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Start small, think big: Growth monitoring, genetic analysis, treatment and quality of life in children with growth disorders
Stalman, S.E.
Publication date 2016 Document Version Final published version
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Citation for published version (APA): Stalman, S. E. (2016). Start small, think big: Growth monitoring, genetic analysis, treatment and quality of life in children with growth disorders.
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Download date:02 Oct 2021 Supplemental Materials (Chapter 5)
Supplemental Materials (Chapter 5)
Supplemental Table 1. Genes Known to be Aberrantly Methylated in Low Birthweight Newborns Gene Chromosome Imprinted Association with low birth weight Reference AGR2 7p21.3 Decrease in DNA methylation in FGR-arteries [1] ALDH3B2 11q13 Decreased methylation associated with SGA or FGR [2] ANKRD11 16q24.3 Possibly imprinted gene, associated with 16q24.3 microdele- [3-5] tion, KBG syndrome and hypermethylation of CpG island near ANKRD11 in Silver-Russel syndrome ANXA2R 5p12 Hypomethylated in fetal growth restriction [6] APBA2 15q11-q12 Hypermethylated in small for gestational age placentas [2] APOL1 22q13.1 Hypomethylated in fetal growth restriction [6] ARID5B 10q21.2 Differential methylation associated with decreased birth weight [7] ATL2 2p22.3 Hypermethylated in fetal growth restriction [6] BRCA1 17q21 Hypermethylation described in fetal growth restriction [6] C6orf211 6q25.1 Hypermethylation described in fetal growth restriction [6] CCDC86 11q12.2 Differentially expressed in growth restricted and non-growth [8] restricted placentas CDKAL1 6p22.3 Differentially expressed in growth restricted and non-growth [8] restricted placentas CDKN1C 11p15.5 Yes Highly expressed in placenta, associated with fetal growth [9-12] restriction; Upregulation associated with FGR placentas, loss of function associated with Beckwith-Wiedemann syndrome, gain of function with Silver-Russel syndrome CHML 1q43 Increased methylation associated with SGA or FGR [2] CSTA 3q21 Decreased methylation associated with SGA or FGR [2] DBP 19q13.3 Increased methylation associated with SGA or FGR [6] DHCR24 1p32.3 Differential expressed in growth restricted and non- growth [8] restricted placentas DLK1 14q32 Yes Highly expressed in placenta; associated with pre- and postnatal [10, 13] growth restriction and UPD14 DNAAF1 16q24.1 Increased methylation associated with SGA or FGR [6]
DNAJB4 1p31.1 Decreased methylation associated with SGA or FGR [2] DSTN 20p12.1 Increased methylation associated with SGA or FGR [6] FGF14 13q34 Decreased methylation associated with SGA or FGR [2] FOXP1 3p14.1 Hypermethylated in fetal growth restriction [6] GGPS1 1q43 Decreased methylation associated with SGA or FGR [2] GIMAP2 7q36.1 Decreased methylation associated with SGA or FGR [2] GNAS 20q13.3 Yes Decreased expression observed in FGR placentas [14] GNASAS 20q13.32 Yes Loss of methylation in FGR patients [15]
Supplemental Materials (Chapter 5) 189 Supplemental Table 1. Genes Known to be Aberrantly Methylated in Low Birthweight Newborns (continued) Gene Chromosome Imprinted Association with low birth weight Reference GPR4 19q13.3 Decreased methylation associated with SGA or FGR [2] GRB10 7p12.2 Yes Highly expressed in placenta, implicated in Silver-Russell [10, 15] syndrome, loss of methylation in FGR patients GYS2 12p12.2 Decreased methylation associated with SGA or FGR [2] H19 11p15.5 Yes Highly expressed in the placenta. ICR1 hypomethylation in FGR [3, 9, 10, 15] samples, hypomethylation and copy number variant in Silver- Russell syndrome HIST1H3I 6p22.1 Increased methylation associated with SGA or FGR [6] HIST1H4J 6p22.1 Increased methylation associated with SGA or FGR [6] HIST1H4L 6p22.1 Increased methylation associated with SGA or FGR [6] HNRNPH3 10q22 Increased methylation associated with SGA or FGR [6] HOXB4 17q21.32 Increased methylation associated with SGA or FGR [6] HSD11B2 16q22 Site-specific methylation of placental HSD11B2 gene promoter, [16] hypermethylated in FGR HSD11B1 1q32-q41 Hypomethylated HSD11B1 in LGA infants [17] HSDL1 16q23.3 Increased methylation associated with SGA or FGR [6] HSPBAP1 3q21.1 Increased methylation associated with SGA or FGR [15] IGF2 11p15.5 Yes Highly expressed in placenta; hypomethylation of H19/IGF2 [9, 10, 18, 19] control region is associated with FGR IGF2AS 11p15.5 Yes Expressed in antisense to IGF2 (geneimprint. com) IGF2R 6q26 Yes Highly expressed in placenta; hypomethylated in FGR [10, 15] IGFBP3 7p12.3 Significant differences in promoter methylation rate of IGFBP3 [20] between FGR and AGA newborns IL27RA 19p13.11 Increased methylation associated with SGA or FGR [6] ILK2 11p15.4 Differential expression between growth restricted and non- [8] restricted placentas INS 11p15.5 Yes Imprinted gene on 11p15.5 region. (geneimprint. com) INS-IGF2 11p15.5 Yes Imprinted gene on 11p15.5 region; involved in growth and (geneimprint. metabolism. com)[21] JARID2 6p24-p23 Increased methylation associated with SGA or FGR [6] KCNQ1 11p15.5 Yes Upregulated in FGR samples; genetic variants associated with [9, 22] Beckwith-Wiedemann KCNQ1OT1 11p15 Yes Loss of methylation in FGR patients [15] KLF9 9q13 Differential methylation associated with decreased birth weight [7] KLHL5 4p14 Decreased methylation associated with SGA or FGR [2] LEP 7q31.3 DNA methylation levels in SGA group were not sign. different [21] from AGA group LRRC41 1p34.1 Increased methylation associated with SGA or FGR [6] MACROD2 20p12.2 Decreased methylation associated with SGA or FGR [6]
190 Supplements Supplemental Table 1. Genes Known to be Aberrantly Methylated in Low Birthweight Newborns (continued) Gene Chromosome Imprinted Association with low birth weight Reference MEG3 14q32 Yes Highly expressed in placenta, reduced expression in FGR [10, 14] placentas. MEP1A 6p12-p11 Increased methylation associated with SGA or FGR [2] MEST 7q32 Yes Highly expressed in placenta, implicated in Silver-Russell [10] syndrome MFAP1 15q15.3 Decreased methylation associated with SGA or FGR [2] MRPL36 5p15.3 Decreased methylation associated with SGA or FGR [6]
NBR2 17q21 Increased methylation associated with SGA or FGR [6] NCOA4 10q11.2 Decreased methylation associated with SGA or FGR [2] NDUFS6 5p15.33 decreased methylation associated with SGA or FGR [6] NFKBIZ 3p12-q12 Decreased methylation associated with SGA or FGR [2] NNAT 20q11.2-q12 Yes Hypermethylation in placenta associated with FGR [8] NOS3 7q36 Decrease in DNA methylation in FGR-arteries and increase in [1] FGR-veins NPR3 5p13.3 Hypermethylation described in fetal growth restricted umbilical [6] cord blood. NR3C1 5q31.3 Methylation status of glucocorticoid receptor gene (NR3C1) in [23] placenta correlates with birthweight. NSD1 5q35 Loss of function associated with overgrowth (Sotos syndrome) [24] OAT 10q26 Decreased methylation associated with SGA or FGR [2] OMG 17q11.2 Increased methylation associated with SGA or FGR [2] PBLD 10q21.3 Increased methylation associated with SGA or FGR [6] PDC 1q25.2 Increased methylation associated with SGA or FGR [2] PEG10 7q21.3 Yes Imprinted gene highly expressed in the placenta. Differential ex- [8, 10, 15] pression between growth restricted and non-restricted placentas PEG3 19q13.4 Yes Imprinted gene highly expressed in the placenta. Loss of meth- [10, 15] ylation in FGR patients. PHF21B 22q13.31 Increased methylation associated with SGA or FGR [6] PHLDA2 11p15.4 Yes Highly expressed in placenta. Differential expression between [8-10, 25, 26] growth restricted and non-restricted placentas PIAS3 1q21 Increased methylation associated with SGA or FGR [6] PIK3CG 7q22.3 Increased methylation associated with SGA or FGR [6] PLAGL1 6q24-q25 Yes Highly expressed in placenta. Differential expression between [8, 10, 27] growth restricted and non-restricted placentas. PNPLA3 22q13.31 Increased methylation associated with SGA or FGR [6] QDPR 4p15.31 Increased methylation associated with SGA or FGR [6] RAD50 5q31.3 Increased methylation associated with SGA or FGR [6] RIOK3 18q11.2 Increased methylation associated with SGA or FGR [6] RIT1 1q22 Increased methylation associated with SGA or FGR [6] RMND1 6q25.1 Increased methylation associated with SGA or FGR [6]
Supplemental Materials (Chapter 5) 191 Supplemental Table 1. Genes Known to be Aberrantly Methylated in Low Birthweight Newborns (continued) Gene Chromosome Imprinted Association with low birth weight Reference RPA1 17p13.3 Increased methylation associated with SGA or FGR [6] RPE65 1p31 Increased methylation associated with SGA or FGR [2] RPL14 3p22-p21.2 Increased methylation associated with SGA or FGR [6] RPL17 18q21 Increased methylation associated with SGA or FGR [6] RTL1 14q32.2 Yes Imprinted gene associated with UPD14 phenotypes [28] RTN4 2p16.3 Increased methylation associated with SGA or FGR [6] RUFY1 5q35.3 Increased methylation associated with SGA or FGR [6] SEC1P 19q13.33 Increased methylation associated with SGA or FGR [6] SEPT7 7p14.2 Increased methylation associated with SGA or FGR [6] SERPINA5 14q32.1 Increased methylation associated with SGA or FGR [2] SHC1 1q21 DNA methylation of the p66Shc promoter is decreased in [29] placental tissue from women delivering intrauterine growth restricted neonates SHMT2 12q12-q14 Increased methylation associated with SGA or FGR [6] SLC25A18 11p15.5 Yes Increased methylation associated with SGA or FGR [2] SMYD4 17p13.3 Increased methylation associated with SGA or FGR [6] SNORD58A 18q21 Increased methylation associated with SGA or FGR [6] SPEF1 20p13 Decreased methylation associated with SGA or FGR [2] TAF5 10q24-q25.2 Increased methylation associated with SGA or FGR [6] TAL1 1p32 Increased methylation associated with SGA or FGR [6] TBX15 1p11.1 Promotor hypomethylation leads to TBX15 decrease in FGR [30] placentas TMOD2 15q21.2 Increased methylation associated with SGA or FGR [6] TRPS1 8q24.12 Increased methylation associated with SGA or FGR [6] UQCRH 1p34.1 Increased methylation associated with SGA or FGR [6] WNT2 7q31.2 WNT2 promoter methylation in placenta is associated with low [31] birthweight ZIC1 3q24 Predicted Decreased methylation associated with SGA or FGR [6] ZMIZ1 10q22.3 Increased methylation associated with SGA or FGR [6] ZNF141 4p16.3 Decreased methylation associated with SGA or FGR [6] ZNF331 19q13.42 Differential expression between growth restricted and non- [8] restricted placentas
192 Supplements Supplemental Figure 1. Clustering of Male and Female Samples
Component 2 (7.1%) Component
20 20 0 20 40 60 - Principal 40 40 - 60 60 -
-100 0 100 200 300 Principal Component 1 (16.5%)
Supplemental Materials (Chapter 5) 193 Supplemental Table 2. Genes Known to be Involved in (Regulation of ) DNA-Methylation Gene Chromosome Role in regulation of DNA-methylation Reference AICDA 12p13 May play a role in epigenetic regulation of gene expression by uniprot.org participating in DNA demethylation ALKBH1 14q24.3 Role in DNA demethylation uniprot.org ALKBH2 12q24.11 Dioxygenase that repairs alkylated DNA containing 1-methyladenine uniprot.org and 3-methylcytosine by oxidative demethylation ALKBH3 11p11.2 Dioxygenase that repairs alkylated DNA containing 1-methyladenine uniprot.org (1meA) and 3-methylcytosine (3meC) by oxidative demethylation APEX1 14q11.2 May play a role in epigenetic regulation of gene expression by uniprot.org participating in DNA demethylation APOBEC1 12p13.1 May play a role in epigenetic regulation of gene expression by uniprot.org participating in DNA demethylation APOBEC2 6p21 May a role in epigenetic regulation of gene expression through the uniprot.org process of active DNA demethylation APOBEC3A 22q13.1-q13.2 Role in epigenetic regulation of gene expression through the process of uniprot.org active DNA demethylation APOBEC3C 22q13.1 Role in epigenetic regulation of gene expression through the process of uniprot.org active DNA demethylation APOBEC3F 22q13.1 Role in epigenetic regulation of gene expression through the process of uniprot.org active DNA demethylation ASZ1 7q31.2 Role in DNA methylation involved in gamete generation uniprot.org ATF7IP 12p13.1 Required to stimulate histone methyltransferase activity and facilitates uniprot.org conversion of dimethylated to trimethylated H3 ‘Lys-9’. Represses transcription and couples DNA methylation and histone H3 ‘Lys-9’ trimethylation ATRX Xq21.1 Role in DNA methylation uniprot.org BAZ2A 12q13.3 Mediates silencing of rDNA by recruiting histone-modifying enzymes uniprot.org and DNA methyltransferases. BEND3 6q21 Role in DNA methylation uniprot.org BRCA1 17q21 Regulator of DNA-methylation uniprot.org CTCF 16q22.1 Involved in epigenetic regulation uniprot.org
CTCFL 20q13.31 Involved in gene imprinting in male germline, by participating in the uniprot.org establishment of differential methylation at the IGF2/H19 imprinted control region DMAP1 1p34 DNA methyltransferase 1-associated protein 1. Involved in transcription uniprot.org repression and activation. DNMT1 19p13.2 Methylates CpG residues, essential for epigenetic inheritance. uniprot.org Responsible for maintaining methylation patterns established in development. DNMT3A 2p23 Required for genome-wide de novo methylation and essential for the uniprot.org establishment of DNA methylation patterns during development DNMT3B 20q11.2 Required for genome-wide de novo methylation and essential for uniprot.org establishing DNA methylation patterns during development
194 Supplements Supplemental Table 2. Genes Known to be Involved in (Regulation of ) DNA-Methylation (continued) Gene Chromosome Role in regulation of DNA-methylation Reference DNMT3L 21q22.3 Catalytically inactive regulatory factor of DNA methyltransferases; uniprot.org essential for functioning of DNMT3A and DNMT3B DPPA3 12p13.31 Primordial germ cell (PGCs)-specific protein involved in epigenetic uniprot.org chromatin reprogramming in the zygote following fertilization EHMT1 9q34.3 Histone methyltransferase that specifically mono- and dimethylates uniprot.org ‘Lys-9’ of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin EHMT2 6p21.31 Histone methyltransferase that specifically mono- and dimethylates uniprot.org ‘Lys-9’ of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin EZH2 7q35-q36 Histone-lysine N-methyltransferase EZH2 (EC 2.1.1.43) (ENX-1) uniprot.org (Enhancer of zeste homolog 2) (Lysine N-methyltransferase 6) FKBP6 7q11.23 Role in DNA methylation involved in gamete generation uniprot.org FOS 14q24.3 Fos may transform cells through alterations in DNA methylation uniprot.org FTO 16q12.2 Dioxygenase repairing alkylated DNA and RNA by oxidative uniprot.org demethylation GATA3 10p15 Regulation of histone H3-K27 and H3-K4 methylation ensembl.org GATAD2A 19p13.11 Role in DNA methylation uniprot.org GATAD2B 1q21.3 Role in DNA methylation uniprot.org GNAS 20q13.3 Role in DNA methylation uniprot.org GRHL2 8q22.3 Inhibits DNA methylation, possibly by interfering with DNMT1 enzyme uniprot.org activity H1FOO 3q22.1 May play a role in the control of gene expression during oogenesis and uniprot.org early embryogenesis, presumably through perturbation of chromatin structure H3F3A; 1q42.12; Role in DNA methylation on cytosine. Deposited at sites of nucleosomal uniprot.org H3F3B 17q25.1 displacement throughout transcribed genes, suggesting that it represents an epigenetic imprint of transcriptionally active chromatin HELLS 10q24.2 Required for de novo or maintenance of DNA methylation; may control uniprot.org silencing of CDKN1C gene through DNA methylation HEMK1 3p21.3 N5-glutamine methyltransferase responsible for methylation of the uniprot.org GGQ triplet of the mitochondrial translation release factor MTRF1L HIST1H3A; 6p22.1-2 Role in DNA methylation on cytosine uniprot.org HIST1H3B; HIST1H3C; HIST1H3D; HIST1H3E; HIST1H3F; HIST1H3G; HIST1H3H; HIST1H3I; HIST1H3J
Supplemental Materials (Chapter 5) 195 Supplemental Table 2. Genes Known to be Involved in (Regulation of ) DNA-Methylation (continued) Gene Chromosome Role in regulation of DNA-methylation Reference HIST1H4A; 6p22.1-2 Role in DNA methylation on cytosine uniprot.org HIST1H4B; HIST1H4C; HIST1H4D; HIST1H4E; HIST1H4F; HIST1H4H; HIST1H4I; HIST1H4J; HIST1H4K; HIST1H4L HIST2H4A; 1q21 Role in DNA methylation on cytosine uniprot.org HIST2H4B HIST4H4 12p12.3 Role in DNA methylation on cytosine uniprot.org HIST2H3A; 1q21.2 Role in DNA methylation on cytosine uniprot.org HIST2H3C; HIST2H3D KDM1B 6p22.3 Required for de novo DNA methylation of a subset of imprinted genes uniprot.org during oogenesis KHDC3L 6q13 Possible regulator of genomic imprinting in the human oocyte [32] KMT2A 11q23 Histone methyltransferase that plays an essential role in early uniprot.org development and hematopoiesis KMT2E 7q22.1 Histone methyltransferase that specifically mono- and dimethylates uniprot.org ‘Lys-4’ of histone H3 (H3K4me1 and H3K4me2) MAEL 1q24.1 Role in DNA methylation involved in gamete generation uniprot.org MBD1 18q21 Transcriptional repressor that binds CpG islands in promoters uniprot.org where the DNA is methylated at position 5 of cytosine within CpG dinucleotides MBD3 19p13.3 Transcriptional repressor, plays a role in gene silencing. Binds to DNA uniprot.org with a preference for sites containing methylated CpG dinucleotides. Recruits histone deacetylases and DNA methyltransferases MECP2 Xq28 Chromosomal protein that binds to methylated DNA uniprot.org MGMT 10q26 O6-Methylguanine-DNA methyltransferase, DNA methyltransferase, uniprot.org, known to have significant fetal effects [33] MIS18A 21q22.11 Regulator of DNA methylation uniprot.org MPHOSPH8 13q12.11 Key epigenetic regulator by bridging DNA methylation and chromatin uniprot.org modification MTA2 11q12-q13.1 May be involved in the regulation of gene expression as repressor and uniprot.org activator. The repression might be related to covalent modification of histone proteins MTRR 5p15.31 Necessary for utilization of methyl groups from the folate cycle, thereby uniprot.org affecting transgenerational epigenetic inheritance NLRP2 19q13.42 Mutation NLRP2 associated with familial imprinting disorder [34] NLRP5 19q13.43 Mutations associated with multilocus imprinting disorders [35]
196 Supplements Supplemental Table 2. Genes Known to be Involved in (Regulation of ) DNA-Methylation (continued) Gene Chromosome Role in regulation of DNA-methylation Reference NLRP7 19q13.42 Mutations associated with multilocus inprinting disorders and [35] intrauterine growth retardation PICK1 22q13.1 Role in DNA methylation involved in embryo development and gamete uniprot.org generation PIWIL2 8p21.3 Acts via the piRNA metabolic process, acts upstream of known uniprot.org mediators of DNA methylation. PIWIL4 11q21 Acts via the piRNA metabolic process, acts upstream of known uniprot.org mediators of DNA methylation. PLD6 17p11.2 piRNA-mediated transposon silencing is critical for maintaining uniprot.org genome stability, in particular in germline cells when transposons are mobilized as a consequence of wide-spread genomic demethylation PRDM14 8q13.3 May play an essential role in germ cell development by epigenetic uniprot.org reprogramming PRMT5 14q11.2 Arginine methyltransferase, mediates methylation required for the uniprot.org assembly and biogenesis of snRNP core particles PRMT7 16q22.1 Plays a role in gene imprinting by being recruited by CTCFL at the uniprot.org H19 imprinted control region and methylating histone H4 to form H4R3me2s, possibly leading to recruit DNA methyltransferases at these sites SMCHD1 18p11.32 Required for maintenance of X inactivation in females and uniprot.org hypermethylation of CpG islands associated with inactive X. Involved in a pathway that mediates the methylation of a subset of CpG islands slowly and requires the de novo methyltransferase DNMT3B TDG 12q24.1 DNA glycosylase that plays a key role in active DNA demethylation uniprot.org TDRD1 10q25.3 Role in DNA methylation involved in gamete generation uniprot.org TDRD12 19q13.11 Acts via the piRNA metabolic process, which mediates the repression uniprot.org of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. TDRD5 1q25.2 Probably acts via the piRNA metabolic process, which mediates the uniprot.org repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons TDRD9 14q32.33 Acts via the piRNA metabolic process, which mediates the repression uniprot.org of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons TDRKH 1q21 The piRNA metabolic process mediates the repression of transposable uniprot.org elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons TET1 10q21 Dioxygenase that catalyzes the conversion of the modified genomic uniprot.org base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation
Supplemental Materials (Chapter 5) 197 Supplemental Table 2. Genes Known to be Involved in (Regulation of ) DNA-Methylation (continued) Gene Chromosome Role in regulation of DNA-methylation Reference TET2 4q24 Dioxygenase that catalyzes the conversion of the modified genomic uniprot.org base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation TET3 2p13.1 Dioxygenase that catalyzes the conversion of the modified genomic uniprot.org base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming in the zygote following fertilization TRIM28 19q13.4 Role in DNA methylation involved in embryo development and negative uniprot.org regulation of DNA demethylation. UHRF1 19p13.3 Key epigenetic regulator by bridging DNA methylation and chromatin uniprot.org modification UHRF2 9p24.1 Through cooperative DNA and histone binding, may contribute to a uniprot.org tighter epigenetic control of gene expression in differentiated cells USP7 16p13.3 Involved in maintenance of DNA methylation via its interaction with uniprot.org UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1 ZFP57 6p22.1 Transcription regulator required to maintain maternal and paternal uniprot.org, gene imprinting, including DNA methylation. Acts by controlling DNA [36] methylation during the earliest multicellular stages of development at multiple imprinting control regions
198 Supplements Supplemental Table 3. Genes in which Sequence Variants are Associated with a Low Birthweight Gene Chromosome Disorder Inheritance Reference ACAN 15q26.1 Spondyloepimetaphy-al dysplasia aggrecan type; AR; AD [37, 38] Spondyloepiphyseal dysplasia type Kimberley ADA 20q13.12 Dwarfism - immunodeficiency type 1 AR [39]
ADAMTS10 19p13.2 Weill–Marchesani syndrome AR [40] ADCY5 3q21.1 Associated with fetal growth and birthweight [41] ALG12 22q13.33 Congenital disorder of glycosylation type 1g AR [39]
ALMS1 2p13 Almström syndrome AR [42] ANKRD11 16q24.3 KBG syndrome AD [39] ARID1A 1p35.3 Coffin–Siris syndrome AD [43] ARID1B 6q25.1 Coffin–Siris syndrome AD [43] ALB4 1 Defective nonhomologous endjoining DNA damage AR [44] repair ATP6VOA2 12q24.31 Cutis laxa type IIA AR [39]
PAPSS2 10q24 Spondyloepimetaphyseal dysplasia type Pakistan AR [39]
ATR 3q23 Seckel syndrome AR [45] ATRIP 3p21.31 Seckel syndrome AR [45] ATRX Xq21.1 X-linked intellectual disability - hypotonic facies XLR [46] syndrome AUTS2 7q11.22 Chromosome 7q11.22 microdeletion Microdeletion [39]
B3GALTL 13 Peters’ plus syndrome AR [39] BCS1L 2q33 Gracile bone syndrome AR [39] BLM 15q26.1 Bloom syndrome AR [39] BMP2 20p12 Brachydactyly A2 AD [47]
BMPR1B 4q22-q24 Brachydactyly A1 AD [48] BRAF 7q34 Noonan syndrome; LEOPARD syndrome AD [49] BSND 1p32.1 Bartter syndrome AR [39]
BTK Xq21.33-q22 Isolated GHD type III XLR [50, 51] MPLKIP 7p14.1 Trichothiodystrophy AR [39] CALY 10q26.3 Chromosome 10q26 microdeletion Microdeletion [3]
CBL 11q23.3 Noonan-like syndrome AD [39] CCDC8 19q13.32 Three-M syndrome AR [39, 52]
Supplemental Materials (Chapter 5) 199 Supplemental Table 3. Genes in which Sequence Variants are Associated with a Low Birthweight (continued) Gene Chromosome Disorder Inheritance Reference CCNL1 3q25.31 Associated with fetal growth and birthweight [41] CDC6 17q21.3 Meier-Gorlin syndrome AR [53] CDKN1C 11p15.5 Silver–Russell syndrome; IMAGe syndrome AD (IMAGe) [54-56] CDT1 16q24.3 Meier-Gorlin syndrome AR [53] CENPE 4q24-q25 Microcephalic primordial dwarfism AR [39] CENPJ 13q12.12 Seckel syndrome AR [57] CEP152 15q21.1 Seckel syndrome AR [58] CEP63 3q22.2 Seckel syndrome AR [59] CERS3 15q26.3 Chromosome 15q26.3 microdeletion Microdeletion [39] CHD7 8q12.2 CHARGE syndrome AD [39, 60, 61] CLCNKA 1p36 Bartter syndrome AR [39] CLCNKB 1p36 Bartter syndrome AR [39] CNTN4 3p26.3 Chromosome 3p26 microdeletion Microdeletion [39] COG1 17q25.1 Cerebro-costo-mandibular-like syndrome AR [39] COL10A1 6q21-q22 Metaphyseal chondro-dysplasia Schmid type AD [62] COL1A1 17q21.33 Osteogenesis imperfecta AD [39] COL2A1 12q13.11 Spondylo-Epiphyseal Dysplasia Congenita; AD [63, 39] Hypochondrogenesis; Achondrogenesis type 2. COL4A5 Xq22 Alport syndrome XLR [39] COL9A1 6q13 Multiple epiphyseal dysplasia AD [64] COL9A2 1p33-p32 Multiple epiphyseal dysplasia AD [64] COL9A3 20q13.3 Multiple epiphyseal dysplasia 3 AD [64] COMP 19p13.1 Multiple epiphyseal dysplasia AD [64] CREBBP 16p13.3 Rubinstein–Taybi syndrome 1 AD [65] CRIPT 2p21 Short stature with microcephaly and distinctive AR [66] facies CTC1 17p13.1 Revesz syndrome (Coats plus syndrome) AR [39] CNTNAP2 7q35 Pitt-Hopkins-like syndrome AR [39] CUL4B Xq23 Intellectual disability, X-linked, syndromic 15 XLR [39] (Cabezas type) CUL7 6p21.1 Three-M syndrome AR [39] CYP19A1 15q21.1 Estrogen deficiency (tall stature) AR [24] DKC1 Xq28 Hoyeraal-Hreidarsson syndrome AR [39] DNA2 10q21.3-q22.1 Seckel syndrome AR [59] DNAJC19 3q26.33 Barth-like syndrome, Canadian Hutterite type AR [39] DUOX2 15q15.3 Thyroid dyshormonogenesis AR [24] EMG1 12p13.3 Bowen-Conradi syndrome AR [39] EP300 22q13.2 Rubinstein-Taybi syndrome AD [65]
200 Supplements Supplemental Table 3. Genes in which Sequence Variants are Associated with a Low Birthweight (continued) Gene Chromosome Disorder Inheritance Reference ERCC3 2q21 Xeroderma pigmentosum, group B/Cockayne AR [65] syndrome ERCC4 16p13.12 Xeroderma pigmentosum, type F/Cockayne AR [65] syndrome ERCC5 13q33 Xeroderma pigmentosum, group G/Cockayne AR [65] syndrome ERCC6 10q11.23 Cockayne syndrome type B AR [65] ERCC8 5q12.1 Cockayne syndrome type A AR [65] ESR1 6q25.1 Estrogen resistance (tall stature) AR [24] FAM111A 11q12.1 Kenny–Caffey syndrome AD [68] COX20 1q44 Chromosome 1q44 microdeletion Microdeletion [39] FANCA 16q24.3 Fanconi anemia AR [69] FBN1 15q21.1 Acromicric dysplasia; Geleophysic dysplasia-2; AD; AD; AR [40, 70, 71] Weill–Marchesani syndrome FEZF2 3p14.2 Chromosome 3p14.3 microdeletion Microdeletion [39] FGD1 Xp11.21 Aarskog–Scott syndrome (faciogenital dysplasia) XLR [72] FGF8 10q24 Pallister–Hall syndrome AR [73, 74] FGFR1 8p11.23-p11.22 Pallister–Hall syndrome; Pfeiffer syndrome AD [76] (acrocephalosyndactyly type V) FGFR2 10q26 Pfeiffer syndrome (acrocephalosyndactyly type V) AD [75] FGFR3 4p16.3 Thanatophoric dysplasia type I; Achondroplasia; AD [39, 77-79] Hypochondroplasia
FMR1 Xq27.3 Chromosome Xq27.3q28 microduplication Microduplication [39] FOXE1 9q22 Thyroid dysgenesis AD, AR [24] GDF5 20q11.2 Brachydactyly A1, A2, C AD [47, 48, 80] GH1 17q24.2 Isolated GHD, type 1A; IB; II; Kowarski syndrome AR; AR; AD; AD [50, 81] GHR 5p13-p12 Laron syndrome AR (AD) [82-84] GHRHR 7p14 Isolated GHD, type IB AR [50, 81] GHSR 3q26.31 Isolated partial GHD AR, AD [85, 86] GINS2 16q24.1 Chromosome 16q24 microduplication Microduplication [39] GLB1 3p21.33 Generalised gangliosidosis type 1 AR [39] GLI2 2q14 Holoprosencephaly AD [87, 88] GLI3 7p13 Pallister-Hall syndrome AD [39, 88] GNAS 20q13.3 Albright hereditary osteodystrophy Imprinted [89] GNPTAB 12q23.2 Mucolipidosis II alpha/beta (I-cell disease) AR [39] H19 11p15.5 Associated with high birth weight Imprinted [90, 91] HDAC8 Xq13 Cornelia de Lange syndrome XLR [39]
Supplemental Materials (Chapter 5) 201 Supplemental Table 3. Genes in which Sequence Variants are Associated with a Low Birthweight (continued) Gene Chromosome Disorder Inheritance Reference HESX1 3p14.3 Septo-optic dysplasia ( Combined pituitary hormone AR, AD [74, 87, 88] deficiency 5) HMGA2 12q15 Pallister-Hall syndrome AD [50, 92] HNRNPU 1q44 Chromosome 1q44 microdeletion Microdeletion [39] HOXD 2q31.1 Chromosome 2q31 microdeletion Microdeletion [39] HRAS 11p15.5 Costello syndrome AD [49] IDUA 4p16.3 Hurler syndrome AR [93] IFT172 2p23.3 Almstrom syndrome AR [94] IGF1 12q23.2 IGF1 deficiency AR [95] IGF1R 15q26.3 Resistance to insulin-like growth factor 1 AD, AR [39, 96] IGF2 11p15.5 Severe growth restriction with distinctive facies Paternal [97] IGF2R 6q26 Associated with high birth weight [90, 98] IGFALS 16p13.3 ALS deficiency AR [99] IGSF1 Xq25 IGSF1 deficiency syndrome XLR [100]
IHH 2q33-q35 Acrocapitofemoral dysplasia AR [101] IKBKB 8p11.2 Immunodeficiency 15 AR, AD [102] IL2RG Xq13.1 X-linked severe combined immunodeficiency XLR [103, 104] INPPL1 11q13 Opsismodysplasia AR [39] INSR 19p13.3-p13.2 Donohue syndrome AR [39] ITSN1 21q22.1-q22.2 Chromosome 21q22.11 microdeletion Microdeletion [39]
IYD 6q25.1 Thyroid dyshormonogenesis AR [24] KANSL1 17q21.31 Chromosome 17q21.31 microdeletion Microdeletion [39]
KCNJ11 11p15.1 Transient neonatal diabetes mellitus type 3 AD [39] KDM6A Xp11.2 Kabuki syndrome AD [105] GSE1 16q24.1 Chromosome 16q24 microduplication Microduplication [39] KMT2A 11q23 Wiedemann-Steiner syndrome AD [39] KMT2D 12q13.12 Kabuki syndrome 1 AD [105] KRAS 12p12.1 Noonan syndrome AD [49, 106, 107] LEKR1 3q25.31 Associated with high birth weight [41] LEMD3 12q14 Chromosome 12q14 microdeletion Microdeletion [39] LHX3 9q34.3 Combined pituitary hormone deficiency 3 AR [87, 88, 108] LHX4 1q25.2 Combined pituitary hormone deficiency 4 AD, AR [87, 88, 108] LIG4 13q33-q34 Defective nonhomologous endjoining DNA damage AR [109] repair LIS1 17p13.3 Miller-Dieker lissencephaly syndrome Microdeletion [39]
202 Supplements Supplemental Table 3. Genes in which Sequence Variants are Associated with a Low Birthweight (continued) Gene Chromosome Disorder Inheritance Reference LMNA 1q22 Hutchinson–Gilford progeria syndrome AD [110] MATN3 2p24-p23 Multiple epiphyseal dysplasia AD [111] MC2R 18p11.2 Familial glucocorticoid deficiency (tall stature) AR [24] MCM4 8q11.2 Natural killer cell and glucocorticoid deficiency with AR [112, 113] DNA repair defect MCM9 6q22.31 Ovarian dysgenesis 4 AR [114] MCPH1 8p23.1 Primary microcephaly 1 AR [39]
MECP2 Xq28 Rett syndrome XLD [115] MEF2C 5q14.3 Chromosome 5q14.3 microdeletion Microdeletion [39]
NBS1 8q21 Nijmegen breakage syndrome AR [116] NF1 17q11.2 Neurofibromatosis-Noonan syndrome; AD; AD [49, 117] Neurofibromatosis type I NHEJ1 2q35 Defective non-homologous endjoining (NHEJ) DNA AR [44, 118] damage repair NIN 14q22.1 Seckel syndrome AR [119] NIPBL 5p13.2 Cornelia de Lange syndrome AD [120] NKX2-1 14q13 Thyroid dysgenesis AD [24] NKX2-5 5q34 Thyroid dysgenesis AD [24] NPR2 9p21-p12 Acromesomelic dysplasia, Maroteaux type, (Dis) AR; AD [121, 122] proportionate short stature NRAS 1p13.2 Noonan syndrome AD [123] NRXN1 2p16.3 Pitt-Hopkins-like syndrome AR [39] NSUN2 5p15.31 Dubowitz-like syndrome AR [39]
OBSL1 2q35 Three-M syndrome AR [52] ORC1 1p32 Meier–Gorlin syndrome 1 AR [39, 53]
ORC4 2q22-q23 Meier–Gorlin syndrome AR [53] ORC6 16q12 Meier–Gorlin syndrome AR [53] OTX2 14q22.3 Combined pituitary hormone deficiency 6 AD [74, 87, 88] PAPPA2 1q25.2 ALS deficiency AR [124] PAPSS2 10q24 Brachyolmia type 4 with mild epiphyseal and AR [125, 126] metaphyseal changes (spondyloepimetaphyseal dysplasia, Pakistani type) PAX6 11p13 Chromosome 11p13 microduplication Microduplication [39] PAX8 2q13 Thyroid dysgenesis AD, AR [24] PCNA 20pter-p12 Hypomorphic PCNA mutation AR [127]
Supplemental Materials (Chapter 5) 203 Supplemental Table 3. Genes in which Sequence Variants are Associated with a Low Birthweight (continued) Gene Chromosome Disorder Inheritance Reference PCNT 21q22.3 Seckel Syndrome 4 AR [88, 128, 129] PIK3R1 5q13.1 SHORT syndrome AD [130] PITX2 4q25 Axenfeld–Rieger syndrome AD [87] PKD2 4q22.1 Chromosome 4q21 microdeletion Microdeletion [39] PLK4 4q28 Microcephaly and chorioretinopathy 2 AR [131] PLOD3 7q22 Ehlers-Danlos syndrome AR [39]
POC1A 3p21.2 Primordial dwarfism, type Shaheen AR [39]
POLG 15q25 Alpers progressive infantile poliodystrophy AR [39]
POU1F1 3p11 Combined pituitary hormone deficiency 1 AR, AD [87, 88, 108] PQBP1 Xp11.23 Sutherland-Haan syndrome XLR [39]
PRKAR1A 17q24.2 Acrodysostosis AD [132] PRKDC 8q11 Defective nonhomologous endjoining DNA damage AR [44, 133] repair PROKR2 20p12.3 Pallister–Hall syndrome AD [76] PROP1 5q35.3 Combined pituitary hormone deficiency 1 AR [87, 88, 108] PTF1A 10p12.2 Neonatal diabetes mellitus (cerebellar hypoplasia) AR [39]
PTHLH 12p12.1-p11.2 Brachydactyly, type E2 AD [134] PTHR1 3p22-p21.1 Jansen type of meta-physeal chondrodys-plasia AD [135] PTPN11 12q24 Noonan syndrome 1; LEOPARD syndrome AD [136, 137] PYCR1 17q25.3 Cutis laxa AR [39] RAD21 8q24 Cornelia de Lange syndrome AD [120] RAF1 3p25 Noonan syndrome AD [136] RASGEF1B 4q21.21 Chromosome 4q21 microdeletion Microdeletion [39] RBBP8 18q11.2 Seckel syndrome AR [59] RECQL4 8q24.3 Rothmund–Thomson syndrome AR [138] RIT1 1q22 Noonan syndrome AD [139] RMRP 9p13.3 Anauxetic dysplasia AR [39]
RNPC3 1p21 Almstrom syndrome AR [140] ROR2 9q22 Robinow syndrome AR [141] RPS6KA3 Xp22.2-p22.1 Coffin–Lowry syndrome XLR [142] SLC39A13 11p11.2 Ehlers-Danlos syndrome, spondylocheiro dysplastic AR [39] form
204 Supplements Supplemental Table 3. Genes in which Sequence Variants are Associated with a Low Birthweight (continued) Gene Chromosome Disorder Inheritance Reference SEMA3E 7q21.11 CHARGE syndrome AD [60] SHOX Xp22.33;Yp11.3 Langer mesomelic dysplasia; Leri–Weill AR; AD [143, 144] dyschondrosteosis SLC17A5 6q13 Sialic acid storage disease, severe infantile type AR [39]
SLC26A2 5q32 de la Chapelle syndrome (neonatal osseous AR [39] dysplasia)
SLC26A4 7q31 Thyroid dyshormonogenesis AR [24] SLC5A5 19p13.11 Thyroid dyshormonogenesis AR [24] DHCR7 11q13.4 Smith-Lemli-Opitz syndrome AR [39]
SMAD4 18q21.1 Myhre syndrome AD [39] SMARCA2 9p22.3 Nicolaides-Baraitser syndrome AD [145] SMARCA4 19p13.2 Coffin–Siris syndrome AD [145] SMARCAL1 2q35 Immunoosseous dysplasia, Schimke type AR [146] SMARCB1 22q11.23; 22q11 Coffin–Siris syndrome AD [145] SMC1A Xp11.22-p11.21 Cornelia de Lange syndrome XLR [120] SMC3 10q25 Cornelia de Lange syndrome AD [120] SOS1 2p21 Noonan syndrome AD [107] SOX2 3q26.33 Optic nerve hypoplasia and abnormalities of the AD [74, 87] central nervous system SOX3 Xq27.1 X-linked panhypopituitarism; Isolated GHD, type III XLR; XLR [50, 74, 81, 87, 88] SOX9 17q24.3 Campomelic dysplasia AD [147] SPINK5 5q32 Netherton syndrome AR [148] SPR 2p14-p12 Dopa-responsive dystonia due to sepiapterin AR [149] reductase deficiency SRCAP 16p11.2 Floating–Harbor syndrome AD [150, 151] STAT3 17q21.31 Multisystem, infantile-onset autoimmune disease AD [152, 153] STAT5B 17q11.2 GH insensitivity with immunodeficiency AR [154] SYNPR 3p14.2 Chromosome 3p14.3 microdeletion Microdeletion [39]
TBCE 1q42.3 Kenny–Caffey syndrome AR [155] TBX15 1p11.1 Cousin syndrome AR [39] HNF1B 17q12 Chromosome 17q12 microdeletion Microdeletion [39]
TG 8q24 Thyroid dyshormonogenesis AR [24] THRA 17q11.2 Thyroid hormone resistance AD [24] THRB 3p24.2 Thyroid hormone resistance AD, AR [24]
Supplemental Materials (Chapter 5) 205 Supplemental Table 3. Genes in which Sequence Variants are Associated with a Low Birthweight (continued) Gene Chromosome Disorder Inheritance Reference TINF2 14q12 Revesz syndrome (Coats plus syndrome) AR [39] TMPO 12q22 Thyroid dyshormonogenesis AR [24] TRIM37 17q23.2 Mulibrey nanism AR [156] TRPV4 12q24.1 Spondyloepimetaphyseal dysplasia - type Maroteaux AD [39]
TSHR 14q31 Thyroid dysgenesis AR [24] TUBGCP6 22q13.31-q13.33 Microcephaly and chorioretinopathy 1 AR [131] RNU4ATAC 2q14.2 MOPD I AR [157] WHSCR1-2 4p16.3 Wolf-Hirschhorn syndrome Microdeletion [39]
WNT4 1p36.23-p35.1 SERKAL syndrome AR [39] WNT5A 3p21-p14 Robinow syndrome AD [141] ERCC3 2q21 Trichothiodystrophy [39]
ERCC2 19q13.3 Trichothiodystrophy [39]
XRCC4 5q14.2 Defective nonhomologous endjoining DNA damage AR [158] repair ZEB2 2q22.3 Mowat-Wilson syndrome AD [39]
206 Supplements Supplemental Table 4. Differential Methylation in Genes Known to Be Aberrantly Methylated in Low Birth- weight Newborns Gene Chromosome (MapInfo) Control Case No. of Main gene function(s) and influence(s) on β-value β-value probes fetal growtha (mean) (mean)
Hypermethylation ANKRD11 16 (89461734-89462359) 0.25 0.51 4 Hypermethylated CpG island near ANKRD11 in Silver-Russel syndrome APBA2 15 (29403333-29410508) 0.49 0.73 6 Hypermethylation associated with SGA or FGR APOL1 22 (36648832-36649144) 0.19 0.47 4 Hypermethylation associated with SGA or FGR BRCA1; 17 (41278135-41278655) 0.19 0.50 14 Hypermethylation associated with SGA or NBR2 FGR DLK1 14 (101196998-101201316) 0.39 0.64 6 Imprinted, highly expressed in the placenta, and associated with UPD14 INS; 11 (2181866-2183824) 0.37 0.63 4 INS is an imprinted gene in the 11p15.5 INS-IGF2 region (geneimprint.com). INS-IGF2 involved in growth and metabolism MEG3; 14 (101317620-101319526) 0.33 0.61 3 Imprinted, highly expressed in the placenta MIR770 which is reduced in FGR 4 RTL1; 14 (101348035-101350872) 0.50 0.76 4 RTL1 relevant to UPD14 phenotypes MIR127; MIR136; MIR432; MIR433
WNT2 7 (116963193-116963500) 0.15 0.41 3 WNT2 promoter methylation in placenta is associated with low birthweight Hypomethylation DBP 19 (49133845-49134105) 0.47 0.23 2 Hypermethylation associated with SGA or FGR FGF14 13 (102568345-102569815) 0.53 0.28 5 Hypomethylation associated with SGA or FGR FOXP1 3 (71112437-71295684) 0.63 0.36 11 Hypermethylated in fetal growth restriction GNAS; 20 (57425515-57471672) 0.74 0.49 28 Hypomethylation of GNASAS associated with GNASAS SGA. Decreased expression of GNAS observed in IUGR placentas HOXB4 17 (46656664-46656690) 0.61 0.38 2 Hypermethylation associated with SGA or FGR
Supplemental Materials (Chapter 5) 207 Supplemental Table 4. Differential Methylation in Genes Known to Be Aberrantly Methylated in Low Birth- weight Newborns (continued) Gene Chromosome (MapInfo) Control Case No. of Main gene function(s) and influence(s) on β-value β-value probes fetal growtha (mean) (mean)
IGF2AS; 11 (2162510-2163299) 0.53 0.28 5 IGF2 is imprinted and highly expressed IGF2; in placenta, hypomethylation of H19/IGF2 INS-IGF2 control region is associated with FGR. INS- IGF2 involved in growth and metabolism. IGF2AS is imprinted and expressed in antisense to IGF2 KCNQ1; 11 (2722440-2722713) 0.80 0.47 5 Upregulated KCNQ1 and loss of KCNQ1OT1 KCNQ1OT1 associated with IUGR; genetic variants of KCNQ1 associated with Beckwith-Wiedemann syndrome MEST 7 (130124971-130126368) 0.55 0.31 4 Imprinted, highly expressed in the placenta, and associated with Silver -Russell syndrome NNAT; 20 (36148154-36151338) 0.77 0.50 28 Hypermethylation of NNAT in placenta BLCAP associated with FGR NPR3 5 (32711429-32714525) 0.39 0.17 5 Hypermethylation associated with FGR NSD1 5 (176558909-176559563) 0.76 0.47 4 Loss of function associated with overgrowth (Sotos syndrome) PLAGL1; 6 (144329887-144386528) 0.72 0.46 10 Imprinted, highly expressed in placenta, HYMAI associated with SGA PEG10; 7 (94284258-94285501) 0.41 0.17 13 Imprinted gene highly expressed in the SGCE placenta. Differential expression between growth restricted and non-restricted placentas SHC1 1 (154942566-154943932) 0.66 0.37 5 Hypomethylation in placenta associated with FGR SLC25A18 22 (18063857-18064224) 0.80 0.52 5 Hypermethylation associated with SGA or FGR TAL1 1 (47693873-47696701) 0.67 0.39 6 Hypermethylation associated with SGA or FGR TBX15 1 (119521928-119532850) 0.65 0.30 27 Promotor hypomethylation leads to TBX15 decrease in FGR placentas aFor references see Supplemental Table 1.
208 Supplements Supplemental Table 5. Differential Methylation and Sequence Variant in Genes Involved in (Regulation of ) DNA-Methylation in Patient SGA3 Gene Chr. (MapInfo) Control Case No. of Main gene function(s) and influence(s) on DNA- β-value β-value probes methylationa (mean) (mean)
Methylation disturbances
Hypermethylated genes
APOBEC3A 22 (39353495-39354115) 0.37 0.63 3 Involved in epigenetic regulation of gene expression through DNA demethylation
BRCA1; 17 (41278135-41278655) 0.19 0.50 14 Regulator of DNA methylation NBR2
MAEL 1 (166958221-166958322) 0.32 0.66 5 Involved in DNA methylation in gamete generation
ZFP57 6 (29641443) 0.60 0.80 1 Zinc finger protein, may function as transcription repressor during early development. Associated with a heritable global imprinting disorder
Hypomethylated genes
ALKBH3 11 (43902134-43903042) 0.39 0.11 5 Dioxygenase that repairs alkylated DNA by demethylation
DNMT1 19 (10304766-10305911) 0.46 0.22 3 Methylates CpG residues, associated with DNA replication and maintaining methylation patterns
DNMT3A 2 (25499619-25500416) 0.72 0.39 4 Involved in genome-wide de novo methylation and in DNA methylation during development
FOS 14 (75746793-75747961) 0.81 0.41 4 May transform cells through alterations in DNA methylation
GNAS; GNASAS 20 (57425515-57471672) 0.74 0.49 28 Involved in DNA methylation
HIST1H4I; HIST1H2BK 6 (27106988-27107718) 0.53 0.25 8 Role in DNA methylation on cytosine
HIST1H3A 6 (26019832) 0.87 0.54 1 Role in DNA methylation on cytosine
MGMT 10 (131323986-131367623) 0.78 0.47 10 DNA methyltransferase, known to have significant fetal effects
TDRD1 10 (115939018-115939284) 0.83 0.52 3 Involved in DNA methylation at gamete generation
TET1 10 (70321668-70322874) 0.67 0.34 5 Key in active DNA demethylation
UHRF1 19 (4911058-4912006) 0.71 0.34 3 Key epigenetic regulator by bridging DNA methylation and chromatin modification
WES variant
Gene Position Alt. MAF SNP ID SIFT PolyPhen2 Main gene function(s) and influence(s) on DNA-methylationa
MPHOSPH8 13: 20224202 G>T 0.02 rs75390100 Deleterious Probably Binds methylated Lys-9 of histone damaging H3 (H3K9me), promotes recruitment of proteins that mediate epigenetic repression (uniprot.org) aFor references see Supplemental Table 2. Alt.=alteration; MAF=minor allele frequency (1000 Genome, ExAC); SNP=single nucleotide polymorphism; SIFT=Sorting Intolerant From Tolerant; PolyPhen2=Polymorphism Phenotyping 2
Supplemental Materials (Chapter 5) 209 References
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