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Clinical Genetics

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https://www.readbyqxmd.com/read/28646536/spectrum-of-mutations-in-cystinuria-patients-presenting-with-prenatal-hyperechoic-colon
#1
Isabelle Tostivint, Nicolas Royer, Mireille Nicolas, Agnes Bourillon, Isabelle Czerkiewicz, Pierre-Hadrien Becker, Françoise Muller, Jean-François Benoist
Cystinuria is a heterogeneous, rare but important cause of inherited kidney stone disease due to mutations in two genes: SLC3A1 and SLC7A9. Antenatal hyperechoic colon has been reported in some patients as a non-pathological consequence of the intestinal transport defect. We report 83 patients affected by cystinuria: 44 presented prenatally with a hyperechoic colon (HEC group) and 39 with a classical postnatal form (CC group). SLC3A1 and SLC7A9 were sequenced. All patients were fully genotyped, and the relationship between the genotype and clinical features was analyzed...
June 24, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28646489/functional-analysis-of-p-ala253_leu254insasn-mutation-in-pls3-responsible-for-x-linked-osteoporosis
#2
Lianqing Wang, Qiaoli Zhai, Peiqing Zhao, Xinxin Xiang, Xiaowei Zhang, Wenxiu Tian, Tao Li
Mutations in Plastin-3 (PLS3) have been identified as a cause of X-linked osteoporosis. To reveal the molecular mechanism of PLS3 on osteoporosis, we characterized the p.Ala253_Leu254insAsn mutation in PLS3. We first identified Lymphocyte cytosolic protein 1 (LCP1) as a binding partner of PLS3 and the mutation disrupted the interaction between them. We then confirmed the roles of PLS3 and LCP1 in the regulation of intracellular Ca(2+) , which was weakened by the mutant PLS3. Moreover, the interaction between PLS3 and LCP1 was enhanced under a low concentration of extracellular Ca(2+) ...
June 24, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28644547/a-genetic-epidemiology-study-of-congenital-adrenal-hyperplasia-in-italy
#3
Alessandro Gialluisi, Soara Menabò, Lilia Baldazzi, Letizia Casula, Antonella Meloni, Maria Carla Farci, Stefano Mariotti, Luisa Balestrino, Rita Ortolano, Stefania Murru, Carlo Carcassi, Sandro Loche, Antonio Balsamo, Giovanni Romeo
Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (21OHD-CAH) is an autosomal recessive disorder affecting steroidogenesis, due to mutations in CYP21A2 (6p21.3). 21OHD-CAH neonatal screening is based on 17-hydroxyprogesterone (17OHP) serum levels, showing high type I error rate and low sensitivity to mild CAH forms. Here, we used an epidemiological approach, which estimates the allelic frequency (q) of an autosomal recessive disorder using the proportion of homozygous patients, the mutational spectrum and the inbreeding coefficient in a sample of affected individuals...
June 23, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28632965/frequent-col4-mutations-in-familial-microhematuria-accompanied-by-later-onset-alport-nephropathy-due-to-focal-segmental-glomerulosclerosis
#4
Louiza Papazachariou, Gregory Papagregoriou, Despina Hadjipanagi, Panagiota Demosthenous, Konstantinos Voskarides, Constantina Koutsofti, Kostas Stylianou, Petros Ioannou, Dimitris Xydakis, Ioannis Tzanakis, Antonia Papadaki, Nicolaos Kallivretakis, Nicolaos Nikolakakis, Garyfalia Perysinaki, Daniel P Gale, Athanasios Diamantopoulos, Pavlos Goudas, Dimitris Goumenos, Andreas Soloukides, Ioannis Boletis, Christina Melexopoulou, Eleni Georgaki, Elena Frysira, Fifi Komianou, Dimitrios Grekas, Christos Paliouras, Polichronis Alivanis, George Vergoulas, Alkis Pierides, Eugenios Daphnis, Constantinos Deltas
Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using Next Generation Sequencing (NGS) for five genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, nine of them novel...
June 20, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28632915/increasing-awareness-and-knowledge-of-lifestyle-recommendations-for-cancer-prevention-in-lynch-syndrome-carriers-randomized-controlled-trial
#5
Alina Vrieling, Annemiek Visser, Meeke Hoedjes, Mirthe Hurks, Encarna Gómez García, Nicoline Hoogerbrugge, Ellen Kampman
Lynch Syndrome (LS) mutation carriers may reduce their cancer risk by adhering to lifestyle recommendations for cancer prevention. This study tested the effect of providing LS mutation carriers with World Cancer Research Fund (WCRF)-NL health promotion materials on awareness and knowledge of and adherence to these recommendations. In this randomized controlled trial (n = 226), the intervention group (n = 114) received WCRF-NL health promotion materials. All LS mutation carriers were asked to fill out questionnaires at 2 weeks before (baseline, T0) and at 2 weeks (T1) and 6 months (T2) after the intervention...
June 20, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28617965/further-delineation-of-the-phenotype-caused-by-biallelic-variants-in-the-wdr4-gene
#6
Aurélien Trimouille, Eulalie Lasseaux, Pascal Barat, Caroline Deiller, Séverine Drunat, Caroline Rooryck, Benoît Arveiler, Didier Lacombe
Microcephalic primordial dwarfisms are a group of rare Mendelian disorders characterized by severe growth retardation and microcephaly. The molecular basis is heterogeneous, with disease-causing genes implicated in different cellular functions. Recently, 2 patients were reported with the same homozygous variant in the WDR4 gene, coding for an enzyme responsible for the m(7) G46 post transcriptional modification of tRNA. We report here two sisters harboring compound heterozygous variants of WDR4. Their phenotype differs from that of the first two described patients: they both have a severe microcephaly but only one of the two sisters had a head circumference at birth below -2 SD, their intellectual deficiency is less severe, and they have a GH deficiency and a partial hypogonadotropic hypogonadotropism...
June 15, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28617938/fragile-x-syndrome-an-overview-and-update-of-the-fmr1-gene
#7
REVIEW
Montserrat Mila, Maria Isabel Alvarez-Mora, Irene Madrigal, Laia Rodriguez-Revenga
Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. FMR1 premutation is the first single-gene cause of primary ovarian failure (FXPOI) and one of the most common causes of ataxia (FXTAS), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account...
June 15, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28598035/genetic-study-of-early-onset-graves-disease-in-the-chinese-han-population
#8
Fei-Fei Yuan, Xiao-Ping Ye, Wei Liu, Li-Qiong Xue, Yu-Ru Ma, Le-Le Zhang, Man-Man Zhang, Feng Sun, Yue-Yue Wan, Qian-Yue Zhang, Shuang-Xia Zhao, Huai-Dong Song
Graves' disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early-onset patients have a shorter exposure time to environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early-onset GD, eleven single nucleotide polymorphisms (SNPs) and their related SNPs (R(2) > 0.6), SNPs located within a ± 1-Mb region of the FOXP3 gene, and twenty validated GD-risk SNPs were selected and screened for genotyping in 3,735 GD and 4,893 control patients to investigate whether early-onset GD is a subtype of GD with distinct susceptibility genes...
June 9, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28598007/large-scale-study-of-clinical-and-biochemical-characteristics-of-chinese-patients-diagnosed-with-krabbe-disease
#9
Shichao Zhao, Xia Zhan, Yu Wang, Jun Ye, Lianshu Han, Wenjuan Qiu, Xiaolan Gao, Xuefan Gu, Huiwen Zhang
Krabbe disease (KD) is a rare disease caused by the deficiency of β-galactocerebrosidase. This study investigated 22 unrelated Chinese patients, including their clinical presentations, plasma psychosine levels and GALC gene mutations. We found the late-onset form of KD present in 82% of the patients in our study, which was more prevalent than in patients from other populations. Plasma psychosine levels were elevated in KD, which were correlated with the severity of clinical presentations. Sanger sequencing identified 8 novel mutations, including 7 missense mutations, p...
June 9, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28597968/genetic-epidemiology-of-familial-mediterranean-fever-through-integrative-analysis-of-whole-genome-and-exome-sequences-from-middle-east-and-north-africa
#10
Remya Koshy, Ambily Sivadas, Vinod Scaria
Familial Mediterranean fever (FMF), an autosomal recessive and rare autoinflammatory disease is caused by genetic mutations in the MEFV gene and is highly prevalent in the Mediterranean basin. Though the carrier frequency of specific disease variants in the MEFV gene has been reported from isolated studies, a comprehensive view of variants in the Mediterranean region has not been possible due to paucity of data. The recent availability of whole-genome and whole-exome datasets prompted us to study the genetic epidemiology of MEFV variants in the region...
June 9, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28594066/novel-biallelic-mutations-in-the-pnpt1-gene-encoding-a-mitochondrial-rna-import-protein-pnpase-cause-delayed-myelination
#11
Ryo Sato, Natsuko Arai-Ichinoi, Atsuo Kikuchi, Tetsuro Matsuhashi, Yurika Numata-Uematsu, Mitsugu Uematsu, Yuji Fujii, Kei Murayama, Akira Ohtake, Takaaki Abe, Shigeo Kure
Recent studies suggest that impaired transcription or mitochondrial translation of small RNAs can cause abnormal myelination. A polynucleotide phosphorylase (PNPase) encoded by PNPT1 facilitates the import of small RNAs into mitochondria. PNPT1 mutations have been reported in patients with neurodevelopmental diseases with mitochondrial dysfunction. We report here two siblings with PNPT1 mutations who presented delayed myelination as well as mitochondrial dysfunction. We identified compound heterozygous mutations (c...
June 8, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28589637/performance-of-brca1-2-mutation-prediction-models-in-male-breast-cancer-patients
#12
Setareh Moghadasi, Vincent Grundeken, Linda A M Janssen, Nizet H Dijkstra, Mar Rodríguez-Girondo, Wendy A G van Zelst-Stams, Jan C Oosterwijk, Margreet G E M Ausems, Rogier A Oldenburg, Muriel A Adank, Eveline W Blom, Mariëlle Ruijs, Theo A M van Os, Carolien H M van Deurzen, John W M Martens, Carolien P Schroder, Juul T Wijnen, Maaike P G Vreeswijk, Christi J van Asperen
To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA, BRCAPRO and the Myriad prevalence table ('Myriad'). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed versus predicted carriers and assessed the area under the receiver operating characteristic (ROC) curve (AUC) for each model...
June 6, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28589569/identification-of-novel-bcl11a-variants-in-patients-with-epileptic-encephalopathy-expanding-the-phenotypic-spectrum
#13
Michiko Yoshida, Mitsuko Nakashima, Tohru Okanishi, Sotaro Kanai, Ayataka Fujimoto, Kazuya Itomi, Masafumi Morimoto, Hirotomo Saitsu, Mitsuhiro Kato, Naomichi Matsumoto, Tomohiro Chiyonobu
BCL11A encodes a zinc finger protein that is highly expressed in hematopoietic tissues and the brain, and that is known to function as a transcriptional repressor of fetal hemoglobin (HbF). Recently, de novo variants in BCL11A have been reported in individuals with intellectual disability syndrome without epilepsy. In this study, we performed whole-exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified two novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p...
June 6, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28589536/distinguishing-pathogenic-mutations-from-background-genetic-noise-in-cardiology-the-use-of-large-genome-databases-for-genetic-interpretation
#14
REVIEW
Jonas Ghouse, Morten W Skov, Robert S Bigseth, Gustav Ahlberg, Jørgen K Kanters, Morten S Olesen
Advances in clinical genetic testing has led to increased insight into the human genome, including how challenging it is to interpret rare genetic variation. In some cases, the ability to detect genetic mutations exceeds the ability to understand their clinical impact, limiting the advantage of these technologies. Obstacles in genomic medicine are many and include: understanding the level of certainty/uncertainty behind pathogenicity determination, the numerous different variant interpretation-guidelines used by clinical laboratories, delivering the certain or uncertain result to the patient, helping patients evaluate medical decisions in light of uncertainty regarding the consequence of the findings...
June 6, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28580595/mutation-screening-of-10-cancer-susceptibility-genes-in-unselected-breast-cancer-patients
#15
Yueliang Xie, Li Guoli, Ming Chen, Xinwu Guo, Lili Tang, Xipeng Luo, Shouman Wang, Wenjun Yi, Lizhong Dai, Jun Wang
Variants of cancer susceptibility genes other than BRCA1/2 have been proved to be associated with increased risks of breast cancer. This study was performed to investigate the spectrum and prevalence of mutations in 10 cancer susceptibility genes in paired tumor/normal tissues of 292 unselected Chinese breast cancer patients. We performed an analysis of germline and somatic variants in ATM, CDH1, CHEK2, ESR1, GATA3, MAP3K1, MSH2, PALB2, RB1 and STK11 genes by integrating microfluidic PCR-based target enrichment and next-generation sequencing technologies...
June 5, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28556953/novel-biallelic-szt2-mutations-in-three-cases-of-early-onset-epileptic-encephalopathy
#16
Naomi Tshuchida, Mitsuko Nakashima, Akihiko Miyauchi, Shinsaku Yoshitomi, Tomokazu Kimizu, Vigneswari Ganesan, Keng Wee Teik, Ch'ng Gaik-Siew, Mitsuhiro Kato, Takeshi Mizuguchi, Atsushi Takata, Satoko Miyatake, Noriko Miyake, Hitoshi Osaka, Takanori Yamagata, Nakajima Hideaki, Hirotomo Saitsu, Naomichi Matsumoto
The seizure threshold 2 (SZT2) gene encodes a large, highly-conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in seven patients (from five families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in three patients with early-onset epileptic encephalopathies...
May 30, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28556904/diagnostic-application-of-a-capture-based-ngs-test-for-the-concurrent-detection-of-variants-in-sequence-and-copy-number-as-well-as-loh
#17
Annalisa Vetro, Didier Godin, Ivan Lesende, Ivan Limongelli, Guglielmina Nadia Ranzani, Francesca Novara, Maria Clara Bonaglia, Berardo Rinaldi, Fabrizia Franchi, Emmanouil Manolakos, Fortunato Lonardo, Francesca Scarano, Gioacchino Scarano, Lucy Costantino, Silvana Tedeschi, Sabrina Giglio, Orsetta Zuffardi
Whole exome sequencing has made increasingly accessible the identification of causative SNVs/InDels associated with rare Mendelian conditions. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative cases, by whole exome sequencing...
May 30, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28548327/a-familial-study-of-twins-with-severe-asthenozoospermia-identified-a-homozygous-spag17-mutation-by-whole-exome-sequencing
#18
Xiaohui Xu, Yan-Wei Sha, Li-Bin Mei, Zhi-Yong Ji, Ping-Ping Qiu, Hong Ji, Ping Li, Tuanlao Wang, Lin Li
Asthenozoospermia (AZS) is a common cause of male infertility, characterized by abnormal reduction in the motility of ejaculated spermatozoa. Here, in a patient from a consanguineous family, we identified a homozygous mutation (c.G4343A, p.R1448Q) in SPAG17 by whole-exome sequencing. The encoded protein, SPAG17, localizes to the axonemal central apparatus and is considered essential for flagellar waveform. In silico analysis revealed that R1448Q is a potential pathogenic mutation. Immunostaining and western blot assays showed that the R1448Q mutation may exert a negative effect on the steady-state of the SPAG17 protein...
May 26, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28542708/novel-col4a2-variant-in-a-large-pedigree-consequences-and-dilemmas
#19
LETTER
M McGovern, O Flanagan, B Lynch, S A Lynch, N M Allen
Pathogenic COL4A2 variants cause abnormalities in collagen production and can have serious implications for a range of organ systems, most notably the brain. Herein, we describe a large family of first-degree relatives affected by a novel heterozygous variant in COL4A2 (c.3490G.A). A wide disease spectrum is described, from asymptomatic to symptomatic, including 2 children with porencephaly and co-existing juvenile idiopathic polyarthritis. During a subsequent pregnancy, antenatal testing identified a positive fetus...
May 25, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28543186/clinical-biochemical-and-genetic-aspects-of-sj%C3%A3-gren-larsson-syndrome
#20
REVIEW
Kye Hee Cho, Sung Han Shim, MinYoung Kim
Sjögren-Larsson syndrome (SLS) is caused by an autosomal recessive mutation in ALDH3A2, which encodes the fatty aldehyde dehydrogenase responsible for the metabolism of long-chain aliphatic aldehydes and alcohols. The pathophysiologic accumulation of aldehydes in various organs, including the skin, brain, and eyes, leads to characteristic features of ichthyosis, intellectual disability, spastic di-/quadriplegia, and low visual acuity with photophobia. The severity of the clinical manifestations thereof can vary greatly, although most patients are bound to a wheelchair due to contractures...
May 23, 2017: Clinical Genetics
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