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(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2017/07/14

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ExCNVSS: A Noise-Robust Method for Copy Number Variation Detection in Whole Exome Sequencing Data.

Biomed Res Int. 2017;2017:9631282

Authors: Kong J, Shin J, Won J, Lee K, Lee U, Yoon J

Abstract
Copy number variations (CNVs) are structural variants associated with human diseases. Recent studies verified that disease-related genes are based on the extraction of rare de novo and transmitted CNVs from exome sequencing data. The need for more efficient and accurate methods has increased, which still remains a challenging problem due to coverage biases, as well as the sparse, small-sized, and noncontinuous nature of exome sequencing. In this study, we developed a new CNV detection method, ExCNVSS, based on read coverage depth evaluation and scale-space filtering to resolve these problems. We also developed the method ExCNVSS_noRatio, which is a version of ExCNVSS, for applying to cases with an input of test data only without the need to consider the availability of a matched control. To evaluate the performance of our method, we tested it with 11 different simulated data sets and 10 real HapMap samples' data. The results demonstrated that ExCNVSS outperformed three other state-of-the-art methods and that our method corrected for coverage biases and detected all-sized CNVs even without matched control data.

PMID: 28698882 [PubMed - in process]

Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders.

Am J Med Genet A. 2017 Jul 11;:

Authors: Bashir RA, Dixit A, Goedhart C, Parboosingh JS, Innes AM, Care for Rare Canada Consortium, Ferreira P, Hasan SU, Au PB

Abstract
We report two patients with sagittal craniosynostosis, hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia. The clinical presentation of both patients was initially thought to be suggestive of Lin-Gettig syndrome (LGS), a multiple malformation syndrome associated with craniosynostosis that was initially reported in two brothers in 1990, with a third patient reported in 2003. Our first patient was subsequently found through exome sequencing to have a de novo mutation in KAT6B, c.4572dupT, p.(Thr1525Tyrfs*16). The second patient was ascertained as possible LGS, but KAT6B mutation testing was pursued clinically after the identification of the KAT6B mutation in Patient 1, and identified a de novo mutation, c.4205_4206delCT, p.(Ser1402Cysfs*5). The phenotypic spectrum of KAT6B mutations has been expanding since identification of KAT6B mutations in genitopatellar syndrome (GPS) and Say Barber Biesecker Young Simpson (SBBYS) syndrome patients. We show that craniosynostosis, which has not been previously reported in association with KAT6B mutations, may be part of the genitopatellar/Say Barber Biesecker Young Simpson spectrum. These two patients also further demonstrate the overlapping phenotypes of genitopatellar and SBBYS syndromes recently observed by others. Furthermore, we propose that it is possible that one or more of the previous cases of LGS may have also been due to mutation in KAT6B, and that LGS may actually be a variant within the KAT6B spectrum and not a distinct clinical entity.

PMID: 28696035 [PubMed - as supplied by publisher]

Identification of two novel SH3PXD2B gene mutations in Frank-Ter Haar syndrome by exome sequencing: Case report and review of the literature.

Gene. 2017 Jul 07;:

Authors: Zrhidri A, Jaouad IC, Lyahyai J, Raymond L, Egéa G, Taoudi M, Mouatassim SEL, Sefiani A

Abstract
BACKGROUND: Frank-Ter Haar syndrome (FTHS) is an autosomal-recessive disorder characterized by skeletal, cardio-vascular, and eye abnormalities, such as increased intraocular pressure, prominent eyes, and hypertelorism. The most common underlying genetic defect in Frank-Ter Haar syndrome appears to be due to mutations in the SH3PXD2B gene on chromosome 5q35.1. Until now, only six mutations in SH3PXD2B gene have been identified. A genetic heterogeneity of FTHS was suggested in previous studies.
DESIGN: FTHS was suspected clinically in a girl of 2years old, born from non-consanguineous Moroccan healthy parents. The patient had been referred to a medical genetics outpatient clinic for dysmorphic facial features. Whole Exome Sequencing (WES) was performed in the patient and her parents, in addition to Sanger sequencing that was carried out to confirm the results.
RESULTS: We report the first description of a Moroccan FTHS patient with two novel compound heterozygous mutations c.806G>A; p.Trp269* (maternal allele) and c.892delC; p.Asp299Thrfs*44 (paternal allele) in the SH3PXD2B gene. Sanger sequencing confirmed this mutation in the affected girl and demonstrated that her parents carry this mutation in heterozygous state.
CONCLUSION: Our results confirm the clinical diagnosis of FTHS in this reported family and contribute to expand the mutational spectrum of this rare disease. Our study shows also, that exome sequencing is a powerful and a cost-effective tool for the diagnosis of a supposed genetically heterogeneous disorder such FTHS.

PMID: 28694206 [PubMed - as supplied by publisher]

Predicting treatment resistance and relapse through circulating DNA.

Breast. 2017 Jul 07;:

Authors: Beddowes E, Sammut SJ, Gao M, Caldas C

Abstract
The use of circulating DNA(ctDNA) to provide a non-invasive, personalised genomic snapshot of a patients' tumour has huge potential. Over the past five years this area of research has gained huge momentum. A number of studies in metastatic breast cancer have shown the potential of ctDNA to predict prognosis and treatment response using ctDNA. Further developments have included deeper sequencing using whole exome and shallow whole genome approaches which has the potential to identify new mutations and chromosomal copy number changes which appear upon resistance to treatment. In early breast cancer, recent work utilising personalised digital PCR probes has shown huge potential in predicting disease relapse and the detection of micrometastatic disease which could lead to improved treatment and outcome for these patients. Specific pathways of resistance can also be monitored and liquid biopsy approaches for the detection of ESR1 mutations have been used which could identify patients who have become resistant to particular endocrine therapies. The identification of PIK3CA mutations in plasma has also been shown to predict a higher response rate to specific PI3K inhibitors and could be used as a non-invasive screening tool prior to treatment. Further work on the detection of exosomal miRNA and hypermethylated DNA in plasma have shown promise in terms of specificity for early breast cancer detection and could be used to monitor treatment response. This review will focus on technological advances in the field, early detection of relapse and the detection of tumour-specific genomic alterations which could predict treatment response and resistance in patients with breast cancer.

PMID: 28694015 [PubMed - as supplied by publisher]

Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis.

J Clin Invest. 2017 Jul 10;:

Authors: Zang S, Li J, Yang H, Zeng H, Han W, Zhang J, Lee M, Moczygemba M, Isgandarova S, Yang Y, Zhou Y, Rao A, You MJ, Sun D, Huang Y

Abstract
Angioimmunoblastic T cell lymphoma (AITL) represents a distinct, aggressive form of peripheral T cell lymphoma with a dismal prognosis. Recent exome sequencing in patients with AITL has revealed the frequent coexistence of somatic mutations in the Rho GTPase RhoA (RhoAG17V) and loss-of-function mutations in the 5-methylcytosine oxidase TET2. Here, we have demonstrated that TET2 loss and RhoAG17V expression in mature murine T cells cooperatively cause abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression, phosphorylation, and subcellular localization, an abnormality that is also detected in human primary AITL tumor samples. Reexpression of FoxO1 attenuated aberrant immune responses induced in mouse models adoptively transferred with T cells and bearing genetic lesions in both TET2 and RhoA. Our findings suggest a mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells that may account for immunoinflammatory responses associated with AITL patients.

PMID: 28691928 [PubMed - as supplied by publisher]

Integrating Next-Generation Genomic Sequencing and Mass Spectrometry to Estimate Allele-Specific Protein Abundance in Human Brain.

J Proteome Res. 2017 Jul 10;:

Authors: Wingo TS, Duong DM, Zhou M, Dammer EB, Wu H, Cutler DJ, Lah JJ, Levey AI, Seyfried NT

Abstract
Gene expression contributes to phenotypic traits and human disease. To date, comparatively less is known about regulators of protein abundance, which is also under genetic control and likely influences clinical phenotypes. However, identifying and quantifying allele-specific protein abundance by bottom-up proteomics is challenging since single nucleotide variants (SNVs) that alter protein sequence are not considered in standard human protein databases. To address this, we developed the GenPro software and used it to create personalized protein databases (PPDs) to identify single amino acid variants (SAAVs) at the protein level from whole exome sequencing. In silico assessment of PPDs generated by GenPro revealed only a 1% increase in tryptic search space compared to a direct translation of all human transcripts and an equivalent search space compared to the UniProtKB reference database. To identify a large unbiased number of SAAV peptides, we performed high-resolution mass spectrometry-based proteomics for two human post-mortem brain samples and searched the collected MS/MS spectra against their respective PPD. We found an average of ~117,000 unique peptides mapping to ~9,300 protein groups for each sample and of these 977 were unique variant peptides. We found that over 400 reference and SAAV peptide pairs were, on average, equally abundant in human brain by label-free ion intensity measurements and confirmed the absolute levels of three reference and SAAV peptide pairs using heavy labeled peptides standards coupled with parallel reaction monitoring (PRM). Our results highlight the utility of integrating genomic and proteomic sequencing data to identify sample-specific SAAV peptides and support the hypothesis that most alleles are equally expressed in human brain.

PMID: 28691493 [PubMed - as supplied by publisher]

Next generation sequencing and array-based comparative genomic hybridization for molecular diagnosis of pediatric endocrine disorders.

Ann Pediatr Endocrinol Metab. 2017 Jun;22(2):90-94

Authors: Fukami M, Miyado M

Abstract
Next-generation sequencing (NGS) and array-based comparative genomic hybridization (array CGH) have enabled us to perform high-throughput mutation screening and genome-wide copy number analysis, respectively. These methods can be used for molecular diagnosis of pediatric endocrine disorders. NGS has determined the frequency and phenotypic variation of mutations in several disease-associated genes. Furthermore, whole exome analysis using NGS has successfully identified several novel causative genes for endocrine disorders. Array CGH is currently used as the standard procedure for molecular cytogenetic analysis. Array CGH can detect various submicroscopic genomic rearrangements involving exons or enhancers of disease-associated genes. This review introduces some examples of the use of NGS and array CGH for the molecular diagnosis of pediatric endocrine disorders.

PMID: 28690986 [PubMed]

Whole-exome sequencing analysis of Waardenburg syndrome in a Chinese family.

Hum Genome Var. 2017;4:17027

Authors: Chen D, Zhao N, Wang J, Li Z, Wu C, Fu J, Xiao H

Abstract
Waardenburg syndrome (WS) is a dominantly inherited, genetically heterogeneous auditory-pigmentary syndrome characterized by non-progressive sensorineural hearing loss and iris discoloration. By whole-exome sequencing (WES), we identified a nonsense mutation (c.598C>T) in PAX3 gene, predicted to be disease causing by in silico analysis. This is the first report of genetically diagnosed case of WS PAX3 c.598C>T nonsense mutation in Chinese ethnic origin by WES and in silico functional prediction methods.

PMID: 28690861 [PubMed - in process]

The detection of a novel insertion mutation in exon 2 of the MEFV gene associated with familial mediterranean fever in a moroccan family.

Hum Genome Var. 2017;4:17023

Authors: Mejtoute T, Sayel H, El-Akhal J, Moufid FZ, Bouguenouch L, El Bouchikhi I, Hida M, Couissi D, Ouldim K

Abstract
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is inherited in an autosomal recessive manner and is caused by mutations in the MEFV gene. As the name indicates, FMF occurs within families and is more common in individuals of Mediterranean descent than in persons of any other ethnicity. To date, 314 mutations have been reported. We studied a Moroccan family with a total of five members, including a mother who was presenting with symptoms of FMF, while her four children remained asymptomatic. The five patients were screened by DNA sequencing of exon 2 and exon 10 of the MEFV gene. Then, complete exome sequencing analysis of the MEFV gene was done for the patients in whom a novel mutation was detected. This analysis identified a novel single base Cytosine (C) insertion mutation in the coding region of the MEFV gene, named c.441dupC (p. Glu148Argfs*5 or E148RfsX5), which resulted in a mutated Pyrin/Marenostrin protein. This is the first report of a new mutation in exon 2 of the MEFV gene in a Moroccan family. This novel insertion mutation may provide important information for further studies of FMF pathogenesis.

PMID: 28690860 [PubMed - in process]

GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant.

Neurobiol Dis. 2017 Jul 05;:

Authors: Giddens MM, Wong JC, Schroeder JP, Farrow EG, Smith BM, Owino S, Soden SE, Meyer RC, Saunders C, LePichon JB, Weinshenker D, Escayg A, Hall RA

Abstract
Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G>T [Lys349Asp]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in GPR37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of GPR37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy.

PMID: 28688853 [PubMed - as supplied by publisher]

Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling.

Circulation. 2017 Jul 07;:

Authors: Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco MR, Chung WK, Dubois J, Lacour JP, Martorell L, Mazereeuw-Hautier J, Pyeritz RE, Amor DJ, Bisdorff A, Blei F, Bombei H, Dompmartin A, Brooks DG, Dupont J, González-Enseñat MA, Frieden IJ, Gérard M, Kvarnung M, Hanson-Kahn AK, Hudgins L, Léauté-Labrèze C, McCuaig C, Metry D, Parent P, Paul C, Petit F, Phan A, Quéré I, Salhi A, Turner AM, Vabres P, Vicente A, Wargon O, Watanabe S, Weibel L, Wilson A, Willing M, Mulliken JB, Boon LM, Vikkula M

Abstract
Background -Most AVMs are localized and occur sporadically; however they also can be multifocal in autosomal dominant disorders, such as Hereditary Hemorrhagic Telangiectasia (HHT) and Capillary Malformation-Arteriovenous Malformation (CM-AVM). Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. Methods -We conducted a genome-wide linkage study on a CM-AVM family. Whole exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate-gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitroResults -We found evidence for linkage in two loci. Whole-exome sequencing data unraveled four distinct damaging variants in EPHB4 in five families that co-segregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 lead to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are non-synonymous variants that result in amino-acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. Conclusions -We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also HHT. RASA1 encoded p120RASGAP is a direct effector of EPHB4. Our data highlights the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for arterio-venous malformations.

PMID: 28687708 [PubMed - as supplied by publisher]

Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia.

Mitochondrion. 2017 Jul 04;:

Authors: Schottmann G, Picker-Minh S, Schwarz JM, Gill E, Rodenburg RJT, Stenzel W, Kaindl AM, Schuelke M

Abstract
Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial complex I and pyruvate dehydrogenase complex (PDHc) deficiency. Whole exome sequencing uncovered a known EXOSC3 mutation p.(D132A) as the underlying cause. In patient fibroblasts, a large portion of the EXOSC3 protein was trapped in the cytosol. MtDNA copy numbers in muscle were reduced to 35%, but mutations in the mtDNA and in nuclear mitochondrial genes were ruled out. RNA-Seq of patient muscle showed highly increased mRNA copy numbers, especially for genes encoding structural subunits of OXPHOS complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.

PMID: 28687512 [PubMed - as supplied by publisher]

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia.

Am J Hum Genet. 2017 Jul 06;101(1):87-103

Authors: Seixas AI, Loureiro JR, Costa C, Ordóñez-Ugalde A, Marcelino H, Oliveira CL, Loureiro JL, Dhingra A, Brandão E, Cruz VT, Timóteo A, Quintáns B, Rouleau GA, Rizzu P, Carracedo Á, Bessa J, Heutink P, Sequeiros J, Sobrido MJ, Coutinho P, Silveira I

Abstract
Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7-400] and [(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5' UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.

PMID: 28686858 [PubMed - in process]

Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome.

PLoS One. 2017;12(7):e0180485

Authors: Hammer MF, Ishii A, Johnstone L, Tchourbanov A, Lau B, Sprissler R, Hallmark B, Zhang M, Zhou J, Watkins J, Hirose S

Abstract
Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.

PMID: 28686619 [PubMed - in process]

Juvenile-onset generalized lipodystrophy due to a novel heterozygous missense LMNA mutation affecting lamin C.

Am J Med Genet A. 2017 Jul 07;:

Authors: Patni N, Xing C, Agarwal AK, Garg A

Abstract
The LMNA gene contains 12 exons and encodes lamins A and C by alternative splicing within exon 10. While mutations in lamin A specific residues cause several diseases including lipodystrophy, progeria, muscular dystrophy, neuropathy, and cardiomyopathy, only three families with mutations in lamin C-specific residues are reported with cardiomyopathy, neuropathy, and muscular dystrophy so far. We now report two brothers with juvenile-onset generalized lipodystrophy due to a lamin C-specific mutation. The proband, a 23-year-old Caucasian male was reported to have generalized lipodystrophy at 3 weeks of age, developed diabetes, hypertriglyceridemia, hypertension and liver problems and died with complications of cirrhosis, and kidney failure. His younger brother, a 37-year-old Caucasian male developed generalized lipodystrophy around 2 years of age and was diagnosed with diabetes, hypertriglyceridemia, fatty liver, and hypertension at 36 years of age. Their father also died of end stage renal disease at age 52 years. Exome sequencing of the proband revealed an extremely rare missense heterozygous variant c.1711_1712CG>TC; p.(Arg571Ser) in LMNA which was confirmed by Sanger sequencing in both the patients. Interestingly, the mutation had no effect on mRNA splicing or relative expression of lamin A or C mRNA and protein in the lymphoblasts. Our observations suggest that mutant lamin C disrupts its interaction with other cellular proteins resulting in generalized lipodystrophy due to defective development and maintenance of adipose tissue.

PMID: 28686329 [PubMed - as supplied by publisher]

Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and three novel SLC37A4 variants.

Clin Genet. 2017 Jul 07;:

Authors: Skakic A, Djordjevic M, Sarajlija A, Klaassen K, Tosic N, Kecman B, Ugrin M, Spasovski V, Pavlovic S, Stojiljkovic M

Abstract
Glycogen storage disease (GSD) type I is inborn metabolic disease characterized by accumulation of glycogen in multiple organs. We analyzed 38 patients with clinical suspicion of GSD I using Sanger and next-generation sequencing (NGS). We identified 28 GSD Ib and five Ia patients. In five patients, GSD III, VI, IX, cholesteryl-ester storage disease and Shwachman-Diamond syndrome diagnoses were set using NGS. Incidences for GSD Ia and GSD Ib were estimated at 1:172746 and 1:60461 live-births respectively. Two variants were identified in G6PC gene: c.247C>T (p.Arg83Cys) and c.518T>C (p.Leu173Pro). In SLC37A4 gene, six variants were detected. Three previously reported variants c.81T>A (p.Asn27Lys), c.162C>A (p.Ser54Arg) and c.1042_1043delCT (p.Leu348Valfs*53) accounted for 87% of all analyzed alleles. Computational, transcription studies and/or clinical presentation in patients confirmed pathogenic effect of three novel variants: c.248G>A (p.Gly83Glu), c.404G>A (p.Gly135Asp) and c.785G>A (p.Ser263Glyfs*33 or p.Gly262Asp). In the cohort, hepatomegaly, hypoglycaemia and failure to thrive were the most frequent presenting signs of GSD Ia, while hepatomegaly and recurrent bacterial infections were clinical hallmarks of GSD Ib. All GSD Ib patients developed neutropenia while 20.6% developed inflammatory bowel disease. Our study revealed the highest worldwide incidence of GSD Ib. Furthermore, description of three novel variants will facilitate medical genetic practice.

PMID: 28685844 [PubMed - as supplied by publisher]

EZH2 and ZFX oncogenes in malignant behaviour of parathyroid neoplasms.

Endocrine. 2016 Oct;54(1):55-59

Authors: Sanpaolo E, Miroballo M, Corbetta S, Verdelli C, Baorda F, Balsamo T, Graziano P, Fabrizio FP, Cinque L, Scillitani A, Muscarella LA, Guarnieri V

Abstract
Several studies reported somatic mutations of many genes (MEN1, CTNNB1, CDKIs and others) in parathyroid adenoma, although with different prevalence. Recently, activating mutations of the EZH2 and ZFX oncogenes were identified in benign parathyroid adenoma by whole exome sequencing. The same mutations had been found in blood and ovary malignant tumours. On one hand, this result raised the hypothesis that these oncogenes may play a role in the onset of parathyroid tumour, but it would also suggest they may be involved in malignant, rather benign, parathyroid neoplasm. Our aim was to verify the occurrence of selected mutations of the EZH2 and ZFX genes in an Italian cohort of 23 sporadic parathyroid carcinomas, 12 atypical and 45 typical adenomas. DNA was extracted from paraffin-embedded tissues, PCR amplified and directly sequenced. No mutations were detected in the coding sequence and boundaries of both genes in any of the samples. Two polymorphisms of the EZH2 gene were identified with different prevalence: the rs2072407 variant was present in the 30 % of the samples, in keeping with the overall frequency in larger populations, while the rs78589034 variant, located close to the 5' end of the exon 16, was detected in only one proband with familial isolated hyperparathyroidism; we investigated the possible outcome on the splicing process. EZH2 and ZFX genes do not seem to have an impact on the onset of most parathyroid tumours, both benign and malignant, though further studies on larger cohorts of different ethnicity are needed.

PMID: 26876532 [PubMed - indexed for MEDLINE]

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene.

Haematologica. 2016 Jul;101(7):853-60

Authors: Rotunno M, McMaster ML, Boland J, Bass S, Zhang X, Burdett L, Hicks B, Ravichandran S, Luke BT, Yeager M, Fontaine L, Hyland PL, Goldstein AM, NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Chanock SJ, Caporaso NE, Tucker MA, Goldin LR

Abstract
Hodgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.

PMID: 27365461 [PubMed - indexed for MEDLINE]

Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing.

Eur J Hum Genet. 2016 Nov;24(11):1635-1638

Authors: Reinstein E, Tzur S, Cohen R, Bormans C, Behar DM

Abstract
Pathogenic variants in the NONO gene have been most recently implicated in X-linked intellectual disability syndrome. This observation has been supported by studies of NONO-deficient mice showing that NONO has an important role in regulating inhibitory synaptic activity. Thus far, the phenotypic spectrum of affected patients remains limited. We applied whole exome sequencing to members of a family in which the proband was presented with a complex phenotype consisting of developmental delay, dysmorphism, and non-compaction cardiomyopathy. Exome analysis identified a novel de novo splice-site variant c.1171+1G>T in exon 11 of NONO gene that is suspected to abolish the donor splicing site. Thus, we propose that the phenotypic spectrum of NONO-related disorder is much broader than described and that pathogenic variants in NONO cause a recognizable phenotype.

PMID: 27329731 [PubMed - indexed for MEDLINE]