Assessment of predicted enzymatic activity of α-N-acetylglucosaminidase variants of unknown significance for CAGI 2016.


:The NAGLU challenge of the fourth edition of the Critical Assessment of Genome Interpretation experiment (CAGI4) in 2016, invited participants to predict the impact of variants of unknown significance (VUS) on the enzymatic activity of the lysosomal hydrolase α-N-acetylglucosaminidase (NAGLU). Deficiencies in NAGLU activity lead to a rare, monogenic, recessive lysosomal storage disorder, Sanfilippo syndrome type B (MPS type IIIB). This challenge attracted 17 submissions from 10 groups. We observed that top models were able to predict the impact of missense mutations on enzymatic activity with Pearson's correlation coefficients of up to .61. We also observed that top methods were significantly more correlated with each other than they were with observed enzymatic activity values, which we believe speaks to the importance of sequence conservation across the different methods. Improved functional predictions on the VUS will help population-scale analysis of disease epidemiology and rare variant association analysis.


Hum Mutat


Human mutation


Clark WT,Kasak L,Bakolitsa C,Hu Z,Andreoletti G,Babbi G,Bromberg Y,Casadio R,Dunbrack R,Folkman L,Ford CT,Jones D,Katsonis P,Kundu K,Lichtarge O,Martelli PL,Mooney SD,Nodzak C,Pal LR,Radivojac P,Savojardo C,Shi




Has Abstract


2019-09-01 00:00:00












  • Can we afford to sequence every newborn baby's genome?

    abstract::Whole-exome sequencing and whole-genome sequencing are gradually entering into the clinical arena. Drops in sequencing prices have led some to suggest that these analyses could be extended to the screening of whole populations or subsets thereof. Herein, we argue that this optimism is presently still unfounded. While ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Beckmann JS

    更新日期:2015-03-01 00:00:00

  • Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex.

    abstract::Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Here, we investigate the effects of 78 TSC2 variants identified in i...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Hoogeveen-Westerveld M,Ekong R,Povey S,Mayer K,Lannoy N,Elmslie F,Bebin M,Dies K,Thompson C,Sparagana SP,Davies P,van Eeghen AM,Thiele EA,van den Ouweland A,Halley D,Nellist M

    更新日期:2013-01-01 00:00:00

  • A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16).

    abstract::Mutations in the KCNJ13 gene that encodes the inwardly rectifying potassium channel Kir7.1 cause snowflake vitreoretinal degeneration (SVD) and leber congenital amaurosis (LCA). Kir7.1 controls the microenvironment between the photoreceptors and the retinal pigment epithelium (RPE) and also contributes to the function...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pattnaik BR,Shahi PK,Marino MJ,Liu X,York N,Brar S,Chiang J,Pillers DA,Traboulsi EI

    更新日期:2015-07-01 00:00:00

  • Rapid classification of phenylketonuria genotypes by analysis of heteroduplexes generated by PCR-amplifiable synthetic DNA.

    abstract::We describe a rapid and simple method for phenylketonuria genotyping which identifies five point mutations within exon 12 of the human phenylalanine hydroxylase gene. The method involves PCR amplification of the target exon and hybridization with a PCR-amplifiable synthetic DNA (universal heteroduplex generator, UHG)....

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Wood N,Tyfield L,Bidwell J

    更新日期:1993-01-01 00:00:00

  • Novel allele containing a 190C>T nonsynonymous substitution in the N-acetyltransferase (NAT2) gene.

    abstract::N-acetyltransferase (NAT2) is an enzyme involved in detoxification of various carcinogens. The gene is highly polymorphic with a number of alleles, and is also known as acetylator phenotypes: the fast, intermediate and slow acetylators. In this report, we describe a novel NAT2 allele, which was found in the allele typ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Shishikura K,Hohjoh H,Tokunaga K

    更新日期:2000-06-01 00:00:00

  • Apolipoprotein A-IV polymorphism in the Hungarian population: gene frequencies, effect on lipid levels, and sequence of two new variants.

    abstract::The genetic polymorphism of human apolipoprotein A-IV was investigated in Hungarian blood donors (n = 202) by isoelectric focusing (IEF) of plasma samples followed by immunoblotting. The frequency of apo A-IV alleles was f(A-IV1) = 0.95, f(A-IV2) = 0.039 and f(A-IV3) = 0.002. This frequency distribution is significant...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Menzel HJ,Dieplinger H,Sandholzer C,Karádi I,Utermann G,Császár A

    更新日期:1995-01-01 00:00:00

  • Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion.

    abstract::Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disease caused by impaired functioning of human liver aldolase (ALDOB). At least 54 subtle/point mutations and only two large intragenic deletions have been found in the ALDOB gene. Here we report two novel ALDOB variants (p.R46W and p.Y343H) an...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Esposito G,Imperato MR,Ieno L,Sorvillo R,Benigno V,Parenti G,Parini R,Vitagliano L,Zagari A,Salvatore F

    更新日期:2010-12-01 00:00:00

  • Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.

    abstract::Lafora disease is the most severe teenage-onset progressive epilepsy, a unique form of glycogenosis with perikaryal accumulation of an abnormal form of glycogen, and a neurodegenerative disorder exhibiting an unusual generalized organellar disintegration. The disease is caused by mutations of the EPM2A gene, which enc...

    journal_title:Human mutation

    pub_type: 杂志文章,多中心研究


    authors: Ianzano L,Young EJ,Zhao XC,Chan EM,Rodriguez MT,Torrado MV,Scherer SW,Minassian BA

    更新日期:2004-02-01 00:00:00

  • The novel p.Ser263Phe mutation in the human high-affinity choline transporter 1 (CHT1/SLC5A7) causes a lethal form of fetal akinesia syndrome.

    abstract::A subset of a larger and heterogeneous class of disorders, the congenital myasthenic syndromes (CMS) are caused by pathogenic variants in genes encoding proteins that support the integrity and function of the neuromuscular junction (NMJ). A central component of the NMJ is the sodium-dependent high-affinity choline tra...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Banerjee M,Arutyunov D,Brandwein D,Janetzki-Flatt C,Kolski H,Hume S,Leonard NJ,Watt J,Lacson A,Baradi M,Leslie EM,Cordat E,Caluseriu O

    更新日期:2019-10-01 00:00:00

  • Broad phenotypic variability in a single pedigree with a novel 1410delC mutation in the PST domain of the PAX6 gene.

    abstract::The PAX6 mutation present in an individual with aniridia was determined and phenotypic features of immediate relatives carrying the same mutation investigated. Mutation analysis revealed a novel single base deletion 1410delC in the PAX6 gene in ten affected individuals. Clinical features ranged from total aniridia to ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Sale MM,Craig JE,Charlesworth JC,FitzGerald LM,Hanson IM,Dickinson JL,Matthews SJ,Heyningen Vv Vv,Fingert JH,Mackey DA

    更新日期:2002-10-01 00:00:00

  • Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine.

    abstract::Chemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genome-based technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the gene...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Jarjanazi H,Kiefer J,Savas S,Briollais L,Tuzmen S,Pabalan N,Ibrahim-Zada I,Mousses S,Ozcelik H

    更新日期:2008-04-01 00:00:00

  • High throughput detection of microsatellite instability by denaturing high-performance liquid chromatography.

    abstract::Microsatellite instability (MSI) is a hallmark of the DNA replication error phenotype, due to the inactivation of mismatch repair genes. MSI has been implicated in colon and many other gastrointestinal cancers. MSI usually can be analyzed by PCR amplification of microsatellite markers followed by electrophoresis and d...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pan KF,Liu W,Lu YY,Zhang L,Li ZP,Lu WL,Thibodeau SN,You WC

    更新日期:2003-11-01 00:00:00

  • A functional variant in the miR-142 promoter modulating its expression and conferring risk of Alzheimer disease.

    abstract::Noncoding RNAs have been widely recognized as essential mediators of gene regulation. However, in contrast to protein-coding genes, much less is known about the influence of noncoding RNAs on human diseases. Here we examined the association of genetic variants located in primary microRNA sequences and long noncoding R...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Ghanbari M,Munshi ST,Ma B,Lendemeijer B,Bansal S,Adams HH,Wang W,Goth K,Slump DE,van den Hout MCGN,van IJcken WFJ,Bellusci S,Pan Q,Erkeland SJ,de Vrij FMS,Kushner SA,Ikram MA

    更新日期:2019-11-01 00:00:00

  • Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families.

    abstract::Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but puta...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Makrythanasis P,Nelis M,Santoni FA,Guipponi M,Vannier A,Béna F,Gimelli S,Stathaki E,Temtamy S,Mégarbané A,Masri A,Aglan MS,Zaki MS,Bottani A,Fokstuen S,Gwanmesia L,Aliferis K,Bustamante Eduardo M,Stamoulis G,Psoni S

    更新日期:2014-10-01 00:00:00

  • Fanconi anemia A due to a novel frameshift mutation in hotspot motifs: lack of FANCA protein.

    abstract::Homozygosity for a frameshift mutation at codon 1213 of FANCA gene was identified in a Turkish patient. Immunoprecipitation-western blot analysis showed the complete absence of the FANCA protein band. This novel mutation, a deletion of T at position 3639 in exon 37 (3639delT), is responsible for the disease and causes...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Balta G,de Winter JP,Kayserili H,Pronk JC,Joenje H

    更新日期:2000-06-01 00:00:00

  • Exome and genome analysis as a tool for disease identification and treatment: the 2011 Human Genome Variation Society scientific meeting.

    abstract::The 2011 annual scientific meeting of the Human Genome Variation Society (HGVS) was held on the 11th of October, in Montreal, Canada. The theme of this meeting was "Exome and Genome Analysis as a Tool for Disease Identification and Treatment." In the last few years, there has been a substantial increase in the use of ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Oetting WS

    更新日期:2012-03-01 00:00:00

  • A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern.

    abstract::The PCDH19 gene consists of six exons encoding a 1,148 amino acid transmembrane protein, Protocadherin 19, which is involved in brain development. Heterozygous pathogenic variants in this gene are inherited in an unusual X-linked dominant pattern in which heterozygous females are affected, while hemizygous males are t...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Niazi R,Fanning EA,Depienne C,Sarmady M,Abou Tayoun AN

    更新日期:2019-03-01 00:00:00

  • Enigmatic in vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome.

    abstract::Sequence analysis of the X-linked iduronate-2-sulfatase (IDS) gene in two Hunter syndrome patients revealed a lack of concordance between IDS genomic DNA and cDNA. These individuals were found to be hemizygous respectively for a nonsense mutation [c.22C>T;p.R8X] and a frameshift micro-insertion [c.10insT;p.P4Sfs] in t...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lualdi S,Tappino B,Di Duca M,Dardis A,Anderson CJ,Biassoni R,Thompson PW,Corsolini F,Di Rocco M,Bembi B,Regis S,Cooper DN,Filocamo M

    更新日期:2010-04-01 00:00:00

  • Germline mutations in the BRCA1 and BRCA2 genes in Turkish breast/ovarian cancer patients.

    abstract::In this study we genotyped Turkish breast/ovarian cancer patients for BRCA1/BRCA2 mutations: protein truncation test (PTT) for exon 11 BRCA1 of and, multiplex PCR and denaturing gradient gel electrophoresis (DGGE) for BRCA2, complemented by DNA sequencing. In addition, a modified restriction assay was used for analysi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Manguoglu AE,Lüleci G,Ozçelik T,Colak T,Schayek H,Akaydin M,Friedman E

    更新日期:2003-04-01 00:00:00

  • Alternative splicing of in-frame exon associated with premature termination codons: implications for readthrough therapies.

    abstract::The correction of premature termination codons (PTCs) by agents that promote readthrough represents a promising emerging tool for the treatment of many genetic diseases. The efficiency of the treatment, however, varies depending on the stop codon itself and the amount of correctible transcripts related to the efficien...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Hinzpeter A,Aissat A,de Becdelièvre A,Bieth E,Sondo E,Martin N,Costes B,Costa C,Goossens M,Galietta LJ,Girodon E,Fanen P

    更新日期:2013-02-01 00:00:00

  • A panel of ancestry informative markers for estimating individual biogeographical ancestry and admixture from four continents: utility and applications.

    abstract::Autosomal ancestry informative markers (AIMs) are useful for inferring individual biogeographical ancestry (I-BGA) and admixture. Ancestry estimates obtained from Y and mtDNA are useful for reconstructing population expansions and migrations in our recent past but individual genomic admixture estimates are useful to t...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Halder I,Shriver M,Thomas M,Fernandez JR,Frudakis T

    更新日期:2008-05-01 00:00:00

  • Impaired development of neural-crest cell-derived organs and intellectual disability caused by MED13L haploinsufficiency.

    abstract::MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12;19) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and musc...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Utami KH,Winata CL,Hillmer AM,Aksoy I,Long HT,Liany H,Chew EG,Mathavan S,Tay SK,Korzh V,Sarda P,Davila S,Cacheux V

    更新日期:2014-11-01 00:00:00

  • Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms.

    abstract::Glucocorticoid (GC) resistance can occur in a number of diseases. It can be either generalized (i.e., familial glucocorticoid resistance) or localized (i.e., asthma). In many cases, a reason for this resistance to steroids lies with mutations or polymorphisms present in the glucocorticoid receptor gene (GR/NR3C1) that...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Bray PJ,Cotton RG

    更新日期:2003-06-01 00:00:00

  • Homozygosity for FARSB mutation leads to Phe-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease.

    abstract::Aminoacyl-tRNA synthetases (ARSs) canonical function is to conjugate specific amino acids to cognate tRNA that are required for the first step of protein synthesis. Genetic mutations that cause dysfunction or absence of ARSs result in various neurodevelopmental disorders. The human phenylalanine-tRNA synthetase (PheRS...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Zadjali F,Al-Yahyaee A,Al-Nabhani M,Al-Mubaihsi S,Gujjar A,Raniga S,Al-Maawali A

    更新日期:2018-10-01 00:00:00

  • Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations.

    abstract::Hereditary hemorrhagic telangiectasia (HHT), or Osler-Rendu-Weber syndrome, is a heterogeneous inherited disorder characterized by multi-systemic vascular dysplasia and wide variation in its phenotypic expression. Hepatic manifestation is seen in about 8 to 30 % of the patients. The molecular basis for liver involveme...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kuehl HK,Caselitz M,Hasenkamp S,Wagner S,El-Harith el-HA,Manns MP,Stuhrmann M

    更新日期:2005-03-01 00:00:00

  • Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217

    abstract::Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 familie...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Taillandier A,Zurutuza L,Muller F,Simon-Bouy B,Serre JL,Bird L,Brenner R,Boute O,Cousin J,Gaillard D,Heidemann PH,Steinmann B,Wallot M,Mornet E

    更新日期:1999-01-01 00:00:00

  • WFS1/wolframin mutations, Wolfram syndrome, and associated diseases.

    abstract::Wolfram syndrome (WS) is the inherited association of juvenile-onset insulin-dependant diabetes mellitus and progressive bilateral optic atrophy. A nuclear gene, WFS1/wolframin, was identified that segregated with disease status and demonstrated an autosomal recessive mode of inheritance. Mutation analysis of the WFS1...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Khanim F,Kirk J,Latif F,Barrett TG

    更新日期:2001-05-01 00:00:00

  • A new PCR assay useful for screening of FRAXE/FMR2 mental impairment among males.

    abstract::FRAXE (FMR2) is a fragile site associated with mental impairment located in Xq28, 600 kb distal to FRAXA (FMR1), the fragile X syndrome fragile site. The FRAXE mutation is an expansion of a CCG repeat that results in methylation of a nearby CpG island. FRAXE alleles could be divided into four categories: normal (6-30 ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Santos CB,Costa Lima MA,Pimentel MM

    更新日期:2001-08-01 00:00:00

  • Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer.

    abstract::The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using informat...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Felicio PS,Grasel RS,Campacci N,de Paula AE,Galvão HCR,Torrezan GT,Sabato CS,Fernandes GC,Souza CP,Michelli RD,Andrade CE,Barros BDF,Matsushita MM,Revil T,Ragoussis J,Couch FJ,Hart SN,Reis RM,Melendez ME,Tonin PN,

    更新日期:2020-12-16 00:00:00

  • The human TBX5 gene mutation database.

    abstract::Germline mutations of the TBX5 gene were identified as the primary cause in up to 70% of patients with Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by malformations of the upper limbs and cardiac defects. Furthermore, somatic mutations of the TBX5 gene have been described in diseased heart ti...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Heinritz W,Shou L,Moschik A,Froster UG

    更新日期:2005-10-01 00:00:00