Whole Exome Sequencing of HIV-1 long-term non-progressors identifies rare variants in genes encoding innate immune sensors and signaling molecules.

Sci Rep. 2018 Oct 15;8(1):15253

Authors: Nissen SK, Christiansen M, Helleberg M, Kjær K, Jørgensen SE, Gerstoft J, Katzenstein TL, Benfield T, Kronborg G, Larsen CS, Laursen A, Pedersen G, Jakobsen MR, Tolstrup M, Mogensen TH

Abstract
Common CCR5-∆32 and HLA alleles only explain a minority of the HIV long-term non-progressor (LTNP) and elite controller (EC) phenotypes. To identify rare genetic variants contributing to the slow disease progression phenotypes, we performed whole exome sequencing (WES) on seven LTNPs and four ECs. HLA and CCR5 allele status, total HIV DNA reservoir size, as well as variant-related functional differences between the ECs, LTNPs, and eleven age- and gender-matched HIV-infected non-controllers on antiretroviral therapy (NCARTs) were investigated. Several rare variants were identified in genes involved in innate immune sensing, CD4-dependent infectivity, HIV trafficking, and HIV transcription mainly within the LTNP group. ECs and LTNPs had a significantly lower HIV reservoir compared to NCARTs. Furthermore, three LTNPs with variants affecting HIV nuclear import showed integrated HIV DNA levels below detection limit after in vitro infection. HIV slow progressors with variants in the TLR and NOD2 pathways showed reduced pro-inflammatory responses compared to matched controls. Low-range plasma levels of fibronectin was observed in a LTNP harboring two FN1 variants. Taken together, this study identified rare variants in LTNPs as well as in one EC, which may contribute to understanding of HIV pathogenesis and these slow progressor phenotypes, especially in individuals without protecting CCR5-∆32 and HLA alleles.

PMID: 30323326 [PubMed - in process]

De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy.

J Med Genet. 2018 Oct 15;:

Authors: Sega AG, Mis EK, Lindstrom K, Mercimek-Andrews S, Ji W, Cho MT, Juusola J, Konstantino M, Jeffries L, Khokha MK, Lakhani SA

Abstract
BACKGROUND: Early infantile epileptic encephalopathies are severe disorders consisting of early-onset refractory seizures accompanied often by significant developmental delay. The increasing availability of next-generation sequencing has facilitated the recognition of single gene mutations as an underlying aetiology of some forms of early infantile epileptic encephalopathies.
OBJECTIVES: This study was designed to identify candidate genes as a potential cause of early infantile epileptic encephalopathy, and then to provide genetic and functional evidence supporting patient variants as causative.
METHODS: We used whole exome sequencing to identify candidate genes. To model the disease and assess the functional effects of patient variants on candidate protein function, we used in vivo CRISPR/Cas9-mediated genome editing and protein overexpression in frog tadpoles.
RESULTS: We identified novel de novo variants in neuronal differentiation factor 2 (NEUROD2) in two unrelated children with early infantile epileptic encephalopathy. Depleting neurod2 with CRISPR/Cas9-mediated genome editing induced spontaneous seizures in tadpoles, mimicking the patients' condition. Overexpression of wild-type NEUROD2 induced ectopic neurons in tadpoles; however, patient variants were markedly less effective, suggesting that both variants are dysfunctional and likely pathogenic.
CONCLUSION: This study provides clinical and functional support for NEUROD2 variants as a cause of early infantile epileptic encephalopathy, the first evidence of human disease caused by NEUROD2 variants.

PMID: 30323019 [PubMed - as supplied by publisher]

Genetic Evidence Supporting the Role of the Calcium Channel, CACNA1S, in Tooth Cusp and Root Patterning.

Front Physiol. 2018;9:1329

Authors: Laugel-Haushalter V, Morkmued S, Stoetzel C, Geoffroy V, Muller J, Boland A, Deleuze JF, Chennen K, Pitiphat W, Dollfus H, Niederreither K, Bloch-Zupan A, Pungchanchaikul P

Abstract
In this study, we report a unique dominantly inherited disorganized supernumerary cusp and single root phenotype presented by 11 affected individuals belonging to 5 north-eastern Thai families. Using whole exome sequencing (WES) we identified a common single missense mutation that segregates with the phenotype in exon 6 of CACNA1S (Cav1.1) (NM_000069.2: c.[865A > G];[=] p.[Ile289Val];[=]), the Calcium Channel, Voltage-Dependent, L Type, Alpha-1s Subunit, OMIM ∗ 114208), affecting a highly conserved amino-acid isoleucine residue within the pore forming subdomain of CACNA1S protein. This is a strong genetic evidence that a voltage-dependent calcium ion channel is likely to play a role in influencing tooth morphogenesis and patterning.

PMID: 30319441 [PubMed]

Identification of an immune modulation locus utilising a bovine mammary gland infection challenge model.

J Dairy Res. 2018 May;85(2):185-192

Authors: Littlejohn MD, Turner SA, Walker CG, Berry SD, Tiplady K, Sherlock RG, Sutherland G, Swift S, Garrick D, Lacy-Hulbert SJ, McDougall S, Spelman RJ, Snell RG, Hillerton JE

Abstract
Inflammation of the mammary gland following bacterial infection, commonly known as mastitis, affects all mammalian species. Although the aetiology and epidemiology of mastitis in the dairy cow are well described, the genetic factors mediating resistance to mammary gland infection are not well known, due in part to the difficulty in obtaining robust phenotypic information from sufficiently large numbers of individuals. To address this problem, an experimental mammary gland infection experiment was undertaken, using a Friesian-Jersey cross breed F2 herd. A total of 604 animals received an intramammary infusion of Streptococcus uberis in one gland, and the clinical response over 13 milkings was used for linkage mapping and genome-wide association analysis. A quantitative trait locus (QTL) was detected on bovine chromosome 11 for clinical mastitis status using micro-satellite and Affymetrix 10 K SNP markers, and then exome and genome sequence data used from the six F1 sires of the experimental animals to examine this region in more detail. A total of 485 sequence variants were typed in the QTL interval, and association mapping using these and an additional 37 986 genome-wide markers from the Illumina SNP50 bovine SNP panel revealed association with markers encompassing the interleukin-1 gene cluster locus. This study highlights a region on bovine chromosome 11, consistent with earlier studies, as conferring resistance to experimentally induced mammary gland infection, and newly prioritises the IL1 gene cluster for further analysis in genetic resistance to mastitis.

PMID: 29785904 [PubMed - indexed for MEDLINE]

Bone matrix hypermineralization associated with low bone turnover in a case of Nasu-Hakola disease.

Bone. 2018 Oct 10;:

Authors: Shboul M, Roschger P, Ganger R, Paschalis L, Rokidi S, Zandieh S, Behunova J, Muschitz C, Fahrleitner-Pammer A, Ng AYJ, Tohari S, Venkatesh B, Bonnard C, Reversade B, Klaushofer K, Al Kaissi A

Abstract
Analysis of tissue from a 34-years-old male patient from Austrian origin with a history of multiple fractures associated with painful episodes over the carpal, tarsal and at the end of the long bones respectively is presented. Radiographic images and axial 3DCT scans showed widespread defects in trabecular bone architecture and ill-defined cortices over these skeletal sites in the form of discrete cystic-like lesions. Family history indicated two sisters (one half and one full biological sisters) also with a history of fractures. Whole exome sequencing revealed two heterozygous missense mutations in TYROBP (MIM 604142; NM_003332.3) gene encoding for a cell-surface adaptor protein, which is part of a signaling complex triggering activation of immune responses. It is expressed in cells of the ectoderm cell linage such as NK and dendritic cells, macrophages, monocytes, myeloid cells, microglia cells and osteoclasts. The phenotype and genotype of the patient were consistent with the diagnosis of Nasu-Hakola disease (NHD) (OMIM 221770). Investigations at the bone material level of a transiliac bone biopsy sample from the patient using polarized light microscopy and backscatter electron imaging revealed disordered lamellar collagen fibril arrangement and extensively increased matrix mineralization. These findings are the first bone material data in a patient with NHD and point toward an osteoclast defect involvement in this genetic condition.

PMID: 30316000 [PubMed - as supplied by publisher]

Human genomics of acute liver failure due to hepatitis B virus infection: an exome sequencing study in liver transplant recipients.

J Viral Hepat. 2018 Oct 13;:

Authors: Asgari S, Chaturvedi N, Scepanovic P, Hammer C, Semmo N, Giostra E, Müllhaupt B, Angus P, Thompson AJ, Moradpour D, Fellay J

Abstract
Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti-HBc and anti-HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis-driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case-control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV-related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals. This article is protected by copyright. All rights reserved.

PMID: 30315682 [PubMed - as supplied by publisher]

Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.

Nat Commun. 2018 Oct 12;9(1):4228

Authors: Tin A, Li Y, Brody JA, Nutile T, Chu AY, Huffman JE, Yang Q, Chen MH, Robinson-Cohen C, Macé A, Liu J, Demirkan A, Sorice R, Sedaghat S, Swen M, Yu B, Ghasemi S, Teumer A, Vollenweider P, Ciullo M, Li M, Uitterlinden AG, Kraaij R, Amin N, van Rooij J, Kutalik Z, Dehghan A, McKnight B, van Duijn CM, Morrison A, Psaty BM, Boerwinkle E, Fox CS, Woodward OM, Köttgen A

Abstract
Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10-56) and SLC2A9 (p = 4.5 × 10-7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10-3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

PMID: 30315176 [PubMed - in process]

EIF2AK3 variants in Dutch patients with Alzheimer's disease.

Neurobiol Aging. 2018 Aug 24;:

Authors: Wong TH, van der Lee SJ, van Rooij JGJ, Meeter LHH, Frick P, Melhem S, Seelaar H, Ikram MA, Rozemuller AJ, Holstege H, Hulsman M, Uitterlinden A, Neumann M, Hoozemans JJM, van Duijn CM, Rademakers R, van Swieten JC

Abstract
Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07-3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.

PMID: 30314817 [PubMed - as supplied by publisher]

Whole-Exome Sequencing Implicates SCN2A in Episodic Ataxia, but Multiple Ion Channel Variants May Contribute to Phenotypic Complexity.

Int J Mol Sci. 2018 Oct 11;19(10):

Authors: Maksemous N, Smith RA, Sutherland HG, Sampaio H, Griffiths LR

Abstract
Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. Molecular genetic tests for episodic ataxia type 2 (EA2) usually target only the specific calcium channel gene (CACNA1A) that is known to cause EA2. In cases where no mutations are identified in the CACNA1A gene, it is important to identify the causal gene so that more effective treatment can be prioritized for patients. Here we present a case of a proband with a complex episodic ataxias (EA)/seizure phenotype with an EA-affected father; and an unaffected mother, all negative for CACNA1A gene mutations. The trio was studied by whole-exome sequencing to identify candidate genes responsible for causing the complex EA/seizure phenotype. Three rare or novel variants in Sodium channel α2-subunit; SCN2A (c.3973G>T: p.Val1325Phe), Potassium channel, Kv3.2; KCNC2 (c.1006T>C: p.Ser336Pro) and Sodium channel Nav1.6; SCN8A (c.3421C>A: p.Pro1141Thr) genes were found in the proband. While the SCN2A variant is likely to be causal for episodic ataxia, each variant may potentially contribute to the phenotypes observed in this family. This study highlights that a major challenge of using whole-exome/genome sequencing is the identification of the unique causative mutation that is associated with complex disease.

PMID: 30314295 [PubMed - in process]

Novel splice receptor-site mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa.

Medicine (Baltimore). 2018 Oct;97(41):e12779

Authors: Wang J, Zhou C, Xiao Y, Liu H

Abstract
RATIONALE: Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous diseases; X-linked retinitis pigmentosa (XLRP) is the most serious type. Mutations in RP GTPase regulator (RPGR) account for over 70% of patients with XLRP.
PATIENT CONCERNS: We report a Chinese family with RP, 5 males presented with night blindness and decreased vision, and 8 females showed different severities of myopia.
DIAGNOSES: Targeted exome capture sequencing was performed in 2 affected males, which revealed a novel variant (NM_000328.2, c.470-1G>A) in the RPGR gene. The mis-splicing causes a substitution of the 157th amino acid from glutamic acid to glycine and finally the 165th codon is changed to stop codon, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The mutation cosegregated with the disease phenotype in the family.
INTERVENTIONS: Medication and cataract surgery.
OUTCOMES: The phenotype of affected males is more serious than that of the carrier females, and the effect of clinical treatment is not very well.
LESSONS: Next-generation sequencing is a suitable method for early detection of pathogenic mutations in RP, which would be helpful for prenatal diagnosis of the disease.

PMID: 30313097 [PubMed - in process]

Case of Neonatal Fatality from Neuromuscular Variant of Glycogen Storage Disease Type IV.

JIMD Rep. 2018 Oct 12;:

Authors: Sandhu T, Polan M, Yu Z, Lu R, Makkar A

Abstract
Glycogen storage disease type IV (GSD-IV), or Andersen disease, is a rare autosomal recessive disorder that results from the deficiency of glycogen branching enzyme (GBE). This in turn results in accumulation of abnormal glycogen molecules that have longer outer chains and fewer branch points. GSD-IV manifests in a wide spectrum, with variable phenotypes depending on the degree and type of tissues in which this abnormal glycogen accumulates. Typically, GSD-IV presents with rapidly progressive liver cirrhosis and death in early childhood. However, there is a severe congenital neuromuscular variant of GSD-IV that has been reported in the literature, with fewer than 20 patient cases thus far. We report an unusual case of GSD-IV neuromuscular variant in a late preterm female infant who was born to non-consanguineous healthy parents with previously healthy children. Prenatally, our patient was found to have decreased fetal movement and polyhydramnios warranting an early delivery. Postnatally, she had severe hypotonia and respiratory failure, with no hepatic or cardiac involvement. Extensive metabolic and neurological workup revealed no abnormalities. However, molecular analysis by whole-exome sequencing revealed two pathogenic variants in the GBE1 gene. Our patient was thus a compound heterozygote of the two pathogenic variants: one of these was inherited from the mother [p.L490WfsX5 (c.1468delC)], and the other pathogenic variant was a de novo change [p.E449X (c.1245G>T)]. As expected in GSD-IV, diffuse intracytoplasmic periodic acid-Schiff-positive, diastase-resistant inclusions were found in the cardiac myocytes, hepatocytes, and skeletal muscle fibers of our patient.

PMID: 30311141 [PubMed - as supplied by publisher]

Exome sequencing in an Italian family with Alzheimer's disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H.

Alzheimers Res Ther. 2018 Oct 12;10(1):106

Authors: Paracchini L, Beltrame L, Boeri L, Fusco F, Caffarra P, Marchini S, Albani D, Forloni G

Abstract
BACKGROUND: The typical familial form of Alzheimer's disease (FAD) accounts for about 5% of total Alzheimer's disease (AD) cases. Presenilins (PSEN1 and PSEN2) and amyloid-β (A4) precursor protein (APP) genes carry all reported FAD-linked mutations. However, other genetic loci may be involved in AD. For instance, seizure-related gene 6 (SEZ6) has been reported in brain development and psychiatric disorders and is differentially expressed in the cerebrospinal fluid of AD cases.
METHODS: We describe a targeted exome sequencing analysis of a large Italian kindred with AD, negative for PSEN and APP variants, that indicated the SEZ6 heterozygous mutation R615H is associated with the pathology.
RESULTS: We overexpressed R615H mutation in H4-SW cells, finding a reduction of amyloid peptide Aβ(1-42). Sez6 expression decreased with age in a mouse model of AD (3xTG-AD), but independently from transgene expression.
CONCLUSIONS: These results support a role of exome sequencing for disease-associated variant discovery and reinforce available data on SEZ6 in AD models.

PMID: 30309378 [PubMed - in process]

No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY.

J Hum Genet. 2018 Jul;63(7):821-829

Authors: Horikawa Y, Hosomichi K, Enya M, Ishiura H, Suzuki Y, Tsuji S, Sugano S, Inoue I, Takeda J

Abstract
MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.

PMID: 29670293 [PubMed - indexed for MEDLINE]

14 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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14 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 2018/10/12

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.

Genomic profiling supports the diagnosis of primary ciliary dyskinesia and reveals novel candidate genes and genetic variants.

PLoS One. 2018;13(10):e0205422

Authors: Andjelkovic M, Minic P, Vreca M, Stojiljkovic M, Skakic A, Sovtic A, Rodic M, Skodric-Trifunovic V, Maric N, Visekruna J, Spasovski V, Pavlovic S

Abstract
Primary ciliary dyskinesia (PCD) is a rare inherited autosomal recessive or X-linked disorder that mainly affects lungs. Dysfunction of respiratory cilia causes symptoms such as chronic rhinosinusitis, coughing, rhinitis, conductive hearing loss and recurrent lung infections with bronchiectasis. It is now well known that pathogenic genetic changes lead to ciliary dysfunction. Here we report usage of clinical-exome based NGS approach in order to reveal underlying genetic causes in cohort of 21 patient with diagnosis of PCD. By detecting 18 (12 novel) potentially pathogenic genetic variants, we established the genetic cause of 11 (9 unrelated) patients. Genetic variants were detected in six PCD disease-causing genes, as well as in SPAG16 and SPAG17 genes, that were not detected in PCD patients so far, but were related to some symptoms of PCD. The most frequently mutated gene in our cohort was DNAH5 (27.77%). Identified variants were in homozygous, compound heterozygous and trans-heterozygous state. For detailed characterization of one novel homozygous genetic variant in DNAI1 gene (c. 947_948insG, p. Thr318TyrfsTer11), RT-qPCR and Western Blot analysis were performed. Molecular diagnostic approach applied in this study enables analysis of 29 PCD disease-causing and related genes. It resulted in mutation detection rate of 50% and enabled discovery of twelve novel mutations and pointed two possible novel PCD candidate genes.

PMID: 30300419 [PubMed - in process]

Very early-onset inflammatory bowel disease: an integrated approach.

Curr Opin Allergy Clin Immunol. 2018 Oct 06;:

Authors: Sullivan KE, Conrad M, Kelsen JR

Abstract
PURPOSE OF THE REVIEW: Immune dysregulation disorders are among the most rapidly growing set of inborn errors of immunity. One particular subset is the category where early-onset inflammatory bowel disease (IBD) is the most common manifestation. These disorders are being increasingly appreciated although there has been minimal effort to articulate a unified approach to their diagnosis and management. This review will cover current thinking and strategies related to diagnosis and management of very early-onset IBD.
RECENT FINDINGS: There is an expanding set of monogenic causes of early-onset IBD. In many cases, the precise genetic cause dictates management. Lessons learned from the management of these monogenic conditions can sometimes be extrapolated to other refractory cases of IBD.
SUMMARY: An integrated approach to diagnosis, risk analysis, and management can include diagnostic approaches not often utilized for traditional IBD such as whole exome sequencing. Management can also include nontraditional approaches such as targeted biologics or hematopoietic cell transplantation.

PMID: 30299395 [PubMed - as supplied by publisher]

Gray Zone Lymphoma Arising in the Neck of a Teenager With a Germline Mutation in TP53.

J Pediatr Hematol Oncol. 2018 Oct 05;:

Authors: Gatineau-Sailliant S, Turcotte K, Quintal MC, Turpin S, Champagne J, Petrella T, Roussy M, Cellot S, Bouron-Dal Soglio D

Abstract
Gray zone lymphoma is an aggressive disease for which appropriate management is still debated. We report a 15-year-old girl with a cervical mass, an enlarged ipsilateral tonsil, and anemia. Both sites showed hypermetabolism on F18-FG positron emission tomography/CT. Surgical resection was diagnostic of Epstein-Barr virus-negative gray zone lymphoma cervical and tonsillar involvement. No abnormality was found in cytogenetic analysis on tumor cells. However, exome sequencing in peripheral blood DNA revealed a germline mutation in TP53. Complete response was achieved after surgery and 6 cycles of rituximab with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen.

PMID: 30299350 [PubMed - as supplied by publisher]

[Analysis of clinical phenotypes and KCNJ2 gene mutations in a Chinese pedigree affected with Andersen-Tawil syndrome].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2018 Oct 10;35(5):675-678

Authors: Sun H, Wan N

Abstract
OBJECTIVE: To analyze the clinical phenotypes of a pedigree affected with periodic paralysis and explore its molecular basis.
METHODS: Clinical data and peripheral blood samples of the pedigree were collected. The proband and his father both complained of periodic paralysis and dysmorphic features. The exome of the proband was screened using Roche NimbleGen probes, and the results were confirmed by Sanger sequencing. Suspected mutations were subjected to bioinformatic and gene-disease correlation analysis.
RESULTS: A c.653G>A (p.R218Q) mutation of the KCNJ2 gene was detected in both the proband and his father. Bioinformatics analysis suggested it to be pathogenic.
CONCLUSION: The clinical manifestation of the pedigree was suggestive of Andersen-Tawil syndrome. KCNJ2 c.653G>A (p.R218Q) was the pathogenic mutation in this pedigree.

PMID: 30298493 [PubMed - in process]

[Analysis of TGFBI gene mutation in a pedigree affected with corneal dystrophy].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2018 Oct 10;35(5):672-674

Authors: Shu A, Li G, Luo H, He J, Hu X, Sun J, Qing Y, Gao L, Zhang J, Yang C, He L, Wan C

Abstract
OBJECTIVE: To detect potential mutation in a large Chinese pedigree affected with congenital corneal dystrophy.
METHODS: Two patients from the pedigree were subjected to whole exome sequencing to determine the candidate gene. Suspected mutation was verified in 13 additional members by directional Sanger sequencing. Ccorrelation between genotype and phenotype was explored.
RESULTS: A missense mutation, c.1877A>C (p.His626Pro), was detected in exon 14 of the TGFBI gene in 8 patients from the pedigree, but not in five unaffected members and 100 unrelated healthy controls. Respectively, the mutation was predicted as "affecting protein function", "probably damaging" and "disease causing" by SIFT, PolyPhen-2 and MutationTaster.
CONCLUSION: The c.1877A>C mutation of the TGFBI gene probably underlies the disease in this pedigree.

PMID: 30298492 [PubMed - in process]