DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins. During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins. DNA replication is a fundamental cellular process necessary to ensure the faithful transmission of genetic information. In eukaryotes, three highly conserved DNA polymerases, polymerase epsilon, delta, and alpha, act in concert at the replication fork. Polymerase epsilon (Pol ε) is the major enzyme responsible for the synthesis of the leading strand1Burgers P.M.J. Kunkel T.A. Eukaryotic DNA replication fork.Annu. Rev. Biochem. 2017; 86: 417-438Crossref PubMed Scopus (262) Google Scholar and is consequently an essential gene.2Hogg M. Johansson E. DNA polymerase ε.Subcell. Biochem. 2012; 62: 237-257Crossref PubMed Scopus (26) Google Scholar POLE encodes the catalytic subunit of Pol ε (POLE1), and somatic and germline missense mutations affecting the proofreading domain of POLE1 have been associated with colon and endometrial cancer.3Palles C. Cazier J.B. Howarth K.M. Domingo E. Jones A.M. Broderick P. Kemp Z. Spain S.L. Guarino E. Salguero I. et al.CORGI ConsortiumWGS500 ConsortiumGermline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.Nat. Genet. 2013; 45: 136-144Crossref PubMed Scopus (707) Google Scholar, 4Church D.N. Briggs S.E. Palles C. Domingo E. Kearsey S.J. Grimes J.M. Gorman M. Martin L. Howarth K.M. Hodgson S.V. et al.NSECG CollaboratorsDNA polymerase ε and δ exonuclease domain mutations in endometrial cancer.Hum. Mol. Genet. 2013; 22: 2820-2828Crossref PubMed Scopus (252) Google Scholar, 5Bellido F. Pineda M. Aiza G. Valdés-Mas R. Navarro M. Puente D.A. Pons T. González S. Iglesias S. Darder E. et al.POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.Genet. Med. 2016; 18: 325-332Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 6Cancer Genome Atlas N. Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (5904) Google Scholar Microcephalic primordial dwarfism comprises a group of prenatal-onset extreme growth disorders characterized by intrauterine growth retardation, short stature, and microcephaly. Genes involved in cell cycle progression, including multiple components of the replication licensing machinery, have been identified as monogenic causes of this disorder.7Bicknell L.S. Bongers E.M. Leitch A. Brown S. Schoots J. Harley M.E. Aftimos S. Al-Aama J.Y. Bober M. Brown P.A. et al.Mutations in the pre-replication complex cause Meier-Gorlin syndrome.Nat. Genet. 2011; 43: 356-359Crossref PubMed Scopus (188) Google Scholar, 8Bicknell L.S. Walker S. Klingseisen A. Stiff T. Leitch A. Kerzendorfer C. Martin C.A. Yeyati P. Al Sanna N. Bober M. et al.Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome.Nat. Genet. 2011; 43: 350-355Crossref PubMed Scopus (162) Google Scholar, 9Fenwick A.L. Kliszczak M. Cooper F. Murray J. Sanchez-Pulido L. Twigg S.R.F. Goriely A. McGowan S.J. Miller K.A. Taylor I.B. et al.WGS500 ConsortiumMutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis.Am. J. Hum. Genet. 2016; 99: 125-138Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 10Cottineau J. Kottemann M.C. Lach F.P. Kang Y.H. Vély F. Deenick E.K. Lazarov T. Gineau L. Wang Y. Farina A. et al.Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency.J. Clin. Invest. 2017; 127: 1991-2006Crossref PubMed Scopus (80) Google Scholar, 11Gineau L. Cognet C. Kara N. Lach F.P. Dunne J. Veturi U. Picard C. Trouillet C. Eidenschenk C. Aoufouchi S. et al.Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency.J. Clin. Invest. 2012; 122: 821-832Crossref PubMed Scopus (206) Google Scholar As the molecular basis for many affected individuals remains to be determined, we performed whole-genome sequencing studies to identify further genes and facilitate more comprehensive diagnosis. Whole-genome sequencing (WGS) of 48 individuals with microcephalic primordial dwarfism identified heterozygous POLE (GenBank: NM_006231.3) loss-of-function (LoF) variants in three subjects (P1, P3, P4; Table 1). These LoF variants were significantly enriched in our cohort compared to a control WGS dataset (GnomAD,12Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6555) Google Scholar p = 5.1 × 10−5, Fisher’s exact test, Table S1). As these variants were present in the unaffected parents, the WGS data were further evaluated and a second rare intronic variant in POLE identified, c.1686+32C>G (dbSNP: rs762985435). This was present in trans with the LoF mutation in all three probands (Table 1). Targeted sequencing of POLE and interrogation of existing whole-exome sequencing (WES) data in additional cases of primordial dwarfism identified five additional subjects compound heterozygous for LoF alleles and the c.1686+32C>G variant (P5–P9, Table 1). Notably, a clinical diagnosis of IMAGe syndrome (GeneReviews in Web Resources) (MIM: 614732) had been considered in individuals P1 and P3, with adrenal failure also reported in P5, P6, and P7. We therefore investigated cases of IMAGe syndrome drawn from other cohorts without an existing molecular diagnosis (i.e., CDKN1C mutation negative). These included three previously published IMAGe-affected case subjects.13Tan T.Y. Jameson J.L. Campbell P.E. Ekert P.G. Zacharin M. Savarirayan R. Two sisters with IMAGe syndrome: cytomegalic adrenal histopathology, support for autosomal recessive inheritance and literature review.Am. J. Med. Genet. A. 2006; 140: 1778-1784Crossref PubMed Scopus (17) Google Scholar, 14Pedreira C.C. Savarirayan R. Zacharin M.R. IMAGe syndrome: a complex disorder affecting growth, adrenal and gonadal function, and skeletal development.J. Pediatr. 2004; 144: 274-277Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Analysis of their WGS data identified additional POLE LoF variants inherited in trans with the intronic variant in individuals P11–P15 (Table 1). The c.1686+32C>G variant was part of a common haplotype in all individuals where WES/WGS performed, extending over 921 kbp (Figure S2, chr12:132341818–133263107, GRCh38). In P10 a missense variant (c.3019G>C) encoding a p.Ala1007Pro substitution was found, at a residue conserved to yeast (Figure S1) within the polymerase domain of the protein (Figure 1). All variants identified were sufficiently rare (MAF < 0.000112Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6555) Google Scholar) and, where DNA available, segregation in families was consistent with an autosomal recessively inherited disorder (Table 1).Table 1Biallelic POLE Mutations (GenBank: NM_006231.3)IDFamSexAllele 1Allele 2Mat AllelePat AlleleCountry of OriginNucleotide ChangeAmino Acid ConsequenceMAFNucleotide ChangeAmino Acid ConsequenceMAFP11Mc.2091dupCp.Phe699Valfs∗110c.1686+32C>Gp.Asn563Valfs∗160.00007112UKP21Fc.2091dupCp.Phe699Valfs∗110c.1686+32C>Gp.Asn563Valfs∗160.00007112UKP32Mc.62+1G>AEssential Splice Site Intron 10c.1686+32C>Gp.Asn563Valfs∗160.00007121IrelandP43Fc.5940G>Ap.Trp1980∗0.000016c.1686+32C>Gp.Asn563Valfs∗160.00007121AustraliaP54Mc.4728+1G>TEssential Splice Site Intron 360c.1686+32C>Gp.Asn563Valfs∗160.00007121USAP65Fc.3264_3275+13delEssential Splice Site Intron 260.000016c.1686+32C>Gp.Asn563Valfs∗160.00007112CanadaP76Mc.1A>Tp.?0.000081c.1686+32C>Gp.Asn563Valfs∗160.000071n/an/aUSAP87Mc.1A>Tp.?0.000081c.1686+32C>Gp.Asn563Valfs∗160.00007121IrelandP97Fc.1A>Tp.?0.000081c.1686+32C>Gp.Asn563Valfs∗160.00007121IrelandP108Fc.3019G>Cp.Ala1007Pro0.000009c.1686+32C>Gp.Asn563Valfs∗160.00007112IrelandP119Fc.5265delGIle1756Serfs∗50c.1686+32C>Gp.Asn563Valfs∗160.00007121AustraliaP129Mc.5265delGIle1756Serfs∗50c.1686+32C>Gp.Asn563Valfs∗160.00007121AustraliaP1310Fc.2049C>Gp.Tyr683∗0.000028c.1686+32C>Gp.Asn563Valfs∗160.00007112AustraliaP1411Mc.6518_6519delCTp.Ser2173Phefs∗1300.000089c.1686+32C>Gp.Asn563Valfs∗160.00007121USAP1512Mc.801+2T>CEssential Splice Site Intron 8–c.1686+32C>Gp.Asn563Valfs∗160.00007112USAAbbreviations: ID, individual number; Fam, family number; Mat, maternal; Pat, paternal; n/a, not available. All subjects harbored a loss-of-function mutation in combination with an intronic variant on the alternate allele identified as part of a shared haplotype and found to alter splicing in RNA studies. MAF indicates minor allele frequency in European (non-Finnish) population observed in gnomAD. None of the variants were present in any Non-European population in gnomAD. Open table in a new tab Abbreviations: ID, individual number; Fam, family number; Mat, maternal; Pat, paternal; n/a, not available. All subjects harbored a loss-of-function mutation in combination with an intronic variant on the alternate allele identified as part of a shared haplotype and found to alter splicing in RNA studies. MAF indicates minor allele frequency in European (non-Finnish) population observed in gnomAD. None of the variants were present in any Non-European population in gnomAD. Phenotypically, affected individuals had severe growth failure of prenatal onset (Figure 2, Table S2). IUGR was present in all case subjects (birth weight was −3.0 ± 0.8 SD) with significant short stature evident postnatally (height −8.1 ± 2.4 SD). While head circumference was also significantly reduced (OFC −5.4 ± 1.5 SD), this was less severe, resulting in a relative macrocephaly. Those affected had a common facial appearance with micrognathia, crowded dentition, long thin nose, short wide neck, and small, low-set, posteriorly rotated ears (Figure 2). 12 individuals had adrenal insufficiency and all affected males had genitourinary abnormalities including bilateral cryptorchidism and/or hypospadias, with the majority of case subjects fulfilling clinical criteria for IMAGe syndrome (GeneReviews in Web Resources; Table 2, Table S3, Supplemental Note). Osteopenia and developmental dysplasia of the hip (DDH) were frequently observed and café-au-lait patches were notably present in a third of individuals.Table 2Individuals with Biallelic Mutations in POLE Were Clinically Diagnosed with Primordial Dwarfism and Features of IMAGe SyndromeIDFamSexAgeIM+SIAGe−IOther FeaturesP11M18YYYYYscoliosis, osteopenia, small patella, seizures, gastrostomy, eczemaP21F1YYY–Y–P32M7YYYYYmidline accessory incisor, osteopenia, infant eczemaP43F50YYN–YIgM paraproteinaemiaP54M12YNAYYYhypopituitarism, T cell lymphoma, gastrostomy, absent patellaP65F10YYY–Ybilat coxa valga, 11 ribs, 6 lumbar vertebrae, scoliosis, gastrostomy, infant eczemaP76M13YYYYNhypopituitarism, atrial septal defect, brachydactyly, gastrostomyP87M3YYNYYDDH, gastrostomyP97F2YYN–YDDH, gastrostomyP108F39YYY–NDDH, 11 ribs, clinodactyly, osteopenia, café au lait patchesP119F0.2YNAY–Ycafé au lait patchP129F12YYY–N–P1310M22YYYYNDDH, café au lait patchP1411F18YYY–Ygastrostomy, hypercalaemia in infancy, café au lait patches, DDH, kyphoscoliosisP1512M31YNAYYYcafé au lait patches, seizures, osteopenia, osteoporosis, nodular sclerosis, Hodgkin’s lymphomaAbbreviations: ID, individual number; Fam, family number; I, intrauterine growth restriction; M+SI, skeletal involvement: metaphyseal dysplasia or other skeletal abnormalities reported in CDKN1C IMAGe-affected individuals (NA, not assessed); A, adrenal insufficiency; Ge, genitourinary abnormalities in males (– female, genitourinary anomalies not applicable); −I, immunodeficiency, either increased susceptibility to infections or DDH, developmental dysplasia of the for clinical data and Open table in a new tab Abbreviations: ID, individual number; Fam, family number; I, intrauterine growth restriction; M+SI, skeletal involvement: metaphyseal dysplasia or other skeletal abnormalities reported in CDKN1C IMAGe-affected individuals (NA, not assessed); A, adrenal insufficiency; Ge, genitourinary abnormalities in males (– female, genitourinary anomalies not applicable); −I, immunodeficiency, either increased susceptibility to infections or DDH, developmental dysplasia of the for clinical data and intronic variant in POLE previously been reported to be associated with immunodeficiency, and short stature immunodeficiency, and short stature, syndrome J. R. N. P. F. M. P. C. L. et mutation in a human syndrome with facial immunodeficiency, and short stature Med. 2012; PubMed Scopus Google Scholar, I. C. J. N. M. L. E. G. et with polymerase deficiency clinical features and with DNA Med. Genet. PubMed Scopus (17) Google Scholar affected individuals identified in this also had increased susceptibility to with lymphocyte and/or identified in P3, and (Table 2, Table of natural killer was present in P3, and P1 had the immunodeficiency, and an Notably, this had the same compound heterozygous POLE at from our findings establish that the of biallelic POLE mutations from IMAGe syndrome to immunodeficiency, in with the and of the previously reported J. R. N. P. F. M. P. C. L. et mutation in a human syndrome with facial immunodeficiency, and short stature Med. 2012; PubMed Scopus Google Scholar, I. C. J. N. M. L. E. G. et with polymerase deficiency clinical features and with DNA Med. Genet. PubMed Scopus (17) Google Scholar establish the variant affected the POLE RNA studies were performed on from subjects (P1, POLE 15 the of a (Figure which sequencing to be due to of part of 15 within POLE (Figure was performed to splicing of this and to the of the c.1686+32C>G This that the c.1686+32C>G variant splicing of the 15 leading to of a alternate in splicing also (Figure The of of intronic DNA in the variant in a which lead to While this be for any protein also be that this at the of the polymerase catalytic with a LoF mutation on the second in POLE1 was therefore of protein from of from affected subjects that POLE1 were (Figure ± for P1 and ± P3, relative to the of control subjects and to ± for = with of POLE1 in and (Figure together with the consistent clinical case we that the identified POLE variants were resulting in a IMAGe syndrome. In with an essential for POLE in M. Johansson E. DNA polymerase ε.Subcell. Biochem. 2012; 62: 237-257Crossref PubMed Scopus (26) Google Scholar the c.1686+32C>G mutation of POLE1 in all case This mutation in trans with mutations be to lead to of As POLE encodes POLE1, the catalytic subunit of the major leading-strand DNA polymerase Pol reduced of POLE1 therefore be to on the of Pol ε DNA polymerase in DNA with delayed of from P1 and P3, of S-phase (Figure While of POLE1 deficiency a been which is for the Pol ε R. C. J. E. G. et and Full Text Full Text PDF PubMed Scopus Google Scholar This also significant prenatal onset growth reduced and reduced lymphocyte Analysis of from this alongside POLE human from P1 and in this that in cases Pol ε deficiency to reduced of Pol ε resulting in replication from reduced of replication R. C. J. E. G. et and Full Text Full Text PDF PubMed Scopus Google Scholar IMAGe syndrome previously been found to be by gain-of-function mutations in the R. A. A. I. et al.Mutations in the domain of CDKN1C cause IMAGe syndrome.Nat. Genet. 2012; PubMed Scopus Google Scholar, N. Y. S. M. S. protein of CDKN1C causes a gain-of-function in patients with IMAGe 2013; PubMed Scopus Google Scholar we establish mutations of POLE as an cause of the IMAGe These mutations with heterozygous germline and somatic mutations that the exonuclease domain of C. Cazier J.B. Howarth K.M. Domingo E. Jones A.M. Broderick P. Kemp Z. Spain S.L. Guarino E. Salguero I. et al.CORGI ConsortiumWGS500 ConsortiumGermline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.Nat. Genet. 2013; 45: 136-144Crossref PubMed Scopus (707) Google Scholar, 4Church D.N. Briggs S.E. Palles C. Domingo E. Kearsey S.J. Grimes J.M. Gorman M. Martin L. Howarth K.M. Hodgson S.V. et al.NSECG CollaboratorsDNA polymerase ε and δ exonuclease domain mutations in endometrial cancer.Hum. Mol. Genet. 2013; 22: 2820-2828Crossref PubMed Scopus (252) Google Scholar, 5Bellido F. Pineda M. Aiza G. Valdés-Mas R. Navarro M. Puente D.A. Pons T. González S. Iglesias S. Darder E. et al.POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.Genet. Med. 2016; 18: 325-332Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 6Cancer Genome Atlas N. Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (5904) Google Scholar (Figure 1). IMAGe and cancer mutations to have leading to DNA replication or to I.B. Johansson E. Kunkel T.A. of the yeast DNA polymerase PubMed Scopus Google Scholar a cancer in POLE1-deficient individuals or POLE heterozygous be a T cell at 11 and Hodgkin’s at also the increased in R. C. J. E. G. et and Full Text Full Text PDF PubMed Scopus Google Scholar POLE1 deficiency therefore an increased of All CDKN1C IMAGe mutations within cell R. A. A. I. et al.Mutations in the domain of CDKN1C cause IMAGe syndrome.Nat. Genet. 2012; PubMed Scopus Google Scholar, N. Y. S. M. S. protein of CDKN1C causes a gain-of-function in patients with IMAGe 2013; PubMed Scopus Google Scholar the E. Mutations in the of CDKN1C cell by the PubMed Scopus Google Scholar As with Pol ε at replication and the with IMAGe syndrome a this studies of a that and is by L. C. of a at of DNA PubMed Scopus Google Scholar, cell to DNA and to DNA polymerase PubMed Scopus (26) Google Scholar (Figure mutations in L. Cognet C. Kara N. Lach F.P. Dunne J. Veturi U. Picard C. Trouillet C. Eidenschenk C. Aoufouchi S. et al.Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency.J. Clin. Invest. 2012; 122: 821-832Crossref PubMed Scopus (206) Google Scholar, L. E. C. A.J. MCM4 mutation causes adrenal short stature, and natural killer cell deficiency in Clin. Invest. 2012; 122: PubMed Scopus Google Scholar (MIM: and F. Al R. A. F. S. et mutation in the gene Clin. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar have been associated with IUGR and short stature, alongside immunodeficiency, with and without adrenal families with GINS1 biallelic mutations have been reported to be associated with growth and NK cell deficiency (MIM: J. Kottemann M.C. Lach F.P. Kang Y.H. Vély F. Deenick E.K. Lazarov T. Gineau L. Wang Y. Farina A. et al.Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency.J. Clin. Invest. 2017; 127: 1991-2006Crossref PubMed Scopus (80) Google Scholar the identification of a cohort of individuals with POLE mutations that all these features this as a group of disorders (Figure Table and cell R. C. J. E. G. et and Full Text Full Text PDF PubMed Scopus Google Scholar the as as growth failure in POLE1-deficient replisome have a on in subjects and NK in or on adrenal is Notably, of primordial Meier-Gorlin syndrome by the of short stature, and is also by biallelic mutations in genes involved in replication licensing and L.S. Bongers E.M. Leitch A. Brown S. Schoots J. Harley M.E. Aftimos S. Al-Aama J.Y. Bober M. Brown P.A. et al.Mutations in the pre-replication complex cause Meier-Gorlin syndrome.Nat. Genet. 2011; 43: 356-359Crossref PubMed Scopus (188) Google Scholar, 8Bicknell L.S. Walker S. Klingseisen A. Stiff T. Leitch A. Kerzendorfer C. Martin C.A. Yeyati P. Al Sanna N. Bober M. et al.Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome.Nat. Genet. 2011; 43: 350-355Crossref PubMed Scopus (162) Google Scholar, 9Fenwick A.L. Kliszczak M. Cooper F. Murray J. Sanchez-Pulido L. Twigg S.R.F. Goriely A. McGowan S.J. Miller K.A. Taylor I.B. et al.WGS500 ConsortiumMutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis.Am. J. Hum. Genet. 2016; 99: 125-138Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, M. S. C. M. S. M. M. J. et al.Mutations in origin recognition complex gene cause Meier-Gorlin syndrome.Nat. Genet. 2011; 43: PubMed Scopus Google Scholar, M. et Mutations Cause Primordial Dwarfism with Meier-Gorlin J. Hum. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar (Figure studies to understand the of the encoded replication along with the cellular and basis for the CDKN1C and Pol therefore be of of the Genome J. L. A. and The of and at of from the genetic testing by We the families and for their and the and with N. and for E. for with sequencing and for WGS We for cell This was by to the from European by a and the The is by for and the reported in this was by the for of the of The is the of the and not the of the is by the which from Cancer the and the a European and and is by the The is by the of the and The Genome for and with Supplemental and Supplemental and and IMAGe

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