The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25.

Neurogenetics. 2018 Jul 24;:

Authors: Leal A, Bogantes-Ledezma S, Ekici AB, Uebe S, Thiel CT, Sticht H, Berghoff M, Berghoff C, Morera B, Meisterernst M, Reis A

Abstract
Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the same MED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.

PMID: 30039206 [PubMed - as supplied by publisher]

An Alzheimer's linked loss-of-function CLN5 variant impairs Cathepsin D maturation consistent with a retromer trafficking defect.

Mol Cell Biol. 2018 Jul 23;:

Authors: Qureshi YH, Patel VM, Berman DE, Kothiya MJ, Neufeld JL, Vardarajan B, Tang M, Reyes-Dumeyer D, Lantigua R, Medrano M, Jimenez-Velazquez I, Small SA, Reitz C

Abstract
In a whole exome sequencing study of multiplex Alzheimer's disease (AD) families we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD- Ceroid lipofuscinosis 3 (CLN3), Ceroid lipofuscinosis 5 (CLN5) and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5's normal cellular location. The AD-associated CLN5 variant is shown here to reduce the normal processing of Cathepsin D and to decrease levels of full-length APP, suggestive of a defect in retromer-dependent trafficking.

PMID: 30037983 [PubMed - as supplied by publisher]

Whole genome sequencing for the management of drug-resistant TB in low income high TB burden settings: Challenges and implications.

Tuberculosis (Edinb). 2017 Dec;107:137-143

Authors: Mahomed S, Naidoo K, Dookie N, Padayatchi N

Abstract
Drug-resistant tuberculosis is emerging as a major global health challenge, fuelled by a limited formulary and reduced ability to timeously diagnose resistance. Furthermore, poorly managed drug-resistant tuberculosis is complicated by poor treatment outcomes and high rates of morbidity and mortality. A rapid diagnosis together with individualized management are essential in order to limit disease and curtail transmission. Recently, the feasibility of Whole Genome Sequencing (WGS) technology for the routine diagnosis and drug susceptibility testing of Mycobacterium Tuberculosis in a high income, low tuberculosis burden setting, was demonstrated. However, the use of WGS in low income settings, with the highest burden of disease, has not been evaluated. This viewpoint highlights the challenges and implications associated with the use of Whole Genome Sequencing for the diagnosis and management of drug-resistant tuberculosis in such settings.

PMID: 29050762 [PubMed - indexed for MEDLINE]

Toll-like receptor 4: a target for chemoprevention of hepatocellular carcinoma in obesity and steatohepatitis.

Oncotarget. 2018 Jun 29;9(50):29495-29507

Authors: Nguyen J, Jiao J, Smoot K, Watt GP, Zhao C, Song X, Stevenson HL, McCormick JB, Fisher-Hoch SP, Zhang J, Futreal PA, Beretta L

Abstract
The incidence of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) is rapidly increasing. We aimed to elucidate the genetic basis of NAFLD-associated HCC and identify candidate targets for chemoprevention. Twenty HCC tumors, distant liver and matched tails from mice with hepatocyte-deletion of Pten (HepPten-) were subjected to whole-exome sequencing. A total of 162 genes with somatic non-synonymous single nucleotide variants or exonic small insertions and deletions in tumors were identified. Ingenuity Pathway Analysis of these 162 genes, further identified Toll-like receptor (TLR) 4, a key mediator of proinflammatory responses, and resatorvid, a TLR4 inhibitor, as the main causal networks of this dataset. Resatorvid treatment strongly prevented HCC development in these mice (p < 0.001). Remarkably, HCC patients with high tumoral TLR4 mRNA expression were more likely to be diagnosed with NAFLD and obese. TLR4 mRNA expression positively correlated with IL-6 and IL-10 mRNA expression in HCC tumors and the correlation was stronger in obese HCC patients. We have identified tumor mutation signatures and associated causal networks in NAFLD-associated HCC in HepPten- mice and further demonstrated the important role of TLR4 in promoting HCC development. This study also identified IL-6 and IL-10 as markers of TLR4 activation in HCC and subjects with NAFLD and obesity as the target population who would benefit from TLR4 inhibition treatment for HCC chemoprevention.

PMID: 30034633 [PubMed]

Whole Genome Sequencing instead of Whole Exome Sequencing is required to identify the Genetic Causes of Polycystic Ovary Syndrome in Pakistani families.

Pak J Med Sci. 2018 May-Jun;34(3):540-545

Authors: Khan MJ, Nazli R, Ahmed J, Basit S

Abstract
Background & Objective: Polycystic Ovary Syndrome (PCOS) is the major cause of infertility in females. PCOS is a complex and multifactorial disease, genetic and environmental factors being important predisposing factors. Diagnosis of PCOS is difficult due to the complexity of this disease; hence, better diagnostic tests are required to improve its management. Aim of the study was to elucidate the genetic causes of PCOS in three Pakistani families.
Methods: Three Pakistani families segregating PCOS in an apparently autosomal recessive mode were recruited. Whole genome Single Nucleotide Polymorphism (SNP) genotyping and Whole Exome Sequencing (WES) were carried out to identify the candidate genes.
Results: SNP genotypes data analyses identified multiple regions of homozygosity on different chromosomes. WES was performed in affected members of the family. Screening for pathogenic mutations in homozygous regions failed to detect any mutation/variant of interest.
Conclusion: PCOS is multifactorial and complex disease so variants in the coding as well as in non-coding regions may be the genetic causes of the disease. To elucidate the genetic cause(s) of the PCOS, Whole Genome Sequencing (WGS) is recommended to cover both coding and non-coding regions of the genome.

PMID: 30034412 [PubMed]

ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function.

Neurobiol Aging. 2018 Jun 25;:

Authors: de Majo M, Topp SD, Smith BN, Nishimura AL, Chen HJ, Gkazi AS, Miller J, Wong CH, Vance C, Baas F, Ten Asbroek ALMA, Kenna KP, Ticozzi N, Redondo AG, Esteban-Pérez J, Tiloca C, Verde F, Duga S, Morrison KE, Shaw PJ, Kirby J, Turner MR, Talbot K, Hardiman O, Glass JD, de Belleroche J, Gellera C, Ratti A, Al-Chalabi A, Brown RH, Silani V, Landers JE, Shaw CE

Abstract
Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations.

PMID: 30033073 [PubMed - as supplied by publisher]

Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.

Am J Hum Genet. 2018 Jul 12;:

Authors: Coban-Akdemir Z, White JJ, Song X, Jhangiani SN, Fatih JM, Gambin T, Bayram Y, Chinn IK, Karaca E, Punetha J, Poli C, Baylor-Hopkins Center for Mendelian Genomics, Boerwinkle E, Shaw CA, Orange JS, Gibbs RA, Lappalainen T, Lupski JR, Carvalho CMB

Abstract
Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.

PMID: 30032986 [PubMed - as supplied by publisher]

Germline mutations in young non-smoking women with lung adenocarcinoma.

Lung Cancer. 2018 Aug;122:76-82

Authors: Donner I, Katainen R, Sipilä LJ, Aavikko M, Pukkala E, Aaltonen LA

Abstract
OBJECTIVES: Although the primary cause of lung cancer is smoking, a considerable proportion of all lung cancers occur in never smokers. Gender influences the risk and characteristics of lung cancer and women are overrepresented among never smokers with the disease. Young age at onset and lack of established environmental risk factors suggest genetic predisposition. In this study, we used population-based sampling of young patients to discover candidate predisposition variants for lung adenocarcinoma in never-smoking women.
MATERIALS AND METHODS: We employed archival normal tissue material from 21 never-smoker women who had been diagnosed with lung adenocarcinoma before the age of 45, and exome sequenced their germline DNA.
RESULTS AND CONCLUSION: Potentially pathogenic variants were found in eight Cancer Gene Census germline genes: BRCA1, BRCA2, ERCC4, EXT1, HNF1 A, PTCH1, SMARCB1 and TP53. The variants in TP53, BRCA1, and BRCA2 are likely to have contributed to the early onset lung cancer in the respective patients (3/21 or 14%). This supports the notion that lung adenocarcinoma can be a component of certain cancer predisposition syndromes. Fifteen genes displayed potentially pathogenic mutations in at least two patients: ABCC10, ATP7B, CACNA1S, CFTR, CLIP4, COL6A1, COL6A6, GCN1, GJB6, RYR1, SCN7A, SEC24A, SP100, TTN and USH2A. Four patients showed a mutation in COL6A1, three in CLIP4 and two in the rest of the genes. Some of these candidate genes may explain a subset of female lung adenocarcinoma.

PMID: 30032850 [PubMed - in process]

Divergent susceptibilities to AAV-SaCas9-gRNA vector-mediated genome-editing in a single-cell-derived cell population.

BMC Res Notes. 2017 Dec 08;10(1):720

Authors: Morsy SG, Tonne JM, Zhu Y, Lu B, Budzik K, Krempski JW, Ali SA, El-Feky MA, Ikeda Y

Abstract
OBJECTIVE: Recombinant adeno-associated virus (AAV)-based vectors are characterized by their robust and safe transgene delivery. The CRISPR/Cas9 and guide RNA (gRNA) system present a promising genome-editing platform, and a recent development of a shorter Cas9 enzyme from Staphylococcus aureus (SaCas9) allows generation of high titer single AAV vectors which carry both saCas9- and gRNA-expression cassettes. Here, we used two AAV-SaCas9 vectors with distinct GFP-targeted gRNA sequences and determined the impact of AAV-SaCas9-gRNA vector treatment in a single cell clone carrying a GFP-expression cassette.
RESULTS: Our results showed comparable GFP knockout efficiencies (40-50%) upon a single low-dose infection. Three consecutive transductions of 25-fold higher doses of vectors showed 80% GFP knockout efficiency. To analyze the "AAV-SaCas9-resistant cell population", we sorted the residual GFP-positive cells and assessed their permissiveness to super-infection with two AAV-Cas9-GFP vectors. We found the sorted cells were significantly more resistant to the GFP knockout mediated by the same AAV vector, but not by the other GFP-targeted AAV vector. Our data therefore demonstrate highly efficient genome-editing by the AAV-SaCas9-gRNA vector system. Differential susceptibilities of single cell-derived cells to the AAV-SaCas9-gRNA-mediated genome editing may represent a formidable barrier to achieve 100% genome editing efficiency by this vector system.

PMID: 29221488 [PubMed - indexed for MEDLINE]

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy.

Circ Cardiovasc Genet. 2017 Dec;10(6):

Authors: Tucker NR, McLellan MA, Hu D, Ye J, Parsons VA, Mills RW, Clauss S, Dolmatova E, Shea MA, Milan DJ, Scott NS, Lindsay M, Lubitz SA, Domian IJ, Stone JR, Lin H, Ellinor PT

Abstract
BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported, and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes.
METHODS AND RESULTS: We evaluated 8 family members across 4 generations by history, physical examination, electrocardiography, and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (filamin C; p.V2297M). FLNC encodes filamin C-a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of FLNC localization in cardiac tissue from an affected family member revealed a diminished localization at the z disk, whereas traditional localization at the intercalated disk was preserved. Stem cell-derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared with controls.
CONCLUSION: We have identified a novel variant in FLNC as pathogenic variant for familial RCM-a finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.

PMID: 29212899 [PubMed - indexed for MEDLINE]

Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome‑wide association study.

Mol Med Rep. 2017 Nov;16(5):5823-5832

Authors: Yamada Y, Sakuma J, Takeuchi I, Yasukochi Y, Kato K, Oguri M, Fujimaki T, Horibe H, Muramatsu M, Sawabe M, Fujiwara Y, Taniguchi Y, Obuchi S, Kawai H, Shinkai S, Mori S, Arai T, Tanaka M

Abstract
An exome‑wide association study (EWAS) was performed to identify genetic variants, particularly low‑frequency or rare coding variants with a moderate to large effect size, that confer susceptibility to atrial fibrillation in Japanese. The EWAS for atrial fibrillation was performed with 13,166 subjects (884 patients with atrial fibrillation and 12,282 controls) using an Illumina HumanExome‑12 DNA Analysis BeadChip or Infinium Exome‑24 BeadChip arrays. The association of atrial fibrillation with allele frequencies of 41,243 single nucleotide polymorphisms (SNPs) that passed quality control was examined with Fisher's exact test. Based on Bonferroni's correction, a P<1.21x10‑6 was considered statistically significant. The EWAS for atrial fibrillation revealed that 122 SNPs were significantly associated with this condition. The association of the identified SNPs to atrial fibrillation was further examined by multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension. Eight SNPs were related (P<0.01) to atrial fibrillation, among which three polymorphisms, rs11552708 [G/A (G67R)]of TNF superfamily member 13 (TNFSF13; dominant model; P=9.36x10‑9; odds ratio, 0.58), rs113710653 [C/T (E231 K)] of spermatogenesis and centriole associated 1 like (SPATC1L; dominant model; P=1.09x10‑5; odds ratio, 3.27), and rs11231397 [G/C (R300T)] of solute carrier family 22 member 25 (SLC22A25; additive model; P=3.71x10‑5; odds ratio, 1.77), were significantly (P<1.02x10‑4) associated with this condition. The minor T allele of rs113710653 and the minor C allele of rs11231397 were risk factors for atrial fibrillation, whereas the minor A allele of rs11552708 was protective against this condition. In addition, rs77538589 [C/T (G117R)] of SALL4 exhibited a tendency to be associated with atrial fibrillation (dominant model; P=0.0002; odds ratio, 1.88), with the minor T allele representing a risk factor for this condition. TNFSF13, SPATC1L, SLC22A25 and SALL4 may thus be novel susceptibility loci for atrial fibrillation in the Japanese population.

PMID: 28849223 [PubMed - indexed for MEDLINE]

A patient with mitochondrial disorder due to a novel mutation in MRPS22.

Metab Brain Dis. 2017 Oct;32(5):1389-1393

Authors: Kılıç M, Oğuz KK, Kılıç E, Yüksel D, Demirci H, Sağıroğlu MŞ, Yücel-Yılmaz D, Özgül RK

Abstract
MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.

PMID: 28752220 [PubMed - indexed for MEDLINE]

MendelProb: Probability and sample size calculations for Mendelian studies of exome and whole genome sequence data.

Bioinformatics. 2018 Jul 19;:

Authors: He Z, DeWan AT, Leal SM

Abstract
Motivation: For the design of genetic studies, it is necessary to perform power calculations. Although for Mendelian traits the power of detecting linkage for pedigree(s) can be determined, it is also of great interest to determine the probability of identifying multiple pedigrees or unrelated cases with variants in the same gene. For many diseases, due to extreme locus heterogeneity this probability can be small. If only one family is observed segregating a variant classified as likely pathogenic or of unknown significance, the gene cannot be implicated in disease etiology. The probability of identifying several disease families or cases is dependent on the gene-specific disease prevalence and the sample size. The observation of multiple disease families or cases with variants in the same gene as well as evidence of pathogenicity from other sources, e.g., in silico prediction, expression, and functional studies, can aid in implicating a gene in disease etiology. MendelProb can determine the probability of detecting a minimum number of families or cases with variants in the same gene. It can also calculate the probability of detecting genes with variants in different data types, e.g., identifying a variant in at least one family that can establish linkage and more the two additional families regardless of their size. Additionally, for a specified probability MendelProb can determine the number of probands which need to be screened to detect a minimum number of individuals with variants within the same gene.
Summary: A single Mendelian disease family is not sufficient to implicate a gene in disease etiology. It is necessary to observe multiple families or cases with potentially pathogenic variants in the same gene. MendelProb, an R library, was developed to determine the probability of observing multiple families and cases with variants within a gene and to also establish the numbers of probands to screen to detect multiple observations of variants within a gene.
Program and documentation: https://github.com/statgenetics/mendelprob.

PMID: 30032240 [PubMed - as supplied by publisher]

Mutational Intratumor Heterogeneity is a Complex and Early Event in the Development of Adult T-cell Leukemia/Lymphoma.

Neoplasia. 2018 Jul 19;20(9):883-893

Authors: Farmanbar A, Firouzi S, Makałowski W, Kneller R, Iwanaga M, Utsunomiya A, Nakai K, Watanabe T

Abstract
The clonal architecture of tumors plays a vital role in their pathogenesis and invasiveness; however, it is not yet clear how this clonality contributes to different malignancies. In this study we sought to address mutational intratumor heterogeneity (ITH) in adult T-cell leukemia/lymphoma (ATL). ATL is a malignancy with an incompletely understood molecular pathogenesis caused by infection with human T-cell leukemia virus type-1 (HTLV-1). To determine the clonal structure through tumor genetic diversity profiles, we investigated 142 whole-exome sequencing data of tumor and matched normal samples from 71 ATL patients. Based on SciClone analysis, the ATL samples showed a wide spectrum of modes over clonal/subclonal frequencies ranging from one to nine clusters. The average number of clusters was six across samples, but the number of clusters differed among different samples. Of these ATL samples, 94% had more than two clusters. Aggressive ATL cases had slightly more clonal clusters than indolent types, indicating the presence of ITH during earlier stages of disease. The known significantly mutated genes in ATL were frequently clustered together and possibly coexisted in the same clone. IRF4, CCR4, TP53, and PLCG1 mutations were almost clustered in subclones with a moderate variant allele frequency (VAF), whereas HLA-B, CARD11, and NOTCH1 mutations were clustered in subclones with lower VAFs. Taken together, these results show that ATL displays a high degree of ITH and a complex subclonal structure. Our findings suggest that clonal/subclonal architecture might be a useful measure for prognostic purposes and personalized assessment of the therapeutic response.

PMID: 30032036 [PubMed - as supplied by publisher]

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Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement.

Mol Genet Metab Rep. 2018 Jun;15:11-14

Authors: Mohammad AN, Bruno KA, Hines S, Atwal PS

Abstract
Sialidosis is an autosomal recessive lysosomal storage disease caused by pathogenic variants in NEU1 which encodes lysosomal sialidase (neuraminidase 1). Lysosomal neuraminidase catalyzes the removal of terminal sialic acid molecules from glycolipids, glycoproteins and oligosaccharides. Sialidosis is classified into two types, based on phenotype and age of onset. Patients with the milder type 1 typically present late, usually in the second or third decade, with myoclonus, ataxia and visual defects. Type 2 is more severe and presents earlier with coarse facial features, developmental delay, hepatosplenomegaly and dysostosis multiplex. Presentation and severity of the disease are related to whether lysosomal sialidase is inactive or there is some residual activity. Diagnosis is suspected based on clinical features and increased urinary bound sialic acid excretion and confirmed by genetic testing showing pathogenic variants in NEU1. We report a patient with type 1 sialidosis who presented mainly with ataxia and both generalized and myoclonic seizures but no visual involvement. Whole exome sequencing of the proband detected compound heterozygous likely pathogenic variants (S182G and G227R) in NEU1.

PMID: 30023283 [PubMed]

The new era of whole-exome sequencing in congenital heart disease: brand-new insights into rare pathogenic variants.

J Thorac Dis. 2018 Jun;10(Suppl 17):S1923-S1929

Authors: Pasipoularides A

PMID: 30023082 [PubMed]

Genome-Wide Association Studies of Coronary Artery Disease: Recent Progress and Challenges Ahead.

Curr Atheroscler Rep. 2018 Jul 18;20(9):47

Authors: Clarke SL, Assimes TL

Abstract
PURPOSE OF REVIEW: Genome-wide association studies (GWAS) have been the primary tool for unbiased assessment of the genetic basis of coronary artery disease (CAD) for more than a decade. We summarize successes as well as shortcomings of recent studies in this context.
RECENT FINDINGS: The number of CAD-associated loci has more than doubled in the past year to 161. This rapid progress has been in large part due to the release of genome-wide genotyping data for the largely European participants of the UK Biobank study which has been combined with existing GWAS from the CARDIoGRAMplusC4D consortium. Additional discoveries have been achieved through large-scale genotyping of participants using custom high-yield genotyping arrays including the Metabochip and the Exome chip. As a consequence, the ability of genetic risk scores in predicting incident CAD events has improved but that improvement has only been shown in European populations. GWAS have proven to be a fruitful approach for uncovering the genetic drivers of CAD. However, determining the mechanisms of association of GWAS findings remains a challenging endeavor requiring long-term investment. Genetic risk scores offer an opportunity for recent findings to have an immediate clinical impact. Going forward, CAD genetics will benefit greatly from the release of more genetic data produced by mega-biobanks. These new data will allow for the more comprehensive examination of underrepresented populations.

PMID: 30022313 [PubMed - in process]

Cardiomyopathy and Preeclampsia: Shared Genetics?

Circulation. 2018 Jul 18;:

Authors: Gammill HS, Chettier R, Brewer A, Roberts JM, Shree R, Tsigas E, Ward K

Abstract
Background -Preeclampsia (PE), is associated with diastolic dysfunction, peripartum cardiomyopathy (CM), and both preexisting and subsequent maternal cardiovascular disease (CVD). Gene mutations causing idiopathic CM were recently implicated in peripartum CM. We sought to determine whether CM gene mutations are also a contributory factor in PE. Methods -Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of PE completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing (WES) was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with CM. Missense variants were deemed "damaging missense" if so classified by any of 7 standard function prediction algorithms. Variants were defined as "loss-of-function" if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from two control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium (ExAC). PE was not excluded in control groups. Results -Of 181 subjects with confirmed PE, 96% were Caucasian. 72% had ≥1 preterm PE delivery <37 weeks. Among PE subjects, WES demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 CM genes considered. The prevalence of these loss-of-function variants was significantly higher in PE subjects (5.5%) compared to the local control (2.5%) population (p=0.014). 68% of women with PE carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum CM, most mutations (55%) were found in the TTN gene. 73% of PE subjects had TTN mutations in PE cohort versus 48% in local controls (p=1.36E-11). Conclusions -Women who develop PE are more likely to carry protein-altering mutations in genes associated with CM, particularly in TTN. Mutations promoting CM are prevalent in PE, idiopathic CM, and peripartum CM, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.

PMID: 30021846 [PubMed - as supplied by publisher]

Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats.

J Am Heart Assoc. 2017 Oct 28;6(11):

Authors: Peng W, Li M, Li H, Tang K, Zhuang J, Zhang J, Xiao J, Jiang H, Li D, Yu Y, Sham PC, Nattel S, Xu Y

Abstract
BACKGROUND: There is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a family with heritable atrial cardiomyopathy manifesting as progressive atrial-selective electromechanical dysfunction, tachyarrhythmias, and bradyarrhythmias requiring pacemaker implantation. Myosin light-chain 4 (MYL4), encoding the atrial-selective essential myosin light chain, was identified as a candidate gene. We used genetically modified rat models to investigate the role of MYL4 in atrial cardiomyopathy.
METHODS AND RESULTS: Exome sequencing and systematic bioinformatic analyses identified a rare missense variant of MYL4 (c.31G>A [p.E11K]) in a large multiplex atrial cardiomyopathy family pedigree. The mutation cosegregated with atrial standstill (selected as the principal presenting trait) with a logarithm of the odds score of 5.3. The phenotype of rats with MYL4 mutation knock-in confirmed the causative role of the mutation. MYL4 knockout rats showed a similar atrial cardiomyopathy phenotype, whereas rats with an adjacent 4-amino-acid deletion showed no phenotype. Both MYL4 p.E11K knock-in rats and MYL4 knockout rats showed progressive atrial electrophysiological, contractile, and fibrotic abnormalities, similar to affected patients. Biochemical analyses of MYL4 p.E11K mutation rats showed activation of proapoptotic and profibrotic signaling, along with increased atrial-cardiomyocyte terminal deoxynucleotidyl transferase dUTP nick end labeling staining, suggesting enhanced apoptotic cell death, findings that were mimicked by in vitro adenoviral transfer of the mutant gene to neonatal-rat cardiomyocytes.
CONCLUSIONS: Loss-of-function MYL4 gene variants cause progressive atrial cardiomyopathy in humans and rats. Our findings identify MYL4 as a key gene required for atrial contractile, electrical and structural integrity. These results improve our understanding of the molecular basis of atrial cardiomyopathy and introduce new models for further mechanistic analysis.

PMID: 29080865 [PubMed - indexed for MEDLINE]