Diagnostic Exome Sequencing in Persons With Severe Intellectual Disability

Ligt, Joep de; Willemsen, Marjolein H.; Bon, Bregje W.M. van; Kleefstra, Tjitske; Silfhout, Anneke T. Vulto-van; Koolen, David A.; Vries, Petra de; Gilissen, Christian; Rosario, Marisol del; Hoischen, Alexander; Scheffer, Hans; Vries, Bert B.A. de; Brunner, Han G.; Veltman, Joris A.; Vissers, Lisenka E.L.M.

doi:10.1097/01.ogx.0000428160.59063.a6

Cited by 223 publications

(333 citation statements)

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“…Variants within the 56 known eye development disease genes (Figure 1, Supplementary Table S1) were selected for further analysis when all of the following conditions were met as in previous similar approaches 23 (Supplementary Figure S1). Variants that were nonsense, frameshift or canonical splice site variants, affecting the two nucleotides immediately adjacent to the splice donor or acceptor sites, were considered to be pathogenic.…”

Section: Variant Prioritisationmentioning

confidence: 99%

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

et al. 2013

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Developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, are caused by mutations encoding many different signalling and structural proteins in the developing eye. All modes of Mendelian inheritance occur and many are sporadic cases, so provision of accurate recurrence risk information for families and affected individuals is highly challenging. Extreme genetic heterogeneity renders testing for all known disease genes clinically unavailable with traditional methods. We used whole-exome sequencing in 11 unrelated developmental eye disease patients, as it provides a strategy for assessment of multiple disease genes simultaneously. We identified five causative variants in four patients in four different disease genes, GJA8, CRYGC, PAX6 and CYP1B1. This detection rate (36%) is high for a group of patients where clinical testing is frequently not undertaken due to lack of availability and cost. The results affected clinical management in all cases. These variants were detected in the cataract/microcornea and Peters anomaly patients. In two patients with coloboma/microphthalmia, variants in ABCB6 and GDF3 were identified with incomplete penetrance, highlighting the complex inheritance pattern associated with this phenotype. In the coloboma/microphthalmia patients, four other variants were identified in CYP1B1, and CYP1B1 emerged as a candidate gene to be considered as a modifier in coloboma/ microphthalmia.

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Section: Variant Prioritisationmentioning

confidence: 99%

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

et al. 2013

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“…3 Given this, several studies have investigated the benefits arising from the application of WES and WGS in the clinic. These studies have primarily focused on intellectual learning disability 4 or Mendelian conditions more broadly, 3,[5][6][7][8][9] consistently reporting diagnostic yields between 25 and 30%. In addition, WES and WGS have often informed prognoses or treatment of patients, for example in inflammatory bowel disease 10 and epilepsies.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, WES and WGS have often informed prognoses or treatment of patients, for example in inflammatory bowel disease 10 and epilepsies. 4,9 Considerable evidence therefore exists that applying WES or WGS in the clinic will improve the diagnosis and (in some cases) treatment of genetic disease, which may improve patient health outcomes and facilitate the more efficient use of health-care resources. However, demand is increasing for evidence on the incremental costs and health outcomes associated with these technologies compared with those used in current practice to support these assertions and to ensure that these new technologies are not merely an expensive add-on to patient care.…”

Section: Introductionmentioning

confidence: 99%

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

Schwarze

Buchanan

Taylor

et al. 2018

Genetics in Medicine

415

198

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Purpose: We conducted a systematic literature review to summarize the current health economic evidence for wholeexome sequencing (WES) and whole-genome sequencing (WGS).Methods: Relevant studies were identified in the EMBASE, MEDLINE, Cochrane Library, EconLit and University of York Centre for Reviews and Dissemination databases from January 2005 to July 2016. Publications were included in the review if they were economic evaluations, cost studies, or outcome studies.Results: Thirty-six studies met our inclusion criteria. These publications investigated the use of WES and WGS in a variety of genetic conditions in clinical practice, the most common being neurological or neurodevelopmental disorders. Study sample size varied from a single child to 2,000 patients. Cost estimates for a single test ranged from $555 to $5,169 for WES and from $1,906 to $24,810 for WGS. Few cost analyses presented data transparently and many publications did not state which components were included in cost estimates. Conclusion:The current health economic evidence base to support the more widespread use of WES and WGS in clinical practice is very limited. Studies that carefully evaluate the costs, effectiveness, and cost-effectiveness of these tests are urgently needed to support their translation into clinical practice.Genet Med advance online publication 15 February 2018

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“…[1][2][3] The PUF60 (Poly-U Binding Splicing Factor 60 kDa) gene encodes a general splicing factor that facilitates 3′ splice-site recognition at the early stages of spliceosome assembly. 4,5 PUF60 has been partly associated with the rare 8q24.3 microdeletion syndrome phenotype, in particular craniofacial and heart manifestations, in six patients and one fetal case.…”

Section: Introductionmentioning

confidence: 99%

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

et al. 2016

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International audienceVerheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletio

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Diagnostic Exome Sequencing in Persons With Severe Intellectual Disability

Cited by 223 publications

References 0 publications

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

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

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

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