{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:08:30Z","timestamp":1790820510413,"version":"4.1.0"},"reference-count":79,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,8,21]],"date-time":"2019-08-21T00:00:00Z","timestamp":1566345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.<\/jats:p>","DOI":"10.3390\/genes10090631","type":"journal-article","created":{"date-parts":[[2019,8,21]],"date-time":"2019-08-21T11:19:06Z","timestamp":1566386346000},"page":"631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7025-2495","authenticated-orcid":false,"given":"Marco","family":"Ritelli","sequence":"first","affiliation":[{"name":"Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1545-4801","authenticated-orcid":false,"given":"Valeria","family":"Cinquina","sequence":"additional","affiliation":[{"name":"Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5692-366X","authenticated-orcid":false,"given":"Edoardo","family":"Giacopuzzi","sequence":"additional","affiliation":[{"name":"Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Venturini","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Clinical and Experimental Sciences, Spedali Civili University Hospital, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1760-5079","authenticated-orcid":false,"given":"Nicola","family":"Chiarelli","sequence":"additional","affiliation":[{"name":"Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3105-5990","authenticated-orcid":false,"given":"Marina","family":"Colombi","sequence":"additional","affiliation":[{"name":"Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers-Danlos syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. J. Med. Genet. C"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.ajhg.2018.02.018","article-title":"Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome","volume":"102","author":"Blackburn","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/ajmg.a.60679","article-title":"A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings","volume":"179","author":"Hebebrand","year":"2019","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1093\/hmg\/ddz024","article-title":"Bi-allelic AEBP1 mutations in two patients with Ehlers-Danlos syndrome","volume":"28","author":"Syx","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ritelli, M., Cinquina, V., Venturini, M., Pezzaioli, L., Formenti, A.M., Chiarelli, N., and Colombi, M. (2019). Expanding the Clinical and Mutational Spectrum of Recessive AEBP1-Related Classical-Like Ehlers-Danlos Syndrome. Genes, 10.","DOI":"10.3390\/genes10020135"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ajmg.c.31432","article-title":"Generalized joint hypermobility, joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type","volume":"169","author":"Castori","year":"2015","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/ajmg.c.31429","article-title":"Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome\/Ehlers-Danlos syndrome hypermobility type compared to other heritable connective tissue disorders","volume":"169","author":"Colombi","year":"2015","journal-title":"Am. J. Med. Genet. Part C"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/S0959-440X(00)00125-1","article-title":"Recent advances in the study of the biosynthesis and functions of sulfated glycosaminoglycans","volume":"10","author":"Sugahara","year":"2000","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev.cellbio.22.010605.093433","article-title":"The molecular diversity of glycosaminoglycans shapes animal development","volume":"22","author":"Hober","year":"2006","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_10","unstructured":"Varki, A., Cummings, R.D., Esko, J.D., Freeze, H.H., Stanley, P., Bertozzi, C.R., Hart, G.W., and Etzler, M.E. (2009). Proteoglycans and Sulfated Glycosaminoglycans. Essential of Glycobiology, Cold Spring Harbor Laboratory Press. [2nd ed.]. Chapter 16."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10953","DOI":"10.1074\/jbc.R112.437038","article-title":"Human genetic disorders caused by mutations in genes encoding biosynthetic enzymes for sulfated glycosaminoglycans","volume":"19","author":"Mizumoto","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1055\/s-0042-118706","article-title":"Abnormal Proteoglycan Synthesis Due to Gene Defects Causes Skeletal Diseases with Overlapping Phenotypes","volume":"48","author":"Taylan","year":"2016","journal-title":"Horm. Metab. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Mizumoto, S., Kosho, T., Yamada, S., and Sugahara, K. (2017). Pathophysiological Significance of Dermatan Sulfate Proteoglycans Revealed by Human Genetic Disorders. Pharmaceuticals, 10.","DOI":"10.3390\/ph10020034"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/ajmg.c.31550","article-title":"The Ehlers-Danlos syndromes, rare types","volume":"175","author":"Brady","year":"2017","journal-title":"Am. J. Med. Genet. C"},{"key":"ref_15","first-page":"436","article-title":"Glycosaminoglycan-free small proteoglycan core protein is secreted by fibroblasts from a patient with a syndrome resembling progeroid","volume":"41","author":"Kresse","year":"1987","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","first-page":"39","article-title":"A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facioskeletal anomalies and Ehlers-Danlos syndrome resembling the progeroid type","volume":"128","author":"Zaidi","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1002\/ajmg.a.36128","article-title":"Redefining the progeroid form of Ehlers-Danlos syndrome: Report of the fourth patient with B4GALT7 deficiency and review of the literature","volume":"161","author":"Guo","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1002\/ajmg.a.37604","article-title":"Further defining the phenotypic spectrum of B4GALT7 mutations","volume":"170","author":"Salter","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1002\/ajmg.a.37809","article-title":"Corneal clouding, cataract, and colobomas with a novel missense mutation in B4GALT7-a review of eye anomalies in the linkeropathy syndromes","volume":"170","author":"Arunrut","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s13023-017-0704-3","article-title":"Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome","volume":"7","author":"Ritelli","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bone.2019.03.029","article-title":"Phenotype and response to growth hormone therapy in siblings with B4GALT7 deficiency","volume":"124","author":"Wambach","year":"2019","journal-title":"Bone"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.ajhg.2013.04.016","article-title":"Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder","volume":"92","author":"Malfait","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.ajhg.2013.04.003","article-title":"Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders","volume":"92","author":"Nakajima","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.spen.2014.04.007","article-title":"A newborn with complex skeletal abnormalities, joint contractures, and bilateral corneal clouding with sclerocornea","volume":"21","author":"Sellars","year":"2014","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_25","first-page":"1","article-title":"Insights in the etiopathology of galactosyltransferase II (GalT-II) deficiency from transcriptome-wide expression profiling of skin fibroblasts of two sisters with compound heterozygosity for two novel B3GALT6 mutations","volume":"20","author":"Ritelli","year":"2014","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s00439-016-1660-z","article-title":"Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue","volume":"135","author":"Alazami","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S54","DOI":"10.7196\/SAMJ.2016.v106i6.10994","article-title":"Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type): A unique South African disorder","volume":"106","author":"Honey","year":"2016","journal-title":"S. Afr. Med. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1093\/hmg\/ddy234","article-title":"Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome","volume":"27","author":"Pang","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.ajhg.2008.05.001","article-title":"Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome\u2014An autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13","volume":"82","author":"Giunta","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Fukada, T., Civic, N., Furuichi, T., Shimoda, S., Mishima, K., Higashiyama, H., Idaira, Y., Asada, Y., Kitamura, H., and Yamasaki, S.T. (2008). The zinc transporter SLC39A13\/ZIP13 is required for connective tissue development; its involvement in BMP\/TGF-\u03b2 signaling pathways. PLoS ONE, 3.","DOI":"10.1371\/annotation\/a6c35a12-e8eb-43a0-9d00-5078fa6da1bb"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1159\/000485881","article-title":"Novel Nonsense Mutation in SLC39A13 Initially Presenting as Myopathy: Case Report and Review of the Literature","volume":"9","author":"Dusanic","year":"2018","journal-title":"Mol. Syndromol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/ejhg.2014.60","article-title":"Expanding the clinical spectrum of B4GALT7 deficiency: Homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome","volume":"23","author":"Cartault","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00439-013-1351-y","article-title":"The missing \u201clink\u201d: An autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation","volume":"133","author":"Schreml","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.ajhg.2014.01.020","article-title":"XYLT1 mutations in Desbuquois dysplasia type 2","volume":"94","author":"Bui","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1002\/ajmg.a.37453","article-title":"Complete and partial XYLT1 deletion in a patient with neonatal short limb skeletal dysplasia","volume":"170","author":"Knoester","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/jhg.2016.30","article-title":"Exome sequencing reveals two novel compound heterozygous XYLT1 mutations in a Polish patient with Desbuquois dysplasia type 2 and growth hormone deficiency","volume":"61","author":"Jamsheer","year":"2016","journal-title":"J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1002\/ajmg.a.37858","article-title":"Desbuquois dysplasia type II in a patient with a homozygous mutation in XYLT1 and new unusual findings","volume":"170","author":"Silveira","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/jhg.2016.143","article-title":"Novel and recurrent XYLT1 mutations in two Turkish families with Desbuquois dysplasia, type 2","volume":"62","author":"Guo","year":"2017","journal-title":"J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1002\/ajmg.a.38244","article-title":"Endoplasmic reticulum retention of xylosyltransferase 1 (XYLT1) mutants underlying Desbuquois dysplasia type II","volume":"173","author":"Ali","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ajhg.2018.11.005","article-title":"GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome","volume":"104","author":"LaCroix","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.ajhg.2015.04.017","article-title":"Homozygosity for frameshift mutations in XYLT2 result in a spondylo-ocular syndrome with bone fragility, cataracts, and hearing defects","volume":"96","author":"Munns","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1002\/jbmr.2834","article-title":"Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum","volume":"31","author":"Taylan","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1002\/ajmg.a.38470","article-title":"Two novel mutations in XYLT2 cause spondyloocular syndrome","volume":"173","author":"Taylan","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1111\/cge.13179","article-title":"Homozygous XYLT2 variants as a cause of spondyloocular syndrome","volume":"93","author":"Umair","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_45","first-page":"30611","article-title":"Intrafamilial variability of XYLT2-related spondyloocular syndrome","volume":"1769","author":"Guleray","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3389\/fgene.2019.00144","article-title":"A Novel Homozygous Frameshift Variant in XYLT2 Causes Spondyloocular Syndrome in a Consanguineous Pakistani Family","volume":"10","author":"Kausar","year":"2019","journal-title":"Front. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ajhg.2011.05.021","article-title":"Faulty initiation of proteoglycan synthesis causes cardiac and joint defects","volume":"15","author":"Baasanjav","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1002\/ajmg.a.36487","article-title":"Skeletal dysplasia, global developmental delay, and multiple congenital anomalies in a 5-year-old boy-report of the second family with B3GAT3 mutation and expansion of the phenotype","volume":"164","author":"Tan","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1007\/s00439-015-1549-2","article-title":"Skeletal dysplasia in a consanguineous clan from the island of Nias\/Indonesia is caused by a novel mutation in B3GAT3","volume":"134","author":"Budde","year":"2015","journal-title":"Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1002\/ajmg.a.37209","article-title":"A homozygous B3GAT3 mutation causes a severe syndrome with multiple fractures, expanding the phenotype of linkeropathy syndromes","volume":"167","author":"Jones","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Job, F., Mizumoto, S., Smith, L., Couser, N., Brazil, A., Saal, H., Patterson, M., Gibson, M.I., Soden, S., and Miller, N. (2016). Functional validation of novel compound heterozygous variants in B3GAT3 resulting in severe osteopenia and fractures: Expanding the disease phenotype. BMC Med. Genet., 17.","DOI":"10.1186\/s12881-016-0344-9"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/gim.2017.109","article-title":"B3GAT3-related disorder with craniosynostosis and bone fragility due to a unique mutation","volume":"20","author":"Yauy","year":"2018","journal-title":"Genet. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s13023-019-1110-9","article-title":"The clinical and mutational spectrum of B3GAT3 linkeropathy: Two case reports and literature review","volume":"14","author":"Colman","year":"2019","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_54","first-page":"421","article-title":"Integrated annotation and analysis of genetic variants from next-generation sequencing studies with variant tools","volume":"1","author":"Wang","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1093\/bioinformatics\/bty303","article-title":"GARFIELD-NGS: Genomic vARiants FIltering by dEep Learning moDels in NGS","volume":"1","author":"Ravasio","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1093\/nar\/gkq603","article-title":"Annovar: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/bioinformatics\/btu703","article-title":"Dann: A deep learning approach for annotating the pathogenicity of genetic variants","volume":"31","author":"Quang","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Petrovski, S., Wang, Q., Heinzen, E.L., Allen, A.S., and Goldstein, D.B. (2013). Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet., 9.","DOI":"10.1371\/annotation\/32c8d343-9e1d-46c6-bfd4-b0cd3fb7a97e"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"13615","DOI":"10.1073\/pnas.1518646112","article-title":"The human gene damage index as a gene-level approach to prioritizing exome variants","volume":"112","author":"Itan","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Rentzsch, P., Witten, D., Cooper, G.M., Shendure, J., and Kircher, M. (2018). CADD: Predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res.","DOI":"10.1093\/nar\/gky1016"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Eugene, V., Davydov, E.V., Goode, D.L., Sirota, M., Cooper, G.M., Sidow, A., and Batzoglou, S. (2010). Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1001025"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1002\/humu.22965","article-title":"UMD-Predictor: A High-Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution","volume":"35","author":"Salgado","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1101\/gr.092619.109","article-title":"Identification of deleterious mutations within three human genomes","volume":"19","author":"Chun","year":"2009","journal-title":"Genom. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1093\/bioinformatics\/btv009","article-title":"An integrative approach to predicting the functional effects of non-coding and coding sequence variation","volume":"31","author":"Shihab","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_69","first-page":"S3","article-title":"Identifying Mendelian disease genes with the Variant Effect Scoring Tool BMC","volume":"14","author":"Carter","year":"2013","journal-title":"Genomics"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/ng.2658","article-title":"Genome-wide inference of natural selection on human transcription factor binding sites","volume":"45","author":"Arbiza","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"34580","DOI":"10.1074\/jbc.M007399200","article-title":"Heparan\/chondroitin sulfate biosynthesis. Structure and mechanism of human glucuronyltransferase I","volume":"277","author":"Pedersen","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"21869","DOI":"10.1074\/jbc.M112343200","article-title":"Crystal structure of \u03b21,3-glucuronyltransferase I in complex with active donor substrate UDP-GlcUA","volume":"277","author":"Pedersen","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines","volume":"100","author":"Li","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"882","DOI":"10.12659\/AJCR.895526","article-title":"Prenatal diagnosis of Antley-Bixler syndrome and POR deficiency","volume":"16","author":"Oldani","year":"2015","journal-title":"Am. J. Case."},{"key":"ref_76","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Stephens, K., and Amemiya, A. (2006). Shprintzen-Goldberg Syndrome. GeneReviews\u00ae, University of Washington."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"25439","DOI":"10.1074\/jbc.M201912200","article-title":"The donor substrate specificity of the human \u03b2 1,3-glucuronosyltransferase I toward UDP-glucuronic acid is determined by two crucial histidine and arginine residues","volume":"227","author":"Ouzzine","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1110\/ps.062089106","article-title":"Phylogenetic and mutational analyses reveal key residues for UDP-glucuronic acid binding and activity of \u03b2 1,3-glucuronosyltransferase I (GlcAT-I)","volume":"15","author":"Lattard","year":"2006","journal-title":"Protein Sci."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Venselaar, H., Te Beek, T.A., Kuipers, R.K., Hekkelman, M.L., and Vriend, G. (2010). Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-548"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/9\/631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:12:49Z","timestamp":1760188369000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/9\/631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,21]]},"references-count":79,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["genes10090631"],"URL":"https:\/\/doi.org\/10.3390\/genes10090631","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,21]]}}}