Summary of clinical findings.

Summary of clinical findings.</p

Putative pathogenic variants in 25 unrelated German patients initially diagnosed with LCA.

Putative pathogenic variants in 25 unrelated German patients initially diagnosed with LCA.</p

Assessment of pathogenicity of missense variants identified in this study.

Assessment of pathogenicity of missense variants identified in this study.</p

Additional file 1: of Expanding the clinical spectrum of COL1A1 mutations in different forms of glaucoma

PCR Primers used for molecular screening of CYP1B1, MYOC, FOXC1, PITX2, PAX6 and COL1A1 genes. (DOCX 20 kb

Additional file 2: of Expanding the clinical spectrum of COL1A1 mutations in different forms of glaucoma

Sequence chromatograms of the variants identified in COL1A1 gene in three different patients: MZ-2, CA-3 and TU-4. (DOCX 129 kb

Pedigrees of six families discussed in detail in the manuscript.

<p>The arrows indicate the patients in whom NGS was performed. Family number and disease-causing mutation(s) are noted above each pedigree. The diagnosis of the patient and the genotype for each mutation are listed below each individual´s symbol. LCA, Leber congenital amaurosis; BBS, Bardet Biedl syndrome; CRD, cone-rod dystrophy; RP, retinitis pigmentosa; ACHM, achromatopsia; ADOAC, autosomal dominant optic atrophy and cataract.</p

Biochemical and functional interactions between (putative) glaucoma disease genes.

<p>Ingenuity diagram of biochemical and functional interactions between the newly identified GAS7 and TMCO1 disease genes implicated in elevated IOP and glaucoma, and previously known glaucoma disease genes (WDR36, MYOC, OPTN, CAV1). Functional relationships in the knowledge database Ingenuity (<a href="http://www.ingenuity.com" target="_blank">www.ingenuity.com</a>) are a compilation of all known gene-relevant biochemical and functional data of in vivo and in vitro experiments involving (molecules, cells and tissues of) rats and mice and man, as well as data from zebrafish and Drosophila and ongoing clinical trials in man. The query genes/proteins GAS7 (including it's drosophila homologue MLL) and TMCO1 are presented in red. Known glaucoma disease genes are given in blue. Blank genes/molecules are generated by the knowledge database to construct a functional network under the criteria specified by the investigator. The diagram was generated using the function “Path Explorer”. In general, solid lines indicate a direct, experimentally verified, physical relationship between two molecules, for example a physical protein-protein interaction, or an enzym-DNA interaction, etc. Dotted lines refer to the existence of an indirect functional relationship, such as co-upregulation in cell cultures under specific experimental conditions. WDR36 = WD Repeat-containing protein 36; OPTN = optineurin; MYOC = myocilin; GAS7 = growth arrest-specific 7; MLL = myeloid/lymphoid or mixed-lineage leukemia; TMCO1 = transmembrane and coiled-coil domains 1; CAV1 = caveolin 1; TGFB1 = transforming growth factor beta 1; CTNNB1 = catenin (cadherin-associated protein) beta 1; RHOA = ras homolog gene family, member A; E2F6 = E2F transcription factor 6; VHL = von Hippel-Lindau; HTT = huntingtin; NOS2 = nitric oxide synthase 2; LOXL1 = lysyl oxidase-like 1; APOE = apolipoprotein E; APP = amyloid beta (A4) precursor protein; CLU = clusterin. As shown, GAS7 (MLL) and TMCO1 interact multiple times and in several ways with previously known glaucoma disease genes. For a specific description of these interactions, see text.</p

Expression levels of GAS7 and TMCO1 in human ocular tissues.

<p>Quantitative determination of <i>GAS7</i> and <i>TMCO1</i> mRNA expression levels in human ocular tissues by using real-time PCR technology (n = 4). The expression levels were normalized against GAPDH and the results are expressed as copynumber/µg RNA. Co, cornea; Tr, trabecular meshwork; Ir, iris; Le, lens; Ci, ciliary body; Re, retina; Ch, choroid; La, lamina cribrosa; Op, optic nerve.</p

Characteristics of the discovery cohorts.

<p>IOP = intraocular pressure; SD = standard deviation; RS = Rotterdam Study; ERF = Erasmus Rucphen Family study.</p

Results of the replication analyses and the joint analysis of discovery and replication cohorts.

<p>DCCT/EDIC = Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications study; WTCCC2/BMES = Wellcome Trust Case-Control Consortium 2 / Blue Mountains Eye Study; SNP = single nucleotide polymorphism; MAF = minor allele frequency; SE = standard error;</p>*<p>Column indicates whether the SNP has been genotyped (G), imputed (I), or partly (P) genotyped, i.e. genotyped in 2/3 of the participants.</p