An atypical case of Noonan syndrome with KRAS mutation diagnosed by targeted exome sequencing.

Ann Pediatr Endocrinol Metab. 2017 Sep;22(3):203-207

Authors: Kim J, Cho SY, Yang A, Jang JH, Choi Y, Lee JE, Jin DK

Abstract
Noonan syndrome (NS) is a genetic disorder caused by autosomal dominant inheritance and is characterized by a distinctive facial appearance, short stature, chest deformity, and congenital heart disease. In individuals with NS, germline mutations have been identified in several genes involved in the RAS/mitogen-activated protein kinase signal transduction pathway. Because of its clinical and genetic heterogeneity, the conventional diagnostic protocol with Sanger sequencing requires a multistep approach. Therefore, molecular genetic diagnosis using targeted exome sequencing (TES) is considered a less expensive and faster method, particularly for patients who do not fulfill the clinical diagnostic criteria of NS. In this case, the patient showed short stature, dysmorphic facial features suggestive of NS, feeding intolerance, cryptorchidism, and intellectual disability in early childhood. At the age of 16, the patient still showed extreme short stature with delayed puberty and characteristic facial features suggestive of NS. Although the patient had no cardiac problems or chest wall deformities, which are commonly present in NS and are major concerns for patients and clinicians, the patient showed several other characteristic clinical features of NS. Considering the possibility of a genetic disorder, including NS, a molecular genetic study with TES was performed. With TES analysis, we detected a pathogenic variant of c.458A > T in KRAS in this patient with atypical NS phenotype and provided appropriate clinical management and genetic counseling. The application of TES enables accurate molecular diagnosis of patients with nonspecific or atypical features in genetic diseases with several responsible genes, such as NS.

PMID: 29025208 [PubMed]

Distal renal tubular acidosis in a Libyan patient: Evidence for digenic inheritance.

Eur J Med Genet. 2017 Oct 09;:

Authors: Nagara M, Papagregoriou G, Ben Abdallah R, Landoulsi Z, Bouyacoub Y, Elouej S, Kefi R, Pippucci T, Konstantinos V, Bashamboo A, McElreavey K, Hachicha M, Romeo G, Seri M, Deltas C, Abdelhak S

Abstract
AIM OF THE STUDY: Recent advances in understanding the underlying molecular mechanism for distal renal tubular acidosis (dRTA), led to an increased attention towards the primary and the familial forms of the disease. Mutations in ATP6V1B1 and ATP6V0A4 are usually responsible for the recessive form of the disease. Mutations in gene AE1 encoding the Cl-/HCO3- exchanger, usually present as dominant dRTA, but a recessive pattern has been recently described. Our objective is to identify the mutational spectrum responsible of dRTA in a consanguineous Libyan family.
MATERIALS AND METHODS: Both ATP6V0A4 and ATP6V1B1 genes were preferentially screened in our patient. Additional whole exome sequencing (WES) in the same patient, offered a wider view on potential chromosomal rearrangements as well as the mutational spectrum of other genes involved in this disease.
RESULTS: The patient is a heterozygote for two different mutations, one in each of the genes ATP6V0A4 and ATP6V1B1, while no deleterious variation was detected in the remaining genes responsible for the recessive form of dRTA. Homozygosity mapping and WES confirmed our findings and supported the hypothesis of a digenic inheritance model existing as an explanation for dRTA.
CONCLUSIONS: To our knowledge, this is the first report describing a Libyan patient with dRTA who suffered from early-onset sensorineural hearing loss, with a digenic mode of inheritance, supported by the identification of two novel mutations. This study increases the understanding of how dRTA is genetically transmitted, while offers a good outline towards the molecular diagnostics and genetic counseling for dRTA in Lybians.

PMID: 29024829 [PubMed - as supplied by publisher]

Left ventricular non-compaction with Ebstein anomaly attributed to a TPM1 mutation.

Eur J Med Genet. 2017 Oct 09;:

Authors: Nijak A, Alaerts M, Kuiperi C, Corveleyn A, Suys B, Paelinck B, Saenen J, Van Craenenbroeck E, Van Laer L, Loeys B, Verstraeten A

Abstract
Left ventricular non-compaction (cardiomyopathy) (LVN(C)) is a rare hereditary cardiac condition, resulting from abnormal embryonic myocardial development. While it mostly occurs as an isolated condition, association with other cardiovascular manifestations such as Ebstein anomaly (EA) has been reported. This congenital heart defect is characterized by downward displacement of the tricuspid valve and leads to diminished ventricular size and function. In an autosomal dominant LVN(C) family consisting of five affected individuals, of which two also presented with EA and two others with mitral valve insufficiency, we pursued the genetic disease cause using whole exome sequencing (WES). WES revealed a missense variant (p.Leu113Val) in TPM1 segregating with the LVN(C) phenotype. TPM1 encodes α-tropomyosin, which is involved in myocardial contraction, as well as in stabilization of non-muscle cytoskeletal actin filaments. So far, LVN(C)-EA has predominantly been linked to pathogenic variants in MYH7. However, one sporadic LVN(C)-EA case with a de novo TPM1 variant has recently been described. We here report the first LVN(C)-EA family segregating a pathogenic TPM1 variant, further establishing the association between EA predisposition and TPM1-related LVN(C). Consequently, we recommend genetic testing for both MYH7 and TPM1 in patients or families in which LVN(C)/non-compaction and EA coincide.

PMID: 29024827 [PubMed - as supplied by publisher]

Incorporating networks in a probabilistic graphical model to find drivers for complex human diseases.

PLoS Comput Biol. 2017 Oct;13(10):e1005580

Authors: Mezlini AM, Goldenberg A

Abstract
Discovering genetic mechanisms driving complex diseases is a hard problem. Existing methods often lack power to identify the set of responsible genes. Protein-protein interaction networks have been shown to boost power when detecting gene-disease associations. We introduce a Bayesian framework, Conflux, to find disease associated genes from exome sequencing data using networks as a prior. There are two main advantages to using networks within a probabilistic graphical model. First, networks are noisy and incomplete, a substantial impediment to gene discovery. Incorporating networks into the structure of a probabilistic models for gene inference has less impact on the solution than relying on the noisy network structure directly. Second, using a Bayesian framework we can keep track of the uncertainty of each gene being associated with the phenotype rather than returning a fixed list of genes. We first show that using networks clearly improves gene detection compared to individual gene testing. We then show consistently improved performance of Conflux compared to the state-of-the-art diffusion network-based method Hotnet2 and a variety of other network and variant aggregation methods, using randomly generated and literature-reported gene sets. We test Hotnet2 and Conflux on several network configurations to reveal biases and patterns of false positives and false negatives in each case. Our experiments show that our novel Bayesian framework Conflux incorporates many of the advantages of the current state-of-the-art methods, while offering more flexibility and improved power in many gene-disease association scenarios.

PMID: 29023450 [PubMed - in process]

Novel ZBTB24 Mutation Associated with Immunodeficiency, Centromere Instability, and Facial Anomalies Type-2 Syndrome Identified in a Patient with Very Early Onset Inflammatory Bowel Disease.

Inflamm Bowel Dis. 2017 Oct 11;:

Authors: Conrad MA, Dawany N, Sullivan KE, Devoto M, Kelsen JR

Abstract
BACKGROUND: Very early onset inflammatory bowel disease, diagnosed in children ≤5 years old, can be the initial presentation of some primary immunodeficiencies.
METHODS: In this study, we describe a 17-month-old boy with recurrent infections, growth failure, facial anomalies, and inflammatory bowel disease. Immune evaluation, whole-exome sequencing, karyotyping, and methylation array were performed to evaluate the child's constellation of symptoms and examination findings.
RESULTS: Whole-exome sequencing revealed that the child was homozygous for a novel variant in ZBTB24, the gene associated with immunodeficiency, centromere instability, and facial anomalies type-2 syndrome.
CONCLUSION: This describes the first case of inflammatory bowel disease associated with immunodeficiency, centromere instability, and facial anomalies type-2 syndrome in a child with a novel disease-causing mutation in ZBTB24 found on whole-exome sequencing.

PMID: 29023266 [PubMed - as supplied by publisher]

Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability.

J Med Genet. 2017 Oct 11;:

Authors: Hamilton MJ, Caswell RC, Canham N, Cole T, Firth HV, Foulds N, Heimdal K, Hobson E, Houge G, Joss S, Kumar D, Lampe AK, Maystadt I, McKay V, Metcalfe K, Newbury-Ecob R, Park SM, Robert L, Rustad CF, Wakeling E, Wilkie AOM, Study TDDD, Twigg SRF, Suri M

Abstract
INTRODUCTION: Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations.
METHODS: Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.
RESULTS: Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.
CONCLUSIONS: These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

PMID: 29021403 [PubMed - as supplied by publisher]

Rapid functional analysis of computationally complex rare human IRF6 gene variants using a novel zebrafish model.

PLoS Genet. 2017 Sep;13(9):e1007009

Authors: Li EB, Truong D, Hallett SA, Mukherjee K, Schutte BC, Liao EC

Abstract
Large-scale sequencing efforts have captured a rapidly growing catalogue of genetic variations. However, the accurate establishment of gene variant pathogenicity remains a central challenge in translating personal genomics information to clinical decisions. Interferon Regulatory Factor 6 (IRF6) gene variants are significant genetic contributors to orofacial clefts. Although approximately three hundred IRF6 gene variants have been documented, their effects on protein functions remain difficult to interpret. Here, we demonstrate the protein functions of human IRF6 missense gene variants could be rapidly assessed in detail by their abilities to rescue the irf6 -/- phenotype in zebrafish through variant mRNA microinjections at the one-cell stage. The results revealed many missense variants previously predicted by traditional statistical and computational tools to be loss-of-function and pathogenic retained partial or full protein function and rescued the zebrafish irf6 -/- periderm rupture phenotype. Through mRNA dosage titration and analysis of the Exome Aggregation Consortium (ExAC) database, IRF6 missense variants were grouped by their abilities to rescue at various dosages into three functional categories: wild type function, reduced function, and complete loss-of-function. This sensitive and specific biological assay was able to address the nuanced functional significances of IRF6 missense gene variants and overcome many limitations faced by current statistical and computational tools in assigning variant protein function and pathogenicity. Furthermore, it unlocked the possibility for characterizing yet undiscovered human IRF6 missense gene variants from orofacial cleft patients, and illustrated a generalizable functional genomics paradigm in personalized medicine.

PMID: 28945736 [PubMed - indexed for MEDLINE]

A syndromic extreme insulin resistance caused by biallelic POC1A mutations in exon 10.

Eur J Endocrinol. 2017 Nov;177(5):K21-K27

Authors: Giorgio E, Rubino E, Bruselles A, Pizzi S, Rainero I, Duca S, Sirchia F, Pasini B, Tartaglia M, Brusco A

Abstract
POC1A encodes a protein with a role in centriole assembly and stability, and in ciliogenesis. Biallelic loss-of-function mutations affecting POC1A cause SOFT syndrome, an ultra-rare condition characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis. Using exome sequencing, we identified a homozygous frameshift mutation (c.1047_1048dupC; p.G337Rfs*25) in a patient presenting with short stature, facial hirsutism, alopecia, dyslipidemia and extreme insulin resistance. The truncating variant affected exon 10, which is retained in only two of the three POC1A-mature RNAs, due to alternative processing of the transcript. Clinical discrepancies with SOFT syndrome support the hypothesis that POC1A mutations affecting exon 10 are associated with a distinct condition, corroborating a previous hypothesis based on a similar case. Furthermore, this report provides an additional example of a genetic condition presenting with clinical heterogeneity due to alternative transcript processing. In conclusion, POC1A mutations in exon 10 should be taken into account in patients with extreme insulin resistance and short stature.

PMID: 28819016 [PubMed - indexed for MEDLINE]

Discovery of novel heart rate-associated loci using the Exome Chip.

Hum Mol Genet. 2017 Jun 15;26(12):2346-2363

Authors: van den Berg ME, Warren HR, Cabrera CP, Verweij N, Mifsud B, Haessler J, Bihlmeyer NA, Fu YP, Weiss S, Lin HJ, Grarup N, Li-Gao R, Pistis G, Shah N, Brody JA, Müller-Nurasyid M, Lin H, Mei H, Smith AV, Lyytikäinen LP, Hall LM, van Setten J, Trompet S, Prins BP, Isaacs A, Radmanesh F, Marten J, Entwistle A, Kors JA, Silva CT, Alonso A, Bis JC, de Boer R, de Haan HG, de Mutsert R, Dedoussis G, Dominiczak AF, Doney ASF, Ellinor PT, Eppinga RN, Felix SB, Guo X, Hagemeijer Y, Hansen T, Harris TB, Heckbert SR, Huang PL, Hwang SJ, Kähönen M, Kanters JK, Kolcic I, Launer LJ, Li M, Yao J, Linneberg A, Liu S, Macfarlane PW, Mangino M, Morris AD, Mulas A, Murray AD, Nelson CP, Orrú M, Padmanabhan S, Peters A, Porteous DJ, Poulter N, Psaty BM, Qi L, Raitakari OT, Rivadeneira F, Roselli C, Rudan I, Sattar N, Sever P, Sinner MF, Soliman EZ, Spector TD, Stanton AV, Stirrups KE, Taylor KD, Tobin MD, Uitterlinden A, Vaartjes I, Hoes AW, van der Meer P, Völker U, Waldenberger M, Xie Z, Zoledziewska M, Tinker A, Polasek O, Rosand J, Jamshidi Y, van Duijn CM, Zeggini E, Jukema JW, Asselbergs FW, Samani NJ, Lehtimäki T, Gudnason V, Wilson J, Lubitz SA, Kääb S, Sotoodehnia N, Caulfield MJ, Palmer CNA, Sanna S, Mook-Kanamori DO, Deloukas P, Pedersen O, Rotter JI, Dörr M, O'Donnell CJ, Hayward C, Arking DE, Kooperberg C, van der Harst P, Eijgelsheim M, Stricker BH, Munroe PB

Abstract
Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

PMID: 28379579 [PubMed - indexed for MEDLINE]

A novel mutation in HAUS7 results in severe oligozoospermia in two brothers.

Gene. 2017 Oct 07;:

Authors: Li L, Sha YW, Su ZY, Mei LB, Ji ZY, Zhang Q, Lin SB, Wang X, Qiu PP, Li P, Yin C

Abstract
Severe oligozoospermia (SO) is a common disease resulting in male infertility; however, its pathophysiology remains unclear. Here, we report two brothers with SO. Whole-exome sequencing (WES) identified a hemizygous variant in HAUS7 (c.G386T:p.G129V), an X-linked gene. HAUS7 has been reported to play a role in the meiotic maturation and chromosome alignment of germ cells. The two patients inherited this variant from their mother, and this variant was considered to be a highly pathogenic mutation by in silico analysis. Moreover, in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) was carried out in both the proband's wife and the brother's wife, but they failed to become pregnant after the embryo transfers. Therefore, this novel mutation in HAUS7 gene may be associated with severe oligozoospermia.

PMID: 29017965 [PubMed - as supplied by publisher]

13 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

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13 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 2017/10/11

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.

A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature.

BMC Med Genet. 2017 Oct 06;18(1):110

Authors: Yang Z, Sun G, Yao F, Tao D, Zhu B

Abstract
BACKGROUND: The pathogenesis of hereditary hyperekplexia is thought to involve abnormalities in the glycinergic neurotransmission system, the most of mutations reported in GLRA1. This gene encodes the glycine receptor α1 subunit, which has an extracellular domain (ECD) and a transmembrane domain (TMD) with 4 α-helices (TM1-TM4).
CASE PRESENTATION: We investigated the genetic cause of hyperekplexia in a Chinese family with one affected member. Whole-exome sequencing of the 5 candidate genes was performed on the proband patient, and direct sequencing was performed to validate and confirm the detected mutation in other family members. We also review and analyse all reported GLRA1 mutations. The proband had a compound heterozygous GLRA1 mutation that comprised 2 novel GLRA1 missense mutations, C.569C > T (p.T190 M) from the mother and C.1270G > A (p.D424N) from the father. SIFT, Polyphen-2 and MutationTaster analysis identified the mutations as disease-causing, but the parents had no signs of hyperekplexia. The p.T190 M mutation is located in the ECD, while p.D424N is located in TM4.
CONCLUSIONS: Our findings contribute to a growing list GLRA1 mutations associated with hyperekplexia and provide new insights into correlations between phenotype and GLRA1 mutations. Some recessive mutations can induce hyperekplexia in combination with other recessive GLRA1 mutations. Mutations in the ECD, TM1, TM1-TM2 loop, TM3, TM3-TM4 loop and TM4 are more often recessive and part of a compound mutation, while those in TM2 and the TM2-TM3 loop are more likely to be dominant hereditary mutations.

PMID: 28985719 [PubMed - in process]

An integrative approach to predicting the functional effects of small indels in non-coding regions of the human genome.

BMC Bioinformatics. 2017 Oct 06;18(1):442

Authors: Ferlaino M, Rogers MF, Shihab HA, Mort M, Cooper DN, Gaunt TR, Campbell C

Abstract
BACKGROUND: Small insertions and deletions (indels) have a significant influence in human disease and, in terms of frequency, they are second only to single nucleotide variants as pathogenic mutations. As the majority of mutations associated with complex traits are located outside the exome, it is crucial to investigate the potential pathogenic impact of indels in non-coding regions of the human genome.
RESULTS: We present FATHMM-indel, an integrative approach to predict the functional effect, pathogenic or neutral, of indels in non-coding regions of the human genome. Our method exploits various genomic annotations in addition to sequence data. When validated on benchmark data, FATHMM-indel significantly outperforms CADD and GAVIN, state of the art models in assessing the pathogenic impact of non-coding variants. FATHMM-indel is available via a web server at indels.biocompute.org.uk.
CONCLUSIONS: FATHMM-indel can accurately predict the functional impact and prioritise small indels throughout the whole non-coding genome.

PMID: 28985712 [PubMed - in process]

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Cell. 2017 Oct 05;171(2):481-494.e15

Authors: Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Nørgaard P, Pedersen M, Gang AO, Høgdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, Dave SS

Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

PMID: 28985567 [PubMed - in process]

Untangling the Web of Lymphoma Somatic Mutations.

Cell. 2017 Oct 05;171(2):270-272

Authors: Teater M, Melnick A

Abstract
In this issue of Cell, Reddy et al. report integrative genetic characterization of diffuse large B cell lymphomas (DLBCL), including large-scale exome capture, transcriptomes, CRISPR screens, and integrative clinical biomarker studies. This provides the first comprehensive overview of DLBCL biology and the basis for future precision medicine approaches to this disease.

PMID: 28985559 [PubMed - in process]

Deficiency of Adenosine Deaminase 2 (DADA2), an Inherited Cause of Polyarteritis Nodosa and a Mimic of Other Systemic Rheumatologic Disorders.

Curr Rheumatol Rep. 2017 Oct 05;19(11):70

Authors: Hashem H, Kelly SJ, Ganson NJ, Hershfield MS

Abstract
PURPOSE OF REVIEW: A new autoinflammatory disease, deficiency of adenosine deaminase 2 (DADA2), caused by mutations in the CECR1 gene, was first reported in 2014. This review aims to update progress in defining, treating, and understanding this multi-faceted disorder.
RECENT FINDINGS: DADA2 was first described in patients with systemic inflammation, mild immune deficiency, and vasculopathy manifested as recurrent stroke or polyarteritis nodosa (PAN). More than 125 patients have now been reported, and the phenotype has expanded to include children and adults presenting primarily with pure red cell aplasia (PRCA), or with antibody deficiency. Age of onset and clinical severity vary widely, even among related patients, and are not clearly related to CECR1 genotype. Inflammatory features often respond to anti-TNF agents, but marrow failure and severe immune deficiency may require hematopoietic stem cell transplantation. ADA2 is expressed and secreted by monocytes and macrophages, but its biological function and the pathogenesis of DADA2 are uncertain and will remain an important area of research. Pre-clinical investigation of ADA2 replacement therapy and CECR1-directed gene therapy are warranted, but complicated by the absence of a suitable animal model.

PMID: 28983775 [PubMed - in process]

Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration.

J Exp Med. 2017 Jul 03;214(7):1937-1947

Authors: Badran YR, Dedeoglu F, Leyva Castillo JM, Bainter W, Ohsumi TK, Bousvaros A, Goldsmith JD, Geha RS, Chou J

Abstract
The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-α (TNF). TNF activates opposing pathways leading to caspase-8-mediated apoptosis as well as nuclear factor κB (NF-κB)-dependent cell survival. We investigated the etiology of autosomal-dominant, mucocutaneous ulceration in a family whose proband was dependent on anti-TNF therapy for sustained remission. A heterozygous mutation in RELA, encoding the NF-κB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients' fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-κB activation, and defective expression of NF-κB-dependent antiapoptotic genes. Rela(+/-) mice have similarly impaired NF-κB activation, develop cutaneous ulceration from TNF exposure, and exhibit severe dextran sodium sulfate-induced colitis, ameliorated by TNF inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF inhibition in this disease.

PMID: 28600438 [PubMed - indexed for MEDLINE]

The Genetic Basis of Pericentral Retinitis Pigmentosa-A Form of Mild Retinitis Pigmentosa.

Genes (Basel). 2017 Oct 05;8(10):

Authors: Comander J, Weigel-DiFranco C, Maher M, Place E, Wan A, Harper S, Sandberg MA, Navarro-Gomez D, Pierce EA

Abstract
Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands with pericentral RP based on a comprehensive analysis of their retinal phenotype. Genetic analyses of DNA samples from these patients were performed using panel-based next-generation sequencing, copy number variations, and whole exome sequencing (WES). Mutations provisionally responsible for disease were found in 19 of the 43 families (44%) analyzed. These include mutations in RHO (five patients), USH2A (four patients), and PDE6B (two patients). Of 28 putatively pathogenic alleles, 15 (54%) have been previously identified in patients with more common forms of typical RP, while the remaining 13 mutations (46%) were novel. Burden testing of WES data successfully identified HGSNAT as a cause of pericentral RP in at least two patients, suggesting it is also a relatively common cause of pericentral RP. While additional sequencing might uncover new genes specifically associated with pericentral RP, the current results suggest that genetically pericentral RP is not a separate clinical entity, but rather is part of the spectrum of mild RP phenotypes.

PMID: 28981474 [PubMed]

ERDS-exome: a Hybrid Approach for Copy Number Variant Detection from Whole-exome Sequencing Data.

IEEE/ACM Trans Comput Biol Bioinform. 2017 Oct 04;:

Authors: Tan R, Wang J, Wu X, Juan L, Zheng L, Ma R, Zhan Q, Wang T, Jin S, Jiang Q, Wang Y

Abstract
Copy number variants (CNVs) play important roles in human disease and evolution. With the rapid development of next-generation sequencing technologies, many tools have been developed for inferring CNVs based on whole-exome sequencing (WES) data. However, as a result of the sparse distribution of exons in the genome, the limitations of the WES technique, and the nature of high-level signal noises in WES data, the efficacy of these variants remains less than desirable. Thus, there is need for the development of an effective tool to achieve a considerable power in WES CNVs discovery. In the present study, we describe a novel method, Estimation by Read Depth (RD) with Single-nucleotide variants from exome sequencing data (ERDS-exome). ERDS-exome employs a hybrid normalization approach to normalize WES data and to incorporate RD and single-nucleotide variation information together as a hybrid signal into a paired hidden Markov model to infer CNVs from WES data. Based on systematic evaluations of real data from the 1000 Genomes Project using other state-of-the-art tools, we observed that ERDS-exome demonstrates higher sensitivity and provides comparable or even better specificity than other tools. ERDS-exome is publicly available at: https://erds-exome.github.io.

PMID: 28981421 [PubMed - as supplied by publisher]