A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia.

Clin Genet. 2018 Jul 26;:

Authors: Uchiyama Y, Yanagisawa K, Kunishima S, Shiina M, Ogawa Y, Nakashima M, Hirato J, Imagawa E, Fujita A, Hamanaka K, Miyatake S, Mitsuhashi S, Takata A, Miyake N, Ogata K, Handa H, Matsumoto N, Mizuguchi T

Abstract
We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss-of-function variants. This article is protected by copyright. All rights reserved.

PMID: 30051457 [PubMed - as supplied by publisher]

Genetic analysis of LRRK2 in Parkinson's disease in Han Chinese population.

Neurobiol Aging. 2018 Jul 04;:

Authors: Zhang JR, Jin H, Li K, Mao CJ, Yang YP, Wang F, Gu CC, Zhang HJ, Chen J, Liu CF

Abstract
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are recognized as the most frequent genetic factors contributing to Parkinson's disease (PD). The aim of our study was to explore LRRK2 variants in PD patients within the mainland Han Chinese population. The whole coding regions of LRRK2 from 296 PD patients were sequenced by targeted regions sequencing and exome sequencing. Eighteen rare variants were identified in 27 PD patients, and 13 of them (M100T, L153W, A459S, S722N, R792K, C925Y, R981K, S1007T, V1447M, R1677S, N2308D, N2313S, and S2350I) were firstly reported in PD. We also tried to explore the genotype-phenotype associations of LRRK2 variants in our data and found that PD with common and rare LRRK2 variants was more likely to have motor fluctuation and nonmotor symptoms. The identification of novel variants in LRRK2 suggests that this gene plays an important role in the pathogenesis and phenotype of PD in Han Chinese population, and our data also rang the alarm bell-more attention should be paid to the whole coding regions of LRRK2.

PMID: 30049590 [PubMed - as supplied by publisher]

Phenotypic expansion and progression of SPATA7-associated retinitis pigmentosa.

Doc Ophthalmol. 2018 04;136(2):125-133

Authors: Sengillo JD, Lee W, Bilancia CG, Jobanputra V, Tsang SH

Abstract
PURPOSE: To report an unusual phenotype of retinitis pigmentosa (RP) caused by compound heterozygous mutations in SPATA7, and describe the progression over a two year follow-up period.
METHODS: Retrospective case study.
RESULTS: A 63-year-old man with a long history of nyctalopia, progressive visual field constriction, and a recent subacute decrease in visual acuity of the left eye presented for evaluation of a suspected retinal degeneration. Multimodal retinal imaging and functional assessment with full-field electroretinogram suggested a severe rod-cone dysfunction masquerading as a choroideremia-like phenotype. A vitreous opacity was found to explain recent changes in the left eye and a 25-guage vitrectomy and membrane peel was performed, yielding no change in visual acuity. Whole-exome sequencing revealed compound heterozygous variants in SPATA7 that were predicted to be pathogenic.
CONCLUSIONS: Compound heterozygous c.1100A > G, p.(Y367C) and c.1102_1103delCT, p.(L368Efs*4) variants in SPATA7 manifest as an unusual RP phenotype in this case, showing extensive choroidal sclerosis and retinal pigment epithelium (RPE) atrophy with evidence of progression over two years on multimodal imaging.

PMID: 29411205 [PubMed - indexed for MEDLINE]

Analysis and Annotation of Whole-Genome or Whole-Exome Sequencing Derived Variants for Clinical Diagnosis.

Curr Protoc Hum Genet. 2017 Oct 18;95:9.24.1-9.24.28

Authors: Worthey EA

Abstract
Over the last 10 years, next-generation sequencing (NGS) has transformed genomic research through substantial advances in technology and reduction in the cost of sequencing, and also in the systems required for analysis of these large volumes of data. This technology is now being used as a standard molecular diagnostic test in some clinical settings. The advances in sequencing have come so rapidly that the major bottleneck in identification of causal variants is no longer the sequencing or analysis (given access to appropriate tools), but rather clinical interpretation. Interpretation of genetic findings in a complex and ever changing clinical setting is scarcely a new challenge, but the task is increasingly complex in clinical genome-wide sequencing given the dramatic increase in dataset size and complexity. This increase requires application of appropriate interpretation tools, as well as development and application of appropriate methodologies and standard procedures. This unit provides an overview of these items. Specific challenges related to implementation of genome-wide sequencing in a clinical setting are discussed. © 2017 by John Wiley & Sons, Inc.

PMID: 29044471 [PubMed - indexed for MEDLINE]

The clinical implications of molecular monitoring and analyses of inherited retinal diseases.

Expert Rev Mol Diagn. 2017 Nov;17(11):1009-1021

Authors: Chacón-Camacho OF, García-Montaño LA, Zenteno JC

Abstract
INTRODUCTION: Retinal dystrophies (RDs) are the most common cause of inherited blindness and one of the most genetically heterogeneous human diseases. RDs arise from mutations in genes involved in development and function of photoreceptors or other retinal cells. Identification of the genetic defect causing RD allows accurate diagnosis, prognosis, and counseling in affected patients. Molecular diagnosis is a tremendous challenge in RDs due to their locus and phenotypic heterogeneity. As conventional DNA sequencing approaches are impractical in such situation, Next Generation Sequencing (NGS)-based protocols are needed to identify RD-causing mutations. This is being accomplished by sequencing RD gene panels or by whole exome or whole genome sequencing approaches. Areas covered: This review discusses the current strategies for molecular diagnosis in RDs including their advantages and limitations, as well as their utility in diagnosis of non-syndromic versus syndromic RDs. Results of ongoing gene therapy protocols in RDs are also presented. Expert commentary: Molecular diagnosis in RD improves the medical management of patients. Importantly, demand for molecular screening for RDs is greatly expanding not only as a result of increasing development and availability of NGS technologies, but also of the growing number of gene-based clinical trials offering a potential treatment to patients.

PMID: 28945154 [PubMed - indexed for MEDLINE]

Whole-Exome Sequencing Reveals Increased Burden of Rare Functional and Disruptive Variants in Candidate Risk Genes in Individuals With Persistent Attention-Deficit/Hyperactivity Disorder.

J Am Acad Child Adolesc Psychiatry. 2016 06;55(6):521-3

Authors: Demontis D, Lescai F, Børglum A, Glerup S, Østergaard SD, Mors O, Li Q, Liang J, Jiang H, Li Y, Wang J, Lesch KP, Reif A, Buitelaar JK, Franke B

PMID: 27238071 [PubMed - indexed for MEDLINE]

Identifying genetically driven clinical phenotypes using linear mixed models.

Nat Commun. 2016 04 25;7:11433

Authors: Mosley JD, Witte JS, Larkin EK, Bastarache L, Shaffer CM, Karnes JH, Stein CM, Phillips E, Hebbring SJ, Brilliant MH, Mayer J, Ye Z, Roden DM, Denny JC

Abstract
We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q<0.05) phenotypes associated with HLA SNP variation and show that hypothyroidism is genetically correlated with Type I diabetes (rG=0.31, s.e. 0.12, P=0.003). We also report novel SNP associations for hypothyroidism near HLA-DQA1/HLA-DQB1 at rs6906021 (combined odds ratio (OR)=1.2 (95% confidence interval (CI): 1.1-1.2), P=9.8 × 10(-11)) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3-1.6), P=1.3 × 10(-10)). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations.

PMID: 27109359 [PubMed - indexed for MEDLINE]

Using exome sequencing to decipher family history in a healthy individual: Comparison of pathogenic and population MTM1 variants.

Mol Genet Genomic Med. 2018 Jul 25;:

Authors: Penon M, Zahed H, Berger V, Su I, Shieh JT

Abstract
BACKGROUND: When a family encounters the loss of a child early in life, extensive genetic testing of the affected neonate is sometimes not performed or not possible. However, the increasing availability of genomic sequencing may allow for direct application to families in cases where there is a condition inherited from parental gene(s). When neonatal testing is not possible, it is feasible to perform family testing as long as there is optimal interpretation of the genomic information. Here, we present an example of a healthy adult woman with a history of recurrent male neonatal losses due to severe respiratory distress who presented to Medical Genetics for evaluation. A family history of additional male neonatal loss was present, suggesting a potential inherited genetic etiology.
METHODS: Although there was no DNA available from the neonates, by performing exome sequencing on the healthy adult woman, we found a missense variant in MTM1 as a potential candidate, which was deemed pathogenic based on multiple criteria including past report.
RESULTS: By performing an analysis of all known MTM1-disease associated mutations and control population variation, we can also better infer the effects of missense variations on MTM1, as not all variants are truncating. MTM1-X-linked myotubular myopathy is a condition that leads to male perinatal respiratory failure and a high risk for early mortality.
CONCLUSIONS: The application of genetic testing in the healthy population here highlights the broader utility of genomic sequencing in evaluating unexplained recurrent neonatal loss, especially when genetic testing is not available on the affected neonates.

PMID: 30047259 [PubMed - as supplied by publisher]

Novel and Recurring Disease-Causing NF1 Variants in Two Chinese Families with Neurofibromatosis Type 1.

J Mol Neurosci. 2018 Jul 25;:

Authors: Xiao H, Yuan L, Xu H, Yang Z, Huang F, Song Z, Yang Y, Zeng C, Deng H

Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder primarily characterized by multiple café-au-lait macules, peripheral neurofibromas, skinfold freckling, and Lisch nodules. The causative genetic factor is the neurofibromin 1 gene (NF1), which encodes a Ras GTPase-activating protein called neurofibromin. NF1 variants may lead to loss of neurofibromin function and activation of downstream cell growth. This study aims to discover the disease-causing variants responsible for NF1 in two Han Chinese families by using exome sequencing combined with Sanger sequencing. A recurrent missense variant c.269T>C (p.Leu90Pro) and a novel nonsense variant c.2993dupA (p.Tyr998*) in the NF1 gene were identified. These variants co-segregated with the disorder in the pedigrees and were absent in the normal controls. The results broaden the NF1 mutation spectrum responsible for NF1. This may be helpful in genetic counseling, clinical management, and gene-targeted therapies for NF1.

PMID: 30046999 [PubMed - as supplied by publisher]

Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.

Hum Genet. 2018 Jul 26;:

Authors: Du R, Dinckan N, Song X, Coban-Akdemir Z, Jhangiani SN, Guven Y, Aktoren O, Kayserili H, Petty LE, Muzny DM, Below JE, Boerwinkle E, Wu N, Gibbs RA, Posey JE, Lupski JR, Letra A, Uyguner ZO

Abstract
Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM #614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and BCOR (Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.

PMID: 30046887 [PubMed - as supplied by publisher]

Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability.

Leukemia. 2018 Jul 25;:

Authors: Dutta AK, Fink JL, Grady JP, Morgan GJ, Mullighan CG, To LB, Hewett DR, Zannettino ACW

Abstract
Multiple myeloma (MM) is a largely incurable haematological malignancy defined by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow. Clonal heterogeneity has recently been established as a feature in MM, however, the subclonal evolution associated with disease progression has not been described. Here, we performed whole-exome sequencing of serial samples from 10 patients, providing new insights into the progression from monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM), to symptomatic MM. We confirm that intraclonal genetic heterogeneity is a common feature at diagnosis and that the driving events involved in disease progression are more subtle than previously reported. We reveal that MM evolution is mainly characterised by the phenomenon of clonal stability, where the transformed subclonal PC populations identified at MM are already present in the asymptomatic MGUS/SMM stages. Our findings highlight the possibility that PC extrinsic factors may play a role in subclonal evolution and MGUS/SMM to MM progression.

PMID: 30046162 [PubMed - as supplied by publisher]

Novel ALPK3 mutation in a Tunisian patient with pediatric cardiomyopathy and facio-thoraco-skeletal features.

J Hum Genet. 2018 Jul 25;:

Authors: Jaouadi H, Kraoua L, Chaker L, Atkinson A, Delague V, Levy N, Benkhalifa R, Mrad R, Abdelhak S, Zaffran S

Abstract
Pediatric cardiomyopathy is a complex disease with clinical and genetic heterogeneity. Recently, the ALPK3 gene was described as a new hereditary cardiomyopathy gene underlying pediatric cardiomyopathies. Only eight patients carrying mutations in ALPK3 have been reported to date. Here, we report a 3-year-old male patient with both hypertrophic and dilated cardiomyopathy. The patient presented dysmorphic features and skeletal deformities of hands and feet, pectus excavatum, and cleft palate. The genetic investigation was performed by whole-exome sequencing in the patient and his parents. We identified a novel homozygous mutation in ALPK3 (c.1531_1532delAA; p.Lys511Argfs*12). Our work extends the phenotypic spectrum of the ALPK3-associated cardiomyopathy by reporting additional clinical features. This is the first study of a Tunisian patient with mutation in the ALPK3 gene. In conclusion, ALPK3 should be included in the list of genes to be considered in genetic studies for patients affected with pediatric syndromic cardiomyopathy.

PMID: 30046096 [PubMed - as supplied by publisher]

Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.

J Am Soc Nephrol. 2018 Jul 24;:

Authors: Tan AY, Zhang T, Michaeel A, Blumenfeld J, Liu G, Zhang W, Zhang Z, Zhu Y, Rennert L, Martin C, Xiang J, Salvatore SP, Robinson BD, Kapur S, Donahue S, Bobb WO, Rennert H

Abstract
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism.
METHODS: We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified.
RESULTS: Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans-heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non-PKD1/2 genes, including other ciliopathy genes and cancer-related genes.
CONCLUSIONS: These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.

PMID: 30042192 [PubMed - as supplied by publisher]

Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome.

Brain Dev. 2018 Jul 02;:

Authors: Takezawa Y, Fujie H, Kikuchi A, Niihori T, Funayama R, Shirota M, Nakayama K, Aoki Y, Sasaki M, Kure S

Abstract
BACKGROUND: IARS2 encodes isoleucine-tRNA synthetase, which is aclass-1 amino acyl-tRNA synthetase. IARS2 mutations are reported to cause Leigh syndrome or cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysphasia syndrome (CAGSSS). To our knowledge, IARS2 mutations and diseases related to it have only been reported in three families. Here we report a case of two Japanese siblings with Leigh syndrome, some features of CAGSSS, and West syndrome that are found to have compound heterozygous novel IARS2 mutations.
CASE REPORT: A 7-month-old Japanese girl presented with infantile spasms. Brain magnetic resonance imaging (MRI) revealed diffuse brain atrophy and hyperintensity in the bilateral basal ganglia. Three years later, her younger sister also presented with infantile spasms. MRI revealed diffuse brain atrophy and hyperintensity of the bilateral ganglia, suggesting Leigh syndrome. The siblings were identified with compound heterozygous missense mutations in IARS2, p.[(Phe227Ser)];[(Arg817His)].
CONCLUSION: This is the first case study reporting Leigh syndrome concomitant with some features of CAGSSS in siblings with novel IARS2 mutations, thereby broadening the phenotypic spectrum of IARS2-related disorders. Further studies are warranted to elucidate the nature of these disorders.

PMID: 30041933 [PubMed - as supplied by publisher]

Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants.

Orphanet J Rare Dis. 2018 Jul 24;13(1):125

Authors: Brasil S, Leal F, Vega A, Navarrete R, Ecay MJ, Desviat LR, Riera C, Padilla N, de la Cruz X, Couce ML, Martin-Hernández E, Morais A, Pedrón C, Peña-Quintana L, Rigoldi M, Specola N, de Almeida IT, Vives I, Yahyaoui R, Rodríguez-Pombo P, Ugarte M, Pérez-Cerda C, Merinero B, Pérez B

Abstract
BACKGROUND: Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects.
RESULTS: This paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B12 (22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants.
CONCLUSIONS: The present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.

PMID: 30041674 [PubMed - in process]

Classification and molecular pathogenesis of NBIA syndromes.

Eur J Paediatr Neurol. 2018 Mar;22(2):272-284

Authors: Di Meo I, Tiranti V

Abstract
Brain iron accumulation is the hallmark of a group of seriously invalidating and progressive rare diseases collectively denominated Neurodegeneration with Brain Iron Accumulation (NBIA), characterized by movement disorder, painful dystonia, parkinsonism, mental disability and early death. Currently there is no established therapy available to slow down or reverse the progression of these conditions. Several genes have been identified as responsible for NBIA but only two encode for proteins playing a direct role in iron metabolism. The other genes encode for proteins either with various functions in lipid metabolism, lysosomal activity and autophagic processes or with still unknown roles. The different NBIA subtypes have been classified and denominated on the basis of the mutated genes and, despite genetic heterogeneity, some of them code for proteins, which share or converge on common metabolic pathways. In the last ten years, the implementation of genetic screening based on Whole Exome Sequencing has greatly accelerated gene discovery, nevertheless our knowledge of the pathogenic mechanisms underlying the NBIA syndromes is still largely incomplete.

PMID: 29409688 [PubMed - indexed for MEDLINE]

DNA testing of pancreatic cyst fluid: is it ready for prime time?

Lancet Gastroenterol Hepatol. 2017 01;2(1):63-72

Authors: Singhi AD, Nikiforova MN, McGrath K

Abstract
Pancreatic cysts are a clinical quandary in both diagnosis and management. Although many cysts, such as pseudocysts and serous cystadenomas, are benign and can be monitored clinically, mucinous cysts, such as intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, have the potential to progress to pancreatic cancer. Considering the poor prognosis of pancreatic cancer, the detection of a pancreatic cyst can be a source of anxiety for both the patient and physician. This diagnosis in turn can lead to expensive, invasive, and even harmful surveillance and treatment options. As a consequence, several national and international guidelines for the management of pancreatic cysts have been developed over the past decade. However, these guidelines rely on standard clinical assessment, radiographical imaging, and ancillary fluid studies that have insufficient sensitivity and specificity. The application of DNA-based molecular techniques has emerged as an adjunct to the assessment of pancreatic cysts. The cellular content of pancreatic cyst fluid aspirate is often suboptimal for analysis, but DNA isolated from lysed or exfoliated cells within the cyst can be analysed for genetic abnormalities. Moreover, whole exome sequencing and targeted sequencing of the major pancreatic cysts has identified unique mutational profiles for cyst type and genetic alterations that coincide with the development of pancreatic cancer. In this Review, we discuss the major cystic lesions of the pancreas and their underlying molecular pathology, current management guidelines for pancreatic cysts, and integration of DNA-based molecular testing within this field.

PMID: 28404017 [PubMed - indexed for MEDLINE]

Exome sequencing revealed a novel deletion in the ERCC8 gene in an Iranian family with Cockayne syndrome.

Ann Hum Genet. 2018 Jul 24;:

Authors: Mohammadi-Asl J, Hajjari M, Tahmasebi Birgani M, Riahi K, Nasiri H, Kollaee A

Abstract
Cockayne syndrome (CS) is one the rare DNA-repair deficiency disorders with autosomal recessive inheritance. Failure to thrive and microcephaly are the major criteria of diagnosis. Owing to genetic heterogeneity of CS, whole exome sequencing is promising way to determine the genetic basis of the disease. Here, we present c.1053delT in ERCC8 gene in an Iranian family with symptom of CS using whole exome sequencing. The deletion was novel and was not previously reported elsewhere.

PMID: 30039856 [PubMed - as supplied by publisher]

Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.

Clin Genet. 2018 Jul 24;:

Authors: Flusser H, Halperin D, Kadir R, Shorer Z, Shelef I, Birk OS

Abstract
Four siblings of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of congenital microcephaly, facial dysmorphism, strabismus, developmental delay and ataxia with positive pyramidal signs. Towards the end of their first decade, they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness, affecting proximal and distal extremities. Physical assessment exhibited kyphoscoliosis, bilateral syndactyly and distal muscle wasting with drop-foot and pes-cavus. MRI demonstrated profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels, previously described as "fork and bracket" signs. Genome-wide linkage analysis identified a single ~1.5Mbp disease-associated locus on chromosome 22q13.33. Whole exome sequencing identified a single novel homozygous deleterious splice-site mutation within this locus in SET binding factor 1 (SBF1). SBF1 missense mutations were shown to underlie Charcot-Marie-Tooth type 4B3 disease, a rare autosomal recessive subtype of CMT4. The novel SBF1 null mutation highlights distinct severe phenotypic manifestations, broadening the clinical spectrum of SBF1-related neuropathies: cerebellar and pyramidal signs evident in the first months of life with peripheral polyneuropathy emerging only towards the end of the first decade, together with unique MRI findings. This article is protected by copyright. All rights reserved.

PMID: 30039846 [PubMed - as supplied by publisher]

Detection of CNVs in NGS Data Using VS-CNV.

Methods Mol Biol. 2018;1833:115-127

Authors: Fortier N, Rudy G, Scherer A

Abstract
Copy number variations have been linked to numerous genetic diseases including cancer, Parkinson's disease, pancreatitis, and lupus. While current best practices for CNV detection often require using microarrays for detecting large CNVs or multiplex ligation-dependent probe amplification (MLPA) for gene-sized CNVs, new methods have been developed with the goal of replacing both of these specialized assays with bioinformatic analysis applied to next-generation sequencing (NGS) data. Because NGS is already used by clinical labs to detect small coding variants, this approach reduces associated costs, resources, and analysis time. This chapter provides an overview of the various approaches to CNV detection via NGS data, and examines VS-CNV, a commercial tool developed by Golden Helix, which provides robust CNV calling capabilities for both gene panel and exome data.

PMID: 30039368 [PubMed - in process]