Abstract：
:Sequence capture enrichment (SCE) strategies and massively parallel next generation sequencing (NGS) are expected to increase the rate of gene discovery for genetically heterogeneous hereditary diseases, but at present, there are very few examples of successful application of these technologic advances in translational research and clinical testing. Our study assessed whether array based target enrichment followed by re-sequencing on the Roche Genome Sequencer FLX (GS FLX) system could be used for novel mutation identification in more than 1000 exons representing 100 candidate genes for ocular birth defects, and as a control, whether these methods could detect two known mutations in the PAX2 gene. We assayed two samples with heterozygous sequence changes in PAX2 that were previously identified by conventional Sanger sequencing. These changes were a c.527G>C (S176T) substitution and a single basepair deletion c.77delG. The nucleotide substitution c.527G>C was easily identified by NGS. A deletion of one base in a long polyG stretch (c.77delG) was not registered initially by the GS Reference Mapper, but was detected in repeated analysis using two different software packages. Different approaches were evaluated for distinguishing false positives (sequencing errors) and benign polymorphisms from potentially pathogenic sequence changes that require further follow-up. Although improvements will be necessary in accuracy, speed, ease of data analysis and cost, our study confirms that NGS can be used in research and diagnostic settings to screen for mutations in hundreds of loci in genetically heterogeneous human diseases.
journal_name
Mol Genet Metabjournal_title
Molecular genetics and metabolismauthors
Raca G,Jackson C,Warman B,Bair T,Schimmenti LAdoi
10.1016/j.ymgme.2010.03.004subject
Has Abstractpub_date
2010-06-01 00:00:00pages
184-92issue
2eissn
1096-7192issn
1096-7206pii
S1096-7192(10)00095-8journal_volume
100pub_type
杂志文章abstract：:Among the numerous congenital disorders of glycosylation concerning glycoproteins, only a single mutation in ganglioside biosynthesis had been reported until a few years ago: one in the ST3GAL5 gene, encoding GM3 synthase. More recently, additional mutations in the same gene were reported, together with several distin...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.ymgme.2018.06.014
更新日期：2018-08-01 00:00:00
abstract：:Over 7000 rare diseases, each <200,000 US residents, affect nearly 30 million people in the United States. Furthermore, for the 10% of people with a rare disease and for their families, these disorders no longer seem rare. Molecular genetics have characterized the cause of many rare diseases and provide unprecedented ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2008.10.003
更新日期：2009-01-01 00:00:00
abstract：:Individuals with early-treated phenylketonuria (ETPKU) most often present with impairment in executive function (EF) and average intelligence compared to the general population. The topic of this review, which is less often discussed, is non-EF impairments that may be associated with ETPKU. Studies that have included ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.ymgme.2009.10.009
更新日期：2010-01-01 00:00:00
abstract：BACKGROUND:Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-αGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2018.11.008
更新日期：2019-02-01 00:00:00
abstract：:Pyruvate dehydrogenase complex (PDC) deficiency is one of the major recognized causes of congenital lactic acidosis. The most common form is due to PDHA 1 gene (Xp22.12) defects. Here, we report the case of a Polynesian girl presenting with delayed neurological development, cortical atrophy, and posterior corpus callo...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2005.08.009
更新日期：2005-12-01 00:00:00
abstract：:Creatine and creatine phosphate provide storage and transmission of phosphate-bound energy in muscle and brain. Of the three inborn errors of creatine metabolism causing brain creatine depletion, l-arginine:glycine amidinotransferase (AGAT) deficiency has been described in only two families. We describe clinical and b...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2010.06.021
更新日期：2010-10-01 00:00:00
abstract：:Orthotopic liver transplant (OLT) significantly improves patient outcomes in maple syrup urine disease (MSUD; OMIM: 248600), yet organ shortages point to the need for alternative therapies. Hepatocyte transplantation has shown both clinical and preclinical efficacy as an intervention for metabolic liver diseases, yet ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2013.02.011
更新日期：2013-06-01 00:00:00
abstract：:Methylcrotonylglycinuria (MCG) is an inborn error of leucine catabolism and has a recessive pattern of inheritance that results from the deficiency of 3-methylcrotonyl-CoA carboxylase (MCC). The clinical phenotypes are highly variable ranging from neonatal onset with severe neurological involvement to asymptomatic adu...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2010.10.008
更新日期：2011-02-01 00:00:00
abstract：:Early age at menarche is a risk factor for breast cancer. A previous study reported a significant positive association between the CYP3A4*1B variant allele and early puberty. We investigated whether polymorphisms of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes predict the age at onset of menarche. Five hundred eighty-t...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1006/mgme.2001.3260
更新日期：2001-12-01 00:00:00
abstract：:Genetic testing for the C282Y mutation of the HFE gene has been a major advance in the diagnosis of hereditary hemochromatosis. In most studies, more than 90% of typical hemochromatosis patients are homozygous for the C282Y mutation. Large-scale population screening studies in predominantly Caucasian populations have ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章,评审
doi：10.1006/mgme.2000.3037
更新日期：2000-09-01 00:00:00
abstract：:The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involved in the degradation of glycosaminoglycans. Hurler syndrome (MPS I) and Sanfilippo syndrome (MPS III) are among the more common diseases in the group, each occurring with an incidence of approximately 1 in 100,000. ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2011.02.011
更新日期：2011-06-01 00:00:00
abstract：:Three functional polymorphisms described in the promoter of receptor for advanced glycation end products (RAGE) gene were shown to have a marked effect on transcriptional activity. The few studies which analyzed the relationship between these three polymorphisms and the diabetic complications have shown conflicting re...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2005.02.010
更新日期：2005-06-01 00:00:00
abstract：:Tandem mass spectrometry (MS/MS) has been introduced in several newborn screening programs for the detection of a large number of inborn errors of metabolism, including fatty acid oxidation disorders (FAOD). Early identification and treatment of FAOD have the potential to improve outcome and may be life-saving in some...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1006/mgme.2001.3282
更新日期：2002-02-01 00:00:00
abstract：:Mutant GBA was found recently to be the most prevalent risk factor for familial parkinsonism. The two diseases do not share common symptoms and there is no direct pathway to explain the mechanism by which GBA mutations can confer the risk. Increased burden on the degradative pathway caused by defective glucocerebrosid...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2010.08.004
更新日期：2010-12-01 00:00:00
abstract：:Pompe Disease (PD) is a lysosomal storage disease caused by acid α-glucosidase deficiency. The infantile form typically results in death in the first year of life. Patient survival has improved with enzyme replacement therapy (ERT), but new complications are being recognized. We report three cases of infantile onset P...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2012.11.013
更新日期：2013-02-01 00:00:00
abstract：:Holocarboxylase synthetase (HCS) catalyses the biotinylation of the four biotin-dependent carboxylases found in humans. A deficiency in HCS results in biotin-responsive multiple carboxylase deficiency. We have evaluated the biotin responsiveness associated with six missense mutations previously identified in affected ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1006/mgme.1998.2785
更新日期：1999-02-01 00:00:00
abstract：:The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes involved in the catabolism of glycosaminoglycans (GAGs). The resulting GAG accumulation in cells and tissues throughout the body leads to progressive multi-organ dysfunction. MPS patients present with several somatic man...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.ymgme.2017.10.006
更新日期：2017-12-01 00:00:00
abstract：:TRMU is a nuclear gene crucial for mitochondrial DNA translation by encoding tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, which thiolates mitochondrial tRNA. Biallelic pathogenic variants in TRMU are associated with transient infantile liver failure. Other less common presentations such as Leigh syndrom...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2021.01.005
更新日期：2021-01-14 00:00:00
abstract：:In Duchenne muscular dystrophy (DMD), identification of one nonsense mutation in the DMD gene has been considered an endpoint of genetic diagnosis. Here, we identified two closely spaced nonsense mutations in the DMD gene. In a Malaysian DMD patient two nonsense mutations (p.234S>X and p.249Q>X, respectively) were ide...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2011.04.002
更新日期：2011-07-01 00:00:00
abstract：:DAX1 encoded by NR0B1, when mutated, is responsible for X-linked adrenal hypoplasia congenita (AHC). AHC is due to failure of the adrenal cortex to develop normally and is fatal if untreated. When duplicated, this gene is associated with an XY sex-reversed phenotype. DAX1 expression is present during development of th...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.ymgme.2003.08.023
更新日期：2003-09-01 00:00:00
abstract：:An approach to treating Gaucher disease is substrate inhibition therapy which seeks to abate the aberrant lysosomal accumulation of glucosylceramide. We have identified a novel inhibitor of glucosylceramide synthase (Genz-112638) and assessed its activity in a murine model of Gaucher disease (D409V/null). Biochemical ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2007.04.001
更新日期：2007-07-01 00:00:00
abstract：:In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) can lead a metabolic disorder Classic Galactosemia. Although the biochemical abnormalities associated with this disease have been described in detail, few attempts have been made to characterize the pathogenic mechanisms of this disorder at the mo...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2005.08.002
更新日期：2005-11-01 00:00:00
abstract：:The thyroid-stimulating hormone (TSH, or thyrotropin) receptor (TSHR) mediates the activating action of TSH to the thyroid gland, resulting in the growth and proliferation of thyrocytes and thyroid hormone production. In Graves' disease, thyroid-stimulating autoantibodies can mimic TSH action and stimulate thyroid cel...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.ymgme.2003.09.001
更新日期：2003-12-01 00:00:00
abstract：:Congenital analbuminemia is a rare autosomal recessive disorder characterized by a trace level of albumin in blood plasma and mild clinical symptoms. Analbuminemic patients generally present associated abnormalities, among which dyslipidemia is a hallmark. In this study, we show that mitochondria isolated from differe...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2011.08.031
更新日期：2011-12-01 00:00:00
abstract：:Lysosomes are an essential organ for cellular metabolism and play an important role in autophagy. We examined the association between methylation and autophagy in a severely affected female patient with Fabry disease, which is caused by mutation of the GLA gene on the X chromosome, and her two sisters, who had few sym...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2019.03.003
更新日期：2019-04-01 00:00:00
abstract：:The insulin-like growth factor I receptor (IGF-I-R) has an important role in breast cancer etiology. The receptor is overexpressed by most breast cancers, where it functions as a potent antiapoptotic agent. BRCA1 is a tumor suppressor gene that is mutated in a large fraction of familial breast and ovarian cancers. Cot...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1006/mgme.1999.2958
更新日期：2000-02-01 00:00:00
abstract：:Globoid cell leukodystrophy (GLD, Krabbe disease), is an autosomal recessive, neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). In the absence of GALC, the toxic metabolite psychosine accumulates in the brain and causes the death of the myelin-producing cells, olig...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2012.05.021
更新日期：2012-09-01 00:00:00
abstract：:Carnitine-acylcarnitine translocase (CATR) deficiency is a severe defect in fatty acid oxidation which presents early in life most frequently with hypoglycemia, hyperammonemia, and severe cardiac abnormalities. CATR exchanges acylcarnitines of various chain lengths for free carnitine across the mitochondrial membrane....
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1006/mgme.1999.2950
更新日期：2000-01-01 00:00:00
abstract：:Abetalipoproteinemia (ABL) is a rare autosomal recessive metabolic disorder, characterized by the absence of plasma apolipoprotein B-containing lipoproteins and very low levels of plasma triglycerides and cholesterol. ABL is caused by mutations of the MTP gene. We investigated the genetic basis for ABL in a cohort of ...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2006.12.010
更新日期：2007-04-01 00:00:00
abstract：BACKGROUND:The number of newborns and the number of disorders detected by large-scale screening programs has increased dramatically in the last decade. Newborn screening is a multi-step process requiring confirmatory testing to establish and refine a diagnosis. Whereas screening cutoffs are established to detect all ca...
journal_title：Molecular genetics and metabolism
pub_type： 杂志文章
doi：10.1016/j.ymgme.2011.08.020
更新日期：2011-12-01 00:00:00
