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Lemos, Roberta R.; Ramos, Eliana M.; Legati, Andrea; Nicolas, Gaël; Jenkinson, Emma M.; Livingston, John H.; Crow, Yanick J.; Campion, Dominique; Coppola, Giovanni; Oliveira, João R. M.
doi: 10.1002/humu.22778pmid: 25726928
Li, Mulin Jun; Deng, Jiaen; Wang, Panwen; Yang, Wanling; Ho, Shu Leong; Sham, Pak Chung; Wang, Junwen; Li, Miaoxin
doi: 10.1002/humu.22766pmid: 25676918
With the rapid advances in high‐throughput sequencing technologies, exome sequencing and targeted region sequencing have become routine approaches for identifying mutations of inherited disorders in both genetics research and molecular diagnosis. There is an imminent need for comprehensive and easy‐to‐use downstream analysis tools to isolate causal mutations in exome sequencing studies. We have developed a user‐friendly online framework, wKGGSeq, to provide systematic annotation, filtration, prioritization, and visualization functions for characterizing causal mutation(s) in exome sequencing studies of inherited disorders. wKGGSeq provides: (1) a novel strategy‐based procedure for downstream analysis of a large amount of exome sequencing data and (2) a disease‐targeted analysis procedure to facilitate clinical diagnosis of well‐studied genetic diseases. In addition, it is also equipped with abundant online annotation functions for sequence variants. We demonstrate that wKGGSeq either outperforms or is comparable to two popular tools in several real exome sequencing samples. This tool will greatly facilitate the downstream analysis of exome sequencing data and can play a useful role for researchers and clinicians in identifying causal mutations of inherited disorders. The wKGGSeq is freely available at http://statgenpro.psychiatry.hku.hk/wkggseq or http://jjwanglab.org/wkggseq, and will be updated frequently.
Dal Mas, Andrea; Fortugno, Paola; Donadon, Irving; Levati, Lauretta; Castiglia, Daniele; Pagani, Franco
doi: 10.1002/humu.22762pmid: 25665175
The c.891C>T synonymous transition in SPINK5 induces exon 11 (E11) skipping and causes Netherton syndrome (NS). Using a specific RNA–protein interaction assay followed by mass spectrometry analysis along with silencing and overexpression of splicing factors, we showed that this mutation affects an exonic bifunctional splicing regulatory element composed by two partially overlapping silencer and enhancer sequences, recognized by hnRNPA1 and Tra2β splicing factors, respectively. The C‐to‐T substitution concomitantly increases hnRNPA1 and weakens Tra2β‐binding sites, leading to pathological E11 skipping. In hybrid minigenes, exon‐specific U1 small nuclear RNAs (ExSpe U1s) that target by complementarity intronic sequences downstream of the donor splice site rescued the E11 skipping defect caused by the c.891C>T mutation. ExSpe U1 lentiviral‐mediated transduction of primary NS keratinocytes from a patient bearing the mutation recovered the correct full‐length SPINK5 mRNA and the corresponding functional lympho‐epithelial Kazal‐type related inhibitor protein in a dose‐dependent manner. This study documents the reliability of a mutation‐specific, ExSpe U1‐based, splicing therapy for a relatively large subset of European NS patients. Usage of ExSpe U1 may represent a general approach for correction of splicing defects affecting skin disease genes.
Grimm, Dominik G.; Azencott, Chloé‐Agathe; Aicheler, Fabian; Gieraths, Udo; MacArthur, Daniel G.; Samocha, Kaitlin E.; Cooper, David N.; Stenson, Peter D.; Daly, Mark J.; Smoller, Jordan W.; Duncan, Laramie E.; Borgwardt, Karsten M.
doi: 10.1002/humu.22768pmid: 25684150
Prioritizing missense variants for further experimental investigation is a key challenge in current sequencing studies for exploring complex and Mendelian diseases. A large number of in silico tools have been employed for the task of pathogenicity prediction, including PolyPhen‐2, SIFT, FatHMM, MutationTaster‐2, MutationAssessor, Combined Annotation Dependent Depletion, LRT, phyloP, and GERP++, as well as optimized methods of combining tool scores, such as Condel and Logit. Due to the wealth of these methods, an important practical question to answer is which of these tools generalize best, that is, correctly predict the pathogenic character of new variants. We here demonstrate in a study of 10 tools on five datasets that such a comparative evaluation of these tools is hindered by two types of circularity: they arise due to (1) the same variants or (2) different variants from the same protein occurring both in the datasets used for training and for evaluation of these tools, which may lead to overly optimistic results. We show that comparative evaluations of predictors that do not address these types of circularity may erroneously conclude that circularity confounded tools are most accurate among all tools, and may even outperform optimized combinations of tools.
Petukh, Marharyta; Kucukkal, Tugba G.; Alexov, Emil
doi: 10.1002/humu.22770pmid: 25689729
Statistical analysis was carried out on large set of naturally occurring human amino acid variations, and it was demonstrated that there is a preference for some amino acid substitutions to be associated with diseases. At an amino acid sequence level, it was shown that the disease‐causing variants frequently involve drastic changes in amino acid physicochemical properties of proteins such as charge, hydrophobicity, and geometry. Structural analysis of variants involved in diseases and being frequently observed in human population showed similar trends: disease‐causing variants tend to cause more changes in hydrogen bond network and salt bridges as compared with harmless amino acid mutations. Analysis of thermodynamics data reported in the literature, both experimental and computational, indicated that disease‐causing variants tend to destabilize proteins and their interactions, which prompted us to investigate the effects of amino acid mutations on large databases of experimentally measured energy changes in unrelated proteins. Although the experimental datasets were linked neither to diseases nor exclusory to human proteins, the observed trends were the same: amino acid mutations tend to destabilize proteins and their interactions. Having in mind that structural and thermodynamics properties are interrelated, it is pointed out that any large change in any of them is anticipated to cause a disease.
Syx, Delfien; Damme, Tim; Symoens, Sofie; Maiburg, Merel C.; Laar, Ingrid; Morton, Jenny; Suri, Mohnish; Del Campo, Miguel; Hausser, Ingrid; Hermanns‐Lê, Trinh; Paepe, Anne; Malfait, Fransiska
doi:
Nurden, Alan T.; Pillois, Xavier; Fiore, Mathieu; Alessi, Marie‐Christine; Bonduel, Mariana; Dreyfus, Marie; Goudemand, Jenny; Gruel, Yves; Benabdallah‐Guerida, Schéhérazade; Latger‐Cannard, Véronique; Négrier, Claude; Nugent, Diane; Oiron, Roseline d; Rand, Margaret L.;
Showing 1 to 10 of 11 Articles
Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT‐2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.
Bi‐allelic variants in CHST14, encoding dermatan 4‐O‐sulfotransferase‐1 (D4ST1), cause musculocontractural Ehlers–Danlos syndrome (MC‐EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi‐allelic variants in DSE, encoding dermatan sulfate epimerase‐1 (DS‐epi1), in a child with MC‐EDS features, suggested locus heterogeneity for this condition. DS‐epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC‐EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC‐EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1‐ as well as DS‐epi1‐deficient patients. However, in D4ST1‐deficiency, the decorin GAG is completely replaced by CS, whereas in DS‐epi1‐deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.
doi: 10.1002/humu.22776pmid: 25728920
We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real‐time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440‐13_c.1440‐1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin.