Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants.

Eur J Med Genet. 2018 Jul 05;:

Authors: Chen H, Qian Y, Yu S, Xiao D, Guo X, Wang Q, Hao L, Lu Y, Dong X, Yan K, Zhou W, Wu B, Wang H

Abstract
BACKGROUND: Developmental delay (DD) is a neurological disorder that presents with defects in gross motor, fine motor, language and cognition functions. WD repeat domain 45 (WDR45) is one of the disease-causing genes of DD. Previously, WDR45 de novo mutations were reported in certain adult and pediatric patients due to iron accumulation.
CLINICAL REPORT: We report five pediatric female patients with DD and epilepsy. Their ages were below 3 years at the first consultation, and precise diagnoses were difficult based on the available clinical information and phenotype.
METHODS: Children with DD and/or epilepsy presenting to the molecular diagnostic center of Children's Hospital of Fudan University between May 2016 and May 2017 were enrolled. The patients and their parents were subjected to whole-exome sequencing (WES), and we characterized the phenotypes of the patients carrying WDR45 variants. Furthermore, we overexpressed the candidate variants in HeLa cells and evaluated their effect on autophagy through Western blot and immunofluorescence staining with confocal microscopy.
RESULTS: Five WDR45 de novo mutations, namely, c.19C > T (p.Arg7*), c.401G > C (p.Arg134Pro), c.503G > A (p.Gly168Glu), c.700C > T (p.Arg234*), and c.912delT (p.Ala305Leufs*25), were detected in 623 enrolled pediatric patients (274 females; 487 patients younger than 6 years). All five patients with WDR45 variants presented with DD and epilepsy. Compared with the control HeLa cells, the cells with the p. Arg134Pro and p. Gly168Glu missense mutations showed accumulation of LC3-containing autophagic structures and an abnormally enlarged cell volume, and Western blotting revealed a significant increase in LC3II/GAPDH.
CONCLUSION: The identification of WDR45 mutations provides further evidence that WES plays an important role in the diagnosis of neurological disorders with common phenotypes and that WDR45 mutations are associated with neurological disorders and are not very rare in Chinese female pediatric patients with DD and/or epilepsy. The diagnosis of patients with WDR45 mutations would enable more precise genetic counseling for the parents of these children.

PMID: 29981852 [PubMed - as supplied by publisher]

Genomic determinants of long-term cardiometabolic complications in childhood acute lymphoblastic leukemia survivors.

BMC Cancer. 2017 Nov 10;17(1):751

Authors: England J, Drouin S, Beaulieu P, St-Onge P, Krajinovic M, Laverdière C, Levy E, Marcil V, Sinnett D

Abstract
BACKGROUND: While cure rates for childhood acute lymphoblastic leukemia (cALL) now exceed 80%, over 60% of survivors will face treatment-related long-term sequelae, including cardiometabolic complications such as obesity, insulin resistance, dyslipidemia and hypertension. Although genetic susceptibility contributes to the development of these problems, there are very few studies that have so far addressed this issue in a cALL survivorship context.
METHODS: In this study, we aimed at evaluating the associations between common and rare genetic variants and long-term cardiometabolic complications in survivors of cALL. We examined the cardiometabolic profile and performed whole-exome sequencing in 209 cALL survivors from the PETALE cohort. Variants associated with cardiometabolic outcomes were identified using PLINK (common) or SKAT (common and rare) and a logistic regression was used to evaluate their impact in multivariate models.
RESULTS: Our results showed that rare and common variants in the BAD and FCRL3 genes were associated (p<0.05) with an extreme cardiometabolic phenotype (3 or more cardiometabolic risk factors). Common variants in OGFOD3 and APOB as well as rare and common BAD variants were significantly (p<0.05) associated with dyslipidemia. Common BAD and SERPINA6 variants were associated (p<0.05) with obesity and insulin resistance, respectively.
CONCLUSIONS: In summary, we identified genetic susceptibility loci as contributing factors to the development of late treatment-related cardiometabolic complications in cALL survivors. These biomarkers could be used as early detection strategies to identify susceptible individuals and implement appropriate measures and follow-up to prevent the development of risk factors in this high-risk population.

PMID: 29126409 [PubMed - indexed for MEDLINE]

ANGPTL3 serum concentration and rare genetic variants in Finnish population.

Scand J Clin Lab Invest. 2017 Dec;77(8):601-609

Authors: Tikka A, Metso J, Jauhiainen M

Abstract
Genetic variants of angiopoietin-like protein 3 (ANGPTL3) are associated with serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) concentration in GWASs. ANGPTL3 deficiency causes declined TG, total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) serum concentration, a phenotype defined as familial combined hypolipidaemia (FHBL2). Our aim is to establish whether ANGPTL3 serum protein concentration correlates with lipoproteins and lipids in hyper- or hypolipidaemic subjects, and whether ANGPTL3 sequence variants are associated with untypical lipid profiles. Additionally, 10 subjects with very low lipoprotein concentrations were sequenced for ANGPTL3 for possible loss-of-function (LOF) variants. Study subjects were selected from Finnish FINRISK and Health 2000 surveys. ANGPTL protein concentrations were measured by ELISA method. As a result, ANGPTL3 serum concentration correlated positively with age, phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) activities, but not with any of the lipid or lifestyle attributes. No ANGPTL3 variants were found among sequenced samples. Subjects who carried ANGPTL3 sequence variants rs12563308 (n = 4) and rs199772471 (n = 1) had abnormally high TC and LDL-C concentrations. Whole exome sequencing data of these five subjects were further analyzed for rare and deleterious missense variants in genes associated with cholesterol metabolism. In conclusion, ANGPTL3 serum protein concentration did not predict lipid concentrations, unlike apolipoprotein C-III (apoC-III) which positively correlated with most of the lipid attributes. ANGPTL3 variant screen yielded five carriers with abnormally high TC concentration; the actual genetic causality, however, could not be verified.

PMID: 28972399 [PubMed - indexed for MEDLINE]

Genetic causes of MCPH in consanguineous Pakistani families.

Clin Genet. 2016 06;89(6):744-5

Authors: Kraemer N, Picker-Minh S, Abbasi AA, Fröhler S, Ninnemann O, Khan MN, Ali G, Chen W, Kaindl AM

PMID: 26548919 [PubMed - indexed for MEDLINE]

Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.

J Thorac Oncol. 2018 Jul 04;:

Authors: Liu Y, Lusk CM, Cho MH, Silverman EK, Qiao D, Zhang R, Scheurer ME, Kheradmand F, Wheeler DA, Tsavachidis S, Armstrong G, Zhu D, Wistuba II, Chow CB, Behrens C, Pikielny CW, Neslund-Dudas C, Pinney SM, Anderson M, Kupert E, Bailey-Wilson J, Gaba C, Mandal D, You M, de Andrade M, Yang P, Field JK, Liloglou T, Davies M, Lissowska J, Swiatkowska B, Zaridze D, Mukeriya A, Janout V, Holcatova I, Mates D, Milosavljevic S, Scelo G, Brennan P, McKay J, Liu G, Hung RJ, COPDGene Investigators, Christiani DC, Schwartz AG, Amos CI, Spitz MR

Abstract
BACKGROUND: Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to lung cancer (LC) susceptibility but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited causal LC variants, we performed focused exome sequencing analyses on genes located in 121 GWAS loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level and smoking behavior.
METHODS: Germline DNA from 260 LC cases and 318 controls were sequenced utilizing VCRome 2.1 exome capture. Filtering was based upon enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1,773 cases and 1,123 controls.
RESULTS: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant BRCA2 K3326X (OR 2.36, 95% CI 1.38 - 3.99) and three newly identified variations: LTB p.Leu87Phe (OR 7.52, 95% CI 1.01 - 16.56), P3H2 p.Gln185His (OR 5.39, 95% CI 0.75 - 15.43), and DAAM2 p.Asp762Gly (OR 0.25, 95% CI 0.10 - 0.79). Burden tests revealed strong associations between ZNF93, DAAM2, BRD9, and LTB genes and LC susceptibility.
CONCLUSION: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.

PMID: 29981437 [PubMed - as supplied by publisher]

Exploration and characterisation of the phenotypic and genetic profiles of patients with early onset schizophrenia associated with autism spectrum disorder and their first-degree relatives: a French multicentre case series study protocol (GenAuDiss).

BMJ Open. 2018 Jul 05;8(7):e023330

Authors: Fernandez A, Dor E, Maurin T, Laure G, Menard ML, Drozd M, Poinso F, Bardoni B, Askenazy F, Thümmler S

Abstract
INTRODUCTION: Early-onset schizophrenia (EOS) is a rare and severe condition. A higher rate of neurodevelopmental abnormalities, such as intellectual or communication impairments as well as attention deficit hyperactivity disorder, is observed in EOS compared with adult-onset schizophrenia. Early signs of autism spectrum disorders (ASD) are present in about 30% of patients. Genetic abnormalities, including copy number variations, are frequent in neurodevelopmental disorders and have been associated to ASD physiopathology. Implicated genes encode proteins involved in brain development, synapses morphology and plasticity and neurogenesis. In addition, an increasing number of genetic abnormalities are shared by EOS and ASD, underlying the neurodevelopmental hypothesis of EOS.The main objective of our study is to identify disease-causing genetic mutations in a cohort of patients affected by both EOS and ASD. Special attention will be paid to genes involved in neurodevelopmental pathways.
METHODS AND ANALYSIS: We describe a multicentric study in a paediatric population. The study started in April 2014. Inclusion criteria are: age 7-22 years, diagnosis of EOS with comorbid ASD and IQ >50; Parents and siblings are also enrolled. We perform psychiatric assessments (Mini International Neuropsychiatric Interview, Kiddie Schedule for Affective Disorders and Schizophrenia -Present and Lifetime Version, Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms) together with neurocognitive evaluations (IQ, Trail Making Test A/B and verbal fluency). Then, we study variants of the coding part of DNA (exome), using next-generation sequencing process on trio (mother, father and child). Bioinformatics tools (RVIS and PolyPhen-2) are used to prioritise disease-causing mutations in candidate genes. The inclusion period will end in November 2019.
ETHICS AND DISSEMINATION: The study protocol was approved by the Local Ethic Committee and by the French National Agency for Medicines and Health Products Safety. All patients signed informed consent on enrolment in the study. Results of the present study should help to unravel the molecular pathology of EOS, paving the way for an early therapeutic intervention.
TRIAL REGISTRATION NUMBER: NCT0256552; Pre-results.

PMID: 29980548 [PubMed - in process]

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.

Am J Hum Genet. 2018 Jul 05;103(1):100-114

Authors: Xu Z, Lo WS, Beck DB, Schuch LA, Oláhová M, Kopajtich R, Chong YE, Alston CL, Seidl E, Zhai L, Lau CF, Timchak D, LeDuc CA, Borczuk AC, Teich AF, Juusola J, Sofeso C, Müller C, Pierre G, Hilliard T, Turnpenny PD, Wagner M, Kappler M, Brasch F, Bouffard JP, Nangle LA, Yang XL, Zhang M, Taylor RW, Prokisch H, Griese M, Chung WK, Schimmel P

Abstract
The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5'-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

PMID: 29979980 [PubMed - in process]

Knobloch syndrome caused by homozygous frameshift mutation of the COL18A1 gene in a Chinese pedigree.

Int J Ophthalmol. 2018;11(6):918-922

Authors: Zhang LS, Li HB, Zeng J, Yang Y, Ding C

Abstract
AIM: To explore the clinical feature and genetic etiology of a Chinese Knobloch syndrome family.
METHODS: Ocular examinations and magnetic resonance imagings (MRIs) were performed on the family. Whole exome sequencing was conducted on the two patients. Sanger sequencing was utilized to validate the presence of variation in the family as well as in 100 normal controls. Real-time quantitative polymerase chain reaction (PCR) was used to detect the expression level of COL18A1 in peripheral blood lymphocytes of the patients and normal carriers.
RESULTS: The affected subjects presented with vision loss, exotropia, cataracts, retinal detachment, and other complications. A homozygous c.4759_4760delCT (p.Leu1587ValfsX72) mutation (rs398122391) in COL18A1 was identified in the two patients, cosegregating with the phenotypes, and did not be detected in 100 normal controls. This mutation caused significant decreased expression of COL18A1 mRNA in the patients.
CONCLUSION: The findings strongly indicate that this mutation is the disease-causing mutation. Moreover, this is the first Knobloch syndrome pedigree reported in the Chinese population.

PMID: 29977801 [PubMed]

Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency.

Eur J Hum Genet. 2018 Jul 05;:

Authors: Srivastava A, Srivastava KR, Hebbar M, Galada C, Kadavigrere R, Su F, Cao X, Chinnaiyan AM, Girisha KM, Shukla A, Bielas SL

Abstract
Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.

PMID: 29976978 [PubMed - as supplied by publisher]

Next generation sequencing identifies novel disease-associated BEST1 mutations in Bestrophinopathy patients.

Sci Rep. 2018 Jul 05;8(1):10176

Authors: Nguyen TT, Poornachandra B, Verma A, Mehta RA, Phalke S, Battu R, Ramprasad VL, Peterson AS, Ghosh A, Seshagiri S

Abstract
Bestinopathies are a spectrum of retinal disorders associated with mutations in BEST1 including autosomal recessive bestrophinopathy (ARB) and autosomal dominant Best vitelliform macular dystrophy (BVMD). We applied whole-exome sequencing on four unrelated Indian families comprising eight affected and twelve unaffected individuals. We identified five mutations in BEST1, including p.Tyr131Cys in family A, p.Arg150Pro in family B, p.Arg47His and p.Val216Ile in family C and p.Thr91Ile in family D. Among these, p.Tyr131Cys, p.Arg150Pro and p.Val216Ile have not been previously reported. Further, the inheritance pattern of BEST1 mutations in the families confirmed the diagnosis of ARB in probands in families A, B and C, while the inheritance of heterozygous BEST1 mutation in family D (p.Thr91Ile) was suggestive of BVMD. Interestingly, the ARB families A and B carry homozygous mutations while family C was a compound heterozygote with a mutation in an alternate BEST1 transcript isoform, highlighting a role for alternate BEST1 transcripts in bestrophinopathy. In the BVMD family D, the heterozygous BEST1 mutation found in the proband was also found in the asymptomatic parent, suggesting an incomplete penetrance and/or the presence of additional genetic modifiers. Our report expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis.

PMID: 29976937 [PubMed - in process]

Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglycerides, and Incident Cardiovascular Disease.

J Am Coll Cardiol. 2018 Jul 10;72(2):156-169

Authors: Saeed A, Feofanova EV, Yu B, Sun W, Virani SS, Nambi V, Coresh J, Guild CS, Boerwinkle E, Ballantyne CM, Hoogeveen RC

Abstract
BACKGROUND: Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG.
OBJECTIVES: The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study.
METHODS: Fasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored.
RESULTS: RLP-C and LDL-TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p < 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p < 5 × 10-8).
CONCLUSIONS: RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.

PMID: 29976289 [PubMed - in process]

Identification of ANKDD1B variants in an ankylosing spondylitis pedigree and a sporadic patient.

BMC Med Genet. 2018 Jul 05;19(1):111

Authors: Tan Z, Zeng H, Xu Z, Tian Q, Gao X, Zhou C, Zheng Y, Wang J, Ling G, Wang B, Yang Y, Ma L

Abstract
BACKGROUND: Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis.
METHODS: We used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient.
RESULTS: We identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS. This variant (p.L87V) co-segregates with all male patients of the pedigree. In females, the penetrance of the symptoms is incomplete with one identified patient out of 5 carriers, consistent with the reduced frequency of AS in females of the general population. We further identified a distinct missense variant affecting a conserved amino acid (p.R102L) of ANKDD1B in a male from 30 sporadic early onset AS patients. Both variants are absent in 500 normal controls. We determined the haplotypes of four major known AS risk loci, including HLA-B*27, 2p15, ERAP1 and IL23R, and found that only HLA-B*27 is strongly associated with patients in our cohort.
CONCLUSIONS: Together these results suggest that ANKDD1B variants might be associated with AS and genetic analyses of more AS patients are warranted to verify this association.

PMID: 29976160 [PubMed - in process]

Mosaicism in Cutaneous Disorders.

Annu Rev Genet. 2017 Nov 27;51:123-141

Authors: Lim YH, Moscato Z, Choate KA

Abstract
Genetic mosaicism arises when a zygote harbors two or more distinct genotypes, typically due to de novo, somatic mutation during embryogenesis. The clinical manifestations largely depend on the differentiation status of the mutated cell; earlier mutations target pluripotent cells and generate more widespread disease affecting multiple organ systems. If gonadal tissue is spared-as in somatic genomic mosaicism-the mutation and its effects are limited to the proband, whereas mosaicism also affecting the gametes, such as germline or gonosomal mosaicism, is transmissible. Mosaicism is easily appreciated in cutaneous disorders, as phenotypically distinct mutant cells often give rise to lesions in patterns determined by the affected cell type. Genetic investigation of cutaneous mosaic disorders has identified pathways central to disease pathogenesis, revealing novel therapeutic targets. In this review, we discuss examples of cutaneous mosaicism, approaches to gene discovery in these disorders, and insights into molecular pathobiology that have potential for clinical translation.

PMID: 29178821 [PubMed - indexed for MEDLINE]

Clinical and Genetic Characteristics Analysis of Korean Patients with Stargardt Disease Using Targeted Exome Sequencing.

Ophthalmologica. 2018 Jul 04;:1-11

Authors: Sung Y, Choi SW, Shim SH, Song WK

Abstract
PURPOSE: To investigate genetic mutations in Korean patients with Stargardt disease (STGD) using exome sequencing, and to analyze the correlations between genetic mutations and clinical phenotypes.
METHODS: Peripheral venous blood was obtained from 24 clinically diagnosed Korean STGD patients, followed by extraction of genomic DNAs. Using exome sequencing we investigated gene mutations for the adenosine triphosphate-binding cassette, subfamily A, member 4 (ABCA4) elongation of very-long-chain fatty acids 4 (ELOVL4), and prominin 1 (PROM1), and confirmed gene mutations by the direct sequencing of polymerase chain reaction products.
RESULTS: ABCA4 mutations were confirmed in 17 of 24 patients, and 12 novel mutations were identified. ELOVL4 and PROM1 gene mutations were not identified in this study. We also identified 16 previously reported mutations related to STGD1. In patients whose disease symptoms occurred before 20 years of age, visual acuity was poorer and atrophic flecks were more frequently found. In addition, more ABCA4 mutations were found in patients who had choroidal silence or atrophic flecks.
CONCLUSIONS: Novel ABCA4 gene mutations were found in Korean patients with STGD1. This study will facilitate better understanding of the relationships between ABCA4 gene mutations and clinical symptoms in Korean patients.

PMID: 29975949 [PubMed - as supplied by publisher]

Using XCAVATOR and EXCAVATOR2 to Identify CNVs from WGS, WES, and TS Data.

Curr Protoc Hum Genet. 2018 Jul 05;:e65

Authors: D'Aurizio R, Semeraro R, Magi A

Abstract
Copy Number Variants (CNVs) are structural rearrangements contributing to phenotypic variation but also associated with many disease states. In recent years, the identification of CNVs from high-throughput sequencing experiments has become a common practice for both research and clinical purposes. Several computational methods have been developed so far. In this unit, we describe and give instructions on how to run two read count-based tools, XCAVATOR and EXCAVATOR2, which are tailored for the detection of both germline and somatic CNVs from different sequencing experiments (whole-genome, whole-exome, and targeted) in various disease contexts and population genetic studies. © 2018 by John Wiley & Sons, Inc.

PMID: 29975818 [PubMed - as supplied by publisher]

Elevated antibodies against Epstein-Barr virus among individuals predicted to carry nasopharyngeal carcinoma susceptibility variants.

J Gen Virol. 2018 Jul 05;:

Authors: Coghill AE, Hsu WL, Yang Q, Wang CP, Lou PJ, Yu KJ, Yu G, Diehl SR, Chen CJ, Goldstein AM, Hildesheim A

Abstract
Epstein-Barr virus (EBV) is an obligatory factor in the development of nasopharyngeal carcinoma (NPC), and anti-EBV IgA antibodies are elevated many years prior to the development of NPC. Nearly all adults are infected with EBV, but only a few develop cancer, suggesting that additional co-factors, including genetic susceptibility, must be required for the disease to manifest. Individuals were selected from the Taiwan Family Study, a cohort of 3389 individuals from NPC multiplex families. Primary analyses were conducted among 671 individuals from 69 pedigrees with the strongest family history of disease (>3 NPC-affected family members). The likelihood that a given family member carried a NPC susceptibility variant was estimated using Mendelian segregation rules, assuming a dominant mode of inheritance. We compared anti-EBV IgA antibody seropositivity between family members predicted to be carriers of NPC-linked genetic variants and those with a lower likelihood of carrying such variants. Obligate carriers of NPC susceptibility variants (100 % predicted probability of harbouring the genetic mutation) were nine-fold more likely to be anti-EBV IgA positive compared to family members predicted not to carry disease-causing variants (OR=9.2; P-trend<0.001). This elevated risk was confirmed in analyses restricted to both unaffected individuals and pedigrees with EBV-related pathway variants identified through exome sequencing. Our data indicate that family members who are more likely to carry NPC susceptibility variants are also more likely to be anti-EBNA1 IgA seropositive. Genetic susceptibility associated with control over this common herpes virus is likely a co-factor in determining which EBV-infected adults develop NPC.

PMID: 29975184 [PubMed - as supplied by publisher]

Acute myeloid/T-lymphoblastic leukaemia (ATML) - a disease entity to look out for.

Br J Haematol. 2018 Jul 05;:

Authors: Hokland P, Hansen MC

PMID: 29974929 [PubMed - as supplied by publisher]

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2) family pedigree via whole-exome sequencing.

Mol Genet Genomic Med. 2018 Jul 04;:

Authors: Yang J, Wang Q, Zhuo Q, Tian H, Li W, Luo F, Zhang J, Bi D, Peng J, Zhou D, Xin H

Abstract
BACKGROUND: Glycosylphosphatidylinositol (GPI) anchoring is a special type of protein posttranslational modification, by which proteins with diverse function are attached to cell membrane through a covalent linkage between the protein and the glycolipid. Phosphatidylinositol glycan anchor biosynthesis class A (PIGA) is a key enzyme in GPI anchor biosynthesis, somatic mutations or genetic variants of which have been associated with paroxysmal nocturnal hemoglobinuria (PNH), or PIGA deficiency, respectively. More than 10 PIGA pathogenic or likely pathogenic variants have been reported in a wide spectrum of clinical syndromes of PIGA deficiency, including multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2).
METHODS: Whole-exome sequencing (WES) was performed on two trios, that is., the proband's family and his affected maternal cousin's family, from a nonconsanguineous Chinese family pedigree with hypotonia-encephalopathy-seizures disease history and putative X-linked recessive inheritance. Sanger sequencing for PIGA variant was performed on affected members as well as unaffected members in the family pedigree to verify its familial segregation.
RESULTS: A novel likely pathogenic variant in PIGA was identified through comparative WES analysis of the two affected families. The single-nucleotide substitution (NC_000023.9:g.15343279T>C) is located in intron 3 of the PIGA gene and within the splice acceptor consensus sequence (NM_002641.3:c.849-5A>G). Even though we have not performed RNA studies, in silico tools predict that this intronic variant may alter normal splicing, causing a four base pair insertion which creates a frameshift and a premature stop codon at position 297 (NP_002632.1:p.(Arg283Serfs*15)). Sanger sequencing analysis of the extended family members confirmed the presence of the variant and its X-linked inheritance.
CONCLUSION: WES data analysis along with familial segregation of a rare intronic variant are suggestive of a diagnosis of X-liked PIGA deficiency with clinical features of MCAHS2.

PMID: 29974678 [PubMed - as supplied by publisher]

Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders.

Kidney Int. 2017 Dec;92(6):1493-1506

Authors: Mallett AJ, McCarthy HJ, Ho G, Holman K, Farnsworth E, Patel C, Fletcher JT, Mallawaarachchi A, Quinlan C, Bennetts B, Alexander SI

Abstract
Inherited kidney disease encompasses a broad range of disorders, with both multiple genes contributing to specific phenotypes and single gene defects having multiple clinical presentations. Advances in sequencing capacity may allow a genetic diagnosis for familial renal disease, by testing the increasing number of known causative genes. However, there has been limited translation of research findings of causative genes into clinical settings. Here, we report the results of a national accredited diagnostic genetic service for familial renal disease. An expert multidisciplinary team developed a targeted exomic sequencing approach with ten curated multigene panels (207 genes) and variant assessment individualized to the patient's phenotype. A genetic diagnosis (pathogenic genetic variant[s]) was identified in 58 of 135 families referred in two years. The genetic diagnosis rate was similar between families with a pediatric versus adult proband (46% vs 40%), although significant differences were found in certain panels such as atypical hemolytic uremic syndrome (88% vs 17%). High diagnostic rates were found for Alport syndrome (22 of 27) and tubular disorders (8 of 10), whereas the monogenic diagnostic rate for congenital anomalies of the kidney and urinary tract was one of 13. Quality reporting was aided by a strong clinical renal and genetic multidisciplinary committee review. Importantly, for a diagnostic service, few variants of uncertain significance were found with this targeted, phenotype-based approach. Thus, use of targeted massively parallel sequencing approaches in inherited kidney disease has a significant capacity to diagnose the underlying genetic disorder across most renal phenotypes.

PMID: 28844315 [PubMed - indexed for MEDLINE]

Alzheimer's Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing.

Mol Diagn Ther. 2018 Jul 03;:

Authors: Goldman JS, Van Deerlin VM

Abstract
The advent of next-generation sequencing has changed genetic diagnostics, allowing clinicians to test concurrently for phenotypically overlapping conditions such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, to interpret genetic results, clinicians require an understanding of the benefits and limitations of different genetic technologies, such as the inability to detect large repeat expansions in such diseases as C9orf72-associated FTD and amyotrophic lateral sclerosis. Other types of mutations such as large deletions or duplications and triple repeat expansions may also go undetected. Additionally, the concurrent testing of multiple genes or the whole exome increases the likelihood of discovering variants of unknown significance. Our goal here is to review the current knowledge about the genetics of AD and FTD and suggest up-to-date guidelines for genetic testing for these dementias. Despite the improvements in diagnosis due to biomarkers testing, AD and FTD can have overlapping symptoms. When used appropriately, genetic testing can elucidate the diagnosis and specific etiology of the disease, as well as provide information for the family and determine eligibility for clinical trials. Prior to ordering genetic testing, clinicians must determine the appropriate genes to test, the types of mutations that occur in these genes, and the best type of genetic test to use. Without this analysis, interpretation of genetic results will be difficult. Patients should be counseled about the benefits and limitations of different types of genetic tests so they can make an informed decision about testing.

PMID: 29971646 [PubMed - as supplied by publisher]