polydactyly type I, Saldino–Noonan type

“…In addition, some related ciliopathies have also been shown to result from mutations in these genes; cranioectodermal dysplasia (OMIM 614378 and 613610) due to abnormalities in WDR19 and WDR35, respectively, and Bardet–Biedl syndrome (OMIM 209901) due to defects in IFT172. However, thus far no genes have been associated with SRP type I .…”

Mutations in TTC21B cause different phenotypes in two childhood cases in China

“…The phenotypic variability observed in glomerular and cystic hereditary kidney diseases supports the hypothesis that mutations in multiple genes encoding proteins that converge in common pathomechanistic pathways may influence clinical presentation and outcome . Mutations in the TTC21B gene, which encodes a retrograde intraflagellar transport (IFT) protein, cause both isolated nephronophthisis (NPHP), syndromic Jeune Asphyxiating Thoracic Dystrophy (JATD) and familial focal segmental glomerulosclerosis (FSGS) . There is a hot spot of p.P209L mutation on TTC21B in Europe and North Africa .…”