Chitayat-Hall and Schaaf-Yang syndromes: a common aetiology: expanding the phenotype of MAGEL2-related disorders.

J Med Genet. 2018 Mar 29;:

Authors: Jobling R, Stavropoulos DJ, Marshall CR, Cytrynbaum C, Axford MM, Londero V, Moalem S, Orr J, Rossignol F, Lopes FD, Gauthier J, Alos N, Rupps R, McKinnon M, Adam S, Nowaczyk MJM, Walker S, Scherer SW, Nassif C, Hamdan FF, Deal CL, Soucy JF, Weksberg R, Macleod P, Michaud JL, Chitayat D

Abstract
BACKGROUND: Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified.
METHODS AND RESULTS: We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion.
CONCLUSIONS: Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication.

PMID: 29599419 [PubMed - as supplied by publisher]

Novel Nonsense Mutation in SLC39A13 Initially Presenting as Myopathy: Case Report and Review of the Literature.

Mol Syndromol. 2018 Feb;9(2):100-109

Authors: Dusanic M, Dekomien G, Lücke T, Vorgerd M, Weis J, Epplen JT, Köhler C, Hoffjan S

Abstract
Myopathies comprise a heterogeneous group of disorders characterized by variable phenotypes. The increasing use of next-generation sequencing allows identification of the causative genes in a much higher percentage of patients with hereditary muscle disorders and also illustrates a considerable degree of overlap with other clinical entities, including connective tissue disorders. Here, we present a 14-year-old German patient who was initially suspected to suffer from myopathy based on his clinical, radiological, and muscle biopsy findings. Exome sequencing revealed a novel homozygous nonsense mutation in the SLC39A13 gene, causative for spondylocheiro dysplastic Ehlers Danlos syndrome (SCD-EDS), suggesting a connective tissue disorder. Including our patient, only 9 affected individuals from 4 families have been described for SCD-EDS so far. The previously reported patients did not show obvious evidence of myopathy, suggesting a broader clinical presentation than originally suspected. We summarize herein the current knowledge on clinical features as well as pathophysiological pathways for this rare connective tissue disease and discuss the high degree of clinical overlap between myopathic and connective tissue disorders.

PMID: 29593477 [PubMed]

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders.

Genet Med. 2018 Mar 29;:

Authors: Ewans LJ, Schofield D, Shrestha R, Zhu Y, Gayevskiy V, Ying K, Walsh C, Lee E, Kirk EP, Colley A, Ellaway C, Turner A, Mowat D, Worgan L, Freckmann ML, Lipke M, Sachdev R, Miller D, Field M, Dinger ME, Buckley MF, Cowley MJ, Roscioli T

Abstract
PurposeWhole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway.MethodsWES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID).ResultsReanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.ConclusionEarly application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.GENETICS in MEDICINE advance online publication, 29 March 2018; doi:10.1038/gim.2018.39.

PMID: 29595814 [PubMed - as supplied by publisher]

AUDIOME: a tiered exome sequencing-based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss.

Genet Med. 2018 Mar 29;:

Authors: Guan Q, Balciuniene J, Cao K, Fan Z, Biswas S, Wilkens A, Gallo DJ, Bedoukian E, Tarpinian J, Jayaraman P, Sarmady M, Dulik M, Santani A, Spinner N, Abou Tayoun AN, Krantz ID, Conlin LK, Luo M

Abstract
PurposeHereditary hearing loss is highly heterogeneous. To keep up with rapidly emerging disease-causing genes, we developed the AUDIOME test for nonsyndromic hearing loss (NSHL) using an exome sequencing (ES) platform and targeted analysis for the curated genes.MethodsA tiered strategy was implemented for this test. Tier 1 includes combined Sanger and targeted deletion analyses of the two most common NSHL genes and two mitochondrial genes. Nondiagnostic tier 1 cases are subjected to ES and array followed by targeted analysis of the remaining AUDIOME genes.ResultsES resulted in good coverage of the selected genes with 98.24% of targeted bases at >15 ×. A fill-in strategy was developed for the poorly covered regions, which generally fell within GC-rich or highly homologous regions. Prospective testing of 33 patients with NSHL revealed a diagnosis in 11 (33%) and a possible diagnosis in 8 cases (24.2%). Among those, 10 individuals had variants in tier 1 genes. The ES data in the remaining nondiagnostic cases are readily available for further analysis.ConclusionThe tiered and ES-based test provides an efficient and cost-effective diagnostic strategy for NSHL, with the potential to reflex to full exome to identify causal changes outside of the AUDIOME test.Genetics in Medicine advance online publication, 29 March 2018; doi:10.1038/gim.2018.48.

PMID: 29595809 [PubMed - as supplied by publisher]

Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort.

Genes Immun. 2018 Mar 28;:

Authors: Shaw KA, Cutler DJ, Okou D, Dodd A, Aronow BJ, Haberman Y, Stevens C, Walters TD, Griffiths A, Baldassano RN, Noe JD, Hyams JS, Crandall WV, Kirschner BS, Heyman MB, Snapper S, Guthery S, Dubinsky MC, Shapiro JM, Otley AR, Daly M, Denson LA, Kugathasan S, Zwick ME

Abstract
In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher's exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.

PMID: 29593342 [PubMed - as supplied by publisher]

p.Val804Met, the most frequent pathogenic mutation in RET, confers a very low lifetime risk of medullary thyroid cancer.

J Clin Endocrinol Metab. 2018 Mar 23;:

Authors: Loveday C, Josephs K, Chubb D, Gunning A, Izatt L, Tischkovitz M, Ellard S, Turnbull C

Abstract
Context: To date, penetrance figures for medullary thyroid cancer (MTC) for variants in RET have been estimated from families ascertained on account of presence of MTC.
Objective: To gain estimates of penetrance unbiased by ascertainment, we analyzed 61 RET mutations assigned as disease-causing by the ATA in population whole exome sequencing data.
Design: For the 61 RET mutations, we used analyses of the observed allele frequencies in ∼51,000 individuals from non-TCGA ExAC, assuming lifetime penetrance for MTC of 90%, 50% and unbounded.
Setting: Population-based. Patients or other participants/Interventions. NA.
Results: 10/61 ATA disease-causing RET mutations were present in the non-TCGA ExAC population with observed frequency consistent with penetrance for MTC of >90%. For p.Val804Met, the lifetime penetrance for MTC estimated from the allele frequency observed was 4% (95% CI: 0.9-8%).
Conclusions: Based on penetrance analysis in carrier relatives of p.Val804Met-positive cases of MTC, p.Val804Met is currently understood to have high lifetime penetrance for MTC (87% by age 70), albeit of later onset of MTC than other RET mutations. Given our unbiased estimate of penetrance for RET p.Val804Met of 4% (95% CI: 0.9-8%), current recommendation by the American Thyroid Association of prophylactic thyroidectomy as standard for all RET mutation carriers is likely inappropriate.

PMID: 29590403 [PubMed - as supplied by publisher]

Additive Effect of Variably Penetrant 22q11.2 Duplication and Pathogenic Mutations in Autism Spectrum Disorder: To Which Extent Does the Tree Hide He Forest?

J Autism Dev Disord. 2018 Mar 27;:

Authors: Demily C, Lesca G, Poisson A, Till M, Barcia G, Chatron N, Sanlaville D, Munnich A

Abstract
The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.

PMID: 29589274 [PubMed - as supplied by publisher]

Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia.

J Clin Immunol. 2018 Mar 27;:

Authors: Alodayani AN, Al-Otaibi AM, Deswarte C, Frayha HH, Bouaziz M, AlHelale M, Le Voyer T, Nieto-Patlan A, Rattina V, AlZahrani M, Halwani R, Al Sohime F, Al-Mousa H, Al-Muhsen S, Alhajjar SH, Dhayhi NS, Abel L, Casanova JL, Bin-Hussain I, AlBarrak MS, Al-Jumaah SA, Bustamante J

Abstract
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30).
METHODS: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain.
RESULTS: Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect.
CONCLUSIONS: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.

PMID: 29589181 [PubMed - as supplied by publisher]

Genetic test utilization and diagnostic yield in adult patients with neurological disorders.

Neurogenetics. 2018 Mar 28;:

Authors: Bardakjian TM, Helbig I, Quinn C, Elman LB, McCluskey LF, Scherer SS, Gonzalez-Alegre P

Abstract
To determine the diagnostic yield of different genetic test modalities in adult patients with neurological disorders, we evaluated all adult patients seen for genetic diagnostic evaluation in the outpatient neurology practice at the University of Pennsylvania between January 2016 and April 2017 as part of the newly created Penn Neurogenetics Program. Subjects were identified through our electronic medical system as those evaluated by the Program's single clinical genetic counselor in that period. A total of 377 patients were evaluated by the Penn Neurogenetics Program in different settings and genetic testing recommended. Of those, 182 (48%) were seen in subspecialty clinic setting and 195 (52%) in a General Neurogenetics Clinic. Genetic testing was completed in over 80% of patients in whom it was recommended. The diagnostic yield was 32% across disease groups. Stratified by testing modality, the yield was highest with directed testing (50%) and array comparative genomic hybridization (45%), followed by gene panels and exome testing (25% each). In conclusion, genetic testing can be successfully requested in clinic in a large majority of adult patients. Age is not a limiting factor for a genetic diagnostic evaluation and the yield of clinical testing across phenotypes (almost 30%) is consistent with previous phenotype-focused or research-based studies. These results should inform the development of specific guidelines for clinical testing and serve as evidence to improve reimbursement by insurance payers.

PMID: 29589152 [PubMed - as supplied by publisher]

Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2.

Epilepsia Open. 2018 Mar;3(1):81-85

Authors: Akamine S, Sagata N, Sakai Y, Kato TA, Nakahara T, Matsushita Y, Togao O, Hiwatashi A, Sanefuji M, Ishizaki Y, Torisu H, Saitsu H, Matsumoto N, Hara T, Sawa A, Kano S, Furue M, Kanba S, Shaw CA, Ohga S

Abstract
Advance in the exome-wide sequencing analysis contributes to identifying hundreds of genes that are associated with early-onset epileptic encephalopathy and neurodevelopmental disorders. On the basis of massive sequencing data, functional interactions among different genes are suggested to explain the common molecular pathway underlying the pathogenic process of these disorders. However, the relevance of such interactions with the phenotypic severity or variety in an affected individual remains elusive. In this report, we present a 45-year-old woman with neurofibromatosis type 1 (NF1), infantile-onset epileptic encephalopathy, and severe developmental delay. Whole-exome sequencing identified de novo pathogenic mutations in NF1 and the Schaaf-Yang syndrome-associated gene, MAGEL2. Literature-curated interaction data predicted that NF1 and MAGEL2 proteins were closely connected in this network via their common interacting proteins. Direct conversion of fibroblasts into neurons in vitro showed that neuronal cells from 9 patients with NF1 expressed significantly lower levels of MAGEL2 (54%, p = 0.0047) than those from healthy individuals. These data provide the first evidence that pathogenic mutations of NF1 deregulate the expression of other neurodevelopmental disease-associated genes. De novo mutations in multiple genes may lead to severe developmental phenotypes through their cumulative effects or synergistic interactions.

PMID: 29588991 [PubMed]

Whole-Genome Linkage Analysis with Whole-Exome Sequencing Identifies a Novel Frameshift Variant in NEFH in a Chinese Family with Charcot-Marie-Tooth 2: A Novel Variant in NEFH for Charcot-Marie-Tooth 2.

Neurodegener Dis. 2018 Mar 27;18(2-3):74-83

Authors: Bian X, Lin P, Li J, Long F, Duan R, Yuan Q, Li Y, Gao F, Gao S, Wei S, Li X, Sun W, Gong Y, Yan C, Liu Q

Abstract
BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common neurodegenerative disorder of the peripheral nervous system. More than 50 genes/loci were found associated with the disease. We found a family with autosomal-dominant CMT2.
OBJECTIVE: To reveal the pathogenic gene of the family and further investigate the function of the variant.
METHODS: DNA underwent whole-genome linkage analysis for all family members and whole-exome sequencing for 2 affected members. Neurofilament light polypeptide and wild-type or mutant neurofilament heavy polypeptide (NEFH) were co-transfected into SW13 (vim-) cells. The nefh-knockdown zebrafish model was produced by using morpholino antisense oligonucleotides.
RESULTS: We identified a novel insertion variant (c.3057insG) in NEFH in the family. The variant led to the loss of a stop codon and an extended 41 amino acids in the protein. Immunofluorescence results revealed that mutant NEFH disrupted the neurofilament network and induced aggregation of NEFH protein. Knockdown of nefh in zebrafish caused a slightly or severely curled tail. The motor ability of nefh-knockdown embryos was impaired or even absent, and the embryos showed developmental defects of axons in motor neurons. The abnormal phenotype and axonal developmental defects could be rescued by injection of human wild-type but not human mutant NEFH mRNA.
CONCLUSIONS: We identified a novel stop loss variant in NEFH that is likely pathogenic for CMT2, and the results provide further evidence for the role of an aberrant assembly of neurofilament in CMT.

PMID: 29587262 [PubMed - as supplied by publisher]

[EXOME ANALYSIS - A GAME CHANGER IN PEDIATRICS].

Harefuah. 2018 Mar;157(3):188-191

Authors: Ta-Shma A, Edvardson S, Elpeleg O, Stepensky P

Abstract
INTRODUCTION: Thirteen years after the completion of the human genome project, the determination of the genomic sequence of the coding parts of the DNA (the exones, hence the exome), has turned into a primary diagnostic tool in daily use in clinical practice. The Department of Genetics at Hadassah was the first in Israel to introduce exome analysis as a robust diagnostic tool into the pediatric departments. Till now 2600 exomes were analyzed at Hadassah, 850 of them in 2016 alone. Exome analysis is cheap and fast, enabling precise and non-invasive diagnosis for a vast array of genetic disorders and congenital malformations. The unique composition of the population which the hospital serves (marked by a high rate of consanguinity) enabled reaching diagnosis in 65% of the cases, twice the rate in medical centers worldwide. The results of this analysis enable genetic counseling to patients' families and prevention of serious disorders. Moreover, the results contribute to the understanding of the biological basis of newly identified disorders and in certain cases assist in the management of the patients. The major limitation of exome analysis is the multitude of identified variants which exist in any individual and which challenge our ability to pick the disease-causing variant. In the case of a disease-causing variant in a new gene, experimental proof is required to validate the causality of the variant; occasionally, an incidental finding with possible clinical significance is identified, raising serious ethical concerns. In this article, we will review the use of this technology through the experience of three pediatric departments at Hadassah.

PMID: 29582952 [PubMed - in process]

Whole exome sequencing reveals a novel missense mutation in the MARS gene related to a rare Charcot-Marie-Tooth neuropathy type 2U.

J Peripher Nerv Syst. 2018 Mar 26;:

Authors: Sagi-Dain L, Shemer L, Zelnik N, Zoabi Y, Sadeh O, Adir V, Schif A, Peleg A

Abstract
BACKGROUND: Charcot-Marie-Tooth (CMT) is a heterogeneous group of progressive disorders, characterized by chronic motor and sensory polyneuropathy. This hereditary disorder is related to numerous genes and varying inheritance patterns. Thus, many patients do not reach a final genetic diagnosis.
PATIENT: We describe a 13-years old girl presenting with progressive bilateral leg weakness and gait instability. Extensive laboratory studies and spinal Magnetic resonance imaging scan were normal. Nerve conduction studies revealed severe lower limb peripheral neuropathy with prominent demyelinative component. Following presumptive diagnosis of chronic inflammatory demyelinating polyneuropathy, the patient received treatment with steroids and intravenous immunoglobulins courses for several months, with no apparent improvement.
RESULTS: Whole exome sequencing revealed a novel heterozygous c.2209C>T (p.Arg737Trp) mutation in the MARS gene (OMIM 156560). This gene has recently been related to CMT type 2U. In-silico prediction programs classified this mutation as a probable cause for protein malfunction. Allele frequency data reported this variant in 0.003% of representative Caucasian population. Family segregation analysis study revealed that the patient had inherited the variant from her 60-years old mother, reported as healthy. Neurologic examination of the mother demonstrated decreased tendon reflexes, while nerve conduction studies were consistent with demyelinative and axonal sensory-motor polyneuropathy.
CONCLUSION: Our report highlights the importance of next generation sequencing approach to facilitate the proper molecular diagnosis of highly heterogeneous neurologic disorders. Amongst other numerous benefits, this approach might prevent unnecessary diagnostic testing and potentially harmful medical treatment. Charcot-Marie-Tooth disease (CMT); CMT2U; MARS.

PMID: 29582526 [PubMed - as supplied by publisher]

Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results.

Clin Res Cardiol. 2018 Mar 26;:

Authors: Chua HC, Servatius H, Asatryan B, Schaller A, Rieubland C, Noti F, Seiler J, Roten L, Baldinger SH, Tanner H, Fuhrer J, Haeberlin A, Lam A, Pless SA, Medeiros-Domingo A

Abstract
OBJECTIVE: Unexplained cardiac arrest (UCA) is often the first manifestation of an inherited arrhythmogenic disease. Genetic testing in UCA is challenging due to the complexities of variant interpretation in the absence of supporting cardiac phenotype. We aimed to investigate if a KCNQ1 variant [p.(Pro64_Pro70del)], previously reported as pathogenic, contributes to the long-QT syndrome phenotype, co-segregates with disease or affects KCNQ1 function in vitro.
METHODS: DNA was extracted from peripheral blood of a 22-year-old male after resuscitation from UCA. Targeted exome sequencing was performed using the TruSight-One Sequencing Panel (Illumina). Variants in 190 clinically relevant cardiac genes with minor allele frequency < 1% were analyzed according to the guidelines of the American College of Medical Genetics. Functional characterization was performed using site-directed mutagenesis, expression in Xenopus laevis oocytes using the two-electrode voltage-clamp technique.
RESULTS: The 12-lead ECG, transthoracic echocardiography and coronary angiography after resuscitation showed no specific abnormalities. Two variants were identified: c.190_210del in-frame deletion in KCNQ1 (p.Pro64_Pro70del), reported previously as pathogenic and c.2431C > A in PKP2 (p.Arg811Ser), classified as likely benign. Two asymptomatic family members with no evident phenotype hosted the KCNQ1 variant. Functional studies showed that the wild-type and mutant channels have no significant differences in current levels, conductance-voltage relationships, as well as activation and deactivation kinetics, in the absence and presence of the auxiliary subunit KCNE1.
CONCLUSIONS: Based on our data and previous reports, available evidence is insufficient to consider the variant KCNQ1:c.190_210del as pathogenic. Our findings call for cautious interpretation of genetic tests in UCA in the absence of a clinical phenotype.

PMID: 29582136 [PubMed - as supplied by publisher]

Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility.

Eur J Hum Genet. 2018 Mar 26;:

Authors: Yıldırım Y, Ouriachi T, Woehlbier U, Ouahioune W, Balkan M, Malik S, Tolun A

Abstract
In affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We detected six sibs afflicted with a unique combination of digit malformation that includes brachydactyly, symphalangism and zygodactyly plus infertility in males owing to azoospermia, sperm immotility or necrospermia, which we hypothesised to have arisen from a defect in a single gene. We mapped the disease locus and by exome sequencing identified in patients homozygous missense variants bone morphogenetic protein receptor type IB (BMPR1B) c.640C>T (p.(Arg214Cys)) and alpha-2 pyruvate dehydrogenase (PDHA2) c.679A>G (p.(Met227Val)). Structural protein modelling, protein sequence conservation and in silico analysis indicate that both variants affect protein function. BMPR1B is known to be responsible for autosomal dominant brachydactyly and autosomal recessive acromesomelic chondrodysplasia. Our findings show that also recessive complex digit malformation can be caused by BMPR1B variant and not all biallelic BMPR1B variants cause acromesomelic dysplasia. PDHA2 is a novel candidate gene for male infertility; the protein product is a mitochondrial enzyme with highest expression in ejaculated sperm. Our findings are a unique example of two linked variants, ~ 711 Kb apart, in different genes that together manifest as a novel syndrome. They demonstrate that exome sequencing and not candidate gene approach should be employed in disease gene hunt, defining new diseases and genetic testing, to rule out the coincidental presence of two variants contributing together to the phenotype, which may be discerned as a novel disease.

PMID: 29581481 [PubMed - as supplied by publisher]

Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea.

Sci Rep. 2018 Mar 26;8(1):5214

Authors: Tong W, Wang Y, Lu Y, Ye T, Song C, Xu Y, Li M, Ding J, Duan Y, Zhang L, Gu W, Zhao X, Yang XA, Jin D

Abstract
Neurodevelopmental delay accompanied unexplained dyspnea is a highly lethal disease in clinic. This study is to investigate the performance characteristics of trio whole exome sequencing (Trio-WES) in a pediatric setting by presenting our patient cohort and displaying the diagnostic yield. A total of 31 pediatric patients showing neurodevelopmental delay accompanied unexplained dyspnea were admitted to our hospital and referred for molecular genetic testing using Trio-WES. Eight genes namely MMACHC, G6PC, G6PT, ETFDH, OTC, NDUFAF5, SLC22A5, and MAGEL2 were suspected to be responsible for the onset of the clinical symptoms and 6 variants were novel. Standard interpretation according to ACMG guideline showed that the variants were pathogenic. Finally, diagnosis of methylmalonic aciduria and homocystinuria, glycogen storage disease, ornithine transcarbamylase deficiency, glutaric acidemia II, mitochondrial complex 1 deficiency, carnitine deficiency, and Schaaf-Yang syndrome was made in 12 out of the 31 patients. Trio-WES is an effective means for molecular diagnosis of infantile neurodevelopmental delay accompanied unexplained dyspnea. As for molecular etiology identification, when routine potential monogenetic inheritance patterns including de novo, autosomal recessive, autosomal dominant, and X-linked recessive inheritance analysis is negative, physicians should take into account imprinted genes.

PMID: 29581464 [PubMed - in process]

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2018/03/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2018/03/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Liquid biopsy by NGS: differential presence of exons (DPE) in cell-free DNA reveals different patterns in metastatic and nonmetastatic colorectal cancer.

Cancer Med. 2018 Mar 23;:

Authors: Olmedillas-López S, García-Olmo DC, García-Arranz M, Peiró-Pastor R, Aguado B, García-Olmo D

Abstract
Next-generation sequencing (NGS) has been proposed as a suitable tool for liquid biopsy in colorectal cancer (CRC), although most studies to date have focused almost exclusively on sequencing of panels of potential clinically actionable genes. We evaluated the clinical value of whole-exome sequencing (WES) of cell-free DNA (cfDNA) circulating in plasma, with the goal of identifying differential clinical profiles in patients with CRC. To this end, we applied an original concept, "differential presence of exons" (DPE). We determined differences in levels of 379 exons in plasma cfDNA and used DPE analysis to cluster and classify patients with disseminated and localized disease. The resultant bioinformatics analysis pipeline allowed us to design a predictive DPE algorithm in a small subset of patients that could not be initially classified based on the selection criteria. This DPE suggests that these nucleic acids could be actively released by both tumor and nontumor cells as a means of intercellular communication and might thus play a role in the process of malignant transformation. DPE is a new technique for the study of plasma cfDNA by WES that might have predictive and prognostic value in patients with CRC.

PMID: 29573240 [PubMed - as supplied by publisher]

A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy and microcephaly.

Hum Mutat. 2018 Mar 23;:

Authors: Pagnamenta AT, Murakami Y, Anzilotti C, Titheradge H, Oates AJ, Morton J, DDD Study, Kinoshita T, Kini U, Taylor JC

Abstract
Defective GPI-anchor biogenesis can cause a spectrum of predominantly neurological problems. For 8 genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7833 parent-child trios and 1792 singletons from the DDD study for biallelic variants in this gene-set uncovered a rare PIGH variant in a boy with epilepsy, microcephaly and behavioural difficulties. Although only 2/2 reads harboured this c.1A > T transversion, the presence of ∼25Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarly-affected sister was also homozygous. FACS analysis of PIGH deficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPI-APs. Truncation of PIGH protein was consistent with the utilisation of an in-frame start-site at codon 63. In summary, we describe siblings harbouring a homozygous c.1A > T variant resulting in defective GPI-anchor biogenesis and highlight the importance of exploring low-coverage variants within autozygous regions. This article is protected by copyright. All rights reserved.

PMID: 29573052 [PubMed - as supplied by publisher]