VariantDB: A flexible annotation and filtering portal for next generation sequencing data

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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“…Variants were prioritized using our program VariantDB. 11 Potentially causative variants were confirmed by Sanger sequencing.…”

Section: Whole Exome Sequencingmentioning

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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“…16 Variant calling was performed with the Genome Analysis Toolkit Unified Genotyper, 17 and variants were annotated and filtered with the in-house-developed database VariantDB. 18 We selected unique variants or variants present in the ESP6500 and 1000 Genomes databases with a MAF<1%, prioritizing nonsense, nonsynonymous, splice-site, and indel variants in both a dominant and a recessive model.…”

mentioning

confidence: 99%

Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome

Meester

Southgate

Stittrich

et al. 2015

The American Journal of Human Genetics

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Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.

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“…Next-generation TAAD gene panel (online supplementary table S1) sequencing was performed on the DNA of probands according to previously described methods 22 23. Analysis of the raw data was performed using SeqPilot (JSI) or a Galaxy pipeline, followed by variant calling with the Genome Analysis Toolkit and variant annotation using an inhouse developed tool, VariantDB 24. Identified (likely) pathogenic variants were genotyped in both affected and unaffected available family members using Sanger sequencing.…”

Section: Methodsmentioning

confidence: 99%

Novel pathogenicSMAD2variants in five families with arterial aneurysm and dissection: further delineation of the phenotype

et al. 2018

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VariantDB: A flexible annotation and filtering portal for next generation sequencing data

Cited by 17 publications

References 37 publications

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

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

Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome

Novel pathogenicSMAD2variants in five families with arterial aneurysm and dissection: further delineation of the phenotype

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