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WO2016005589A2 - Nouveau panel de gènes utilisable en vue du diagnostic d'une cardiomyopathie dilatée - Google Patents

Nouveau panel de gènes utilisable en vue du diagnostic d'une cardiomyopathie dilatée Download PDF

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Publication number
WO2016005589A2
WO2016005589A2 PCT/EP2015/065890 EP2015065890W WO2016005589A2 WO 2016005589 A2 WO2016005589 A2 WO 2016005589A2 EP 2015065890 W EP2015065890 W EP 2015065890W WO 2016005589 A2 WO2016005589 A2 WO 2016005589A2
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seq
dcm
risk
chromosome
sequence
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WO2016005589A3 (fr
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Sebastian Schäfer
Norbert Huebner
Stuart A. Cook
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Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
National University of Singapore
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Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
National University of Singapore
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to the field of medicine and molecular biology, particularly in the field of diagnosis and means for diagnosis, more particular in the filed of diagnosis and risk stratification of Dilated Cardiomyopathy (DCM).
  • DCM Dilated Cardiomyopathy
  • mutations in the genes of the panels are detected and attributed to the presence of DCM and/or the risk of acquiring DCM and/or the risk of heart failure in the subject to be diagnosed.
  • the polymorphisms detected by the inventors lead to alterations in the sequence of the encoded protein. Even if the single polymorphism at a certain position occurred only in rare cases, the overall amount of polymorphism per gene was significant, e.g. up to a disease burden of 19.9 for PIEZOl ; see examples.
  • the skilled person will be able to prepare the regions in order to determine the sequence of polymorphisms therein. He may for example amplify one or more regions using PCR based methods. Such methods may include the use of primers which can be designed by the skilled person using his common skills and the disclosure of the present invention.
  • CDS Alt gives a preferred sequence at the respective position in the coding sequence of the named transcript associated and attributed with the presence of or the risk for DCM or the risk for heart failure.
  • the skilled person will recognize that if the nucleotide of CDS Ref or CDS Alt is the complementary nucleotide compared to the respective "Ref or "Alt” nucleotide that the coding sequence of the gene is on the negative strand of the respective chromosome, "aa Pos” refers to the position of the amino acid corresponding to the SNP position, "aa Ref gives the amino acid coded by the control sequence of "CDS Ref.
  • the one or more polymorphisms in PEEZOl are protein-altering polymorphisms, i.e. the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure is attributed to said subject to be diagnosed if one or more of the determined sequences result in a different sequence of the encoded protein.
  • the presence of a polymorphism resulting to a sequence encoding a protein differing in one or more amino acids from the sequence of SEQ ID NO:2 is attributed to the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure.
  • the one or more polymorphism in PIEZO 1 is preferably located in a region selected from the group consisting of nt 88803047 to nt 88803147 of chromosome 16, nt 88799996 to nt 88800153 of chromosome 16, nt 88798114 to nt 88798318 of chromosome 16, nt 88792955 to nt 88793051 of chromosome 16, nt 88788216 to nt 88788474 of chromosome 16, nt 88787574 to nt 88787838 of chromosome 16, nt 88787024 to 88787156 of chromosome 16, nt 88786793 to nt 88786940 of chromosome 16, nt 88786477 to 88786691 of chromosome 16, nt 88783214 to nt 88783306 of chromosome 16, nt 88782967 to
  • the short alternative amino-terminal sequences encoded by the different first exons direct the targeting of the various isoforms to distinct subcellular locations (Rezniczek GA, Abrahamsberg C, Fuchs P, Spazierer D, Wiche G. Plectin 5 '-transcript diversity: short alternative sequences determine stability of gene products, initiation of translation and subcellular localization of isoforms. Hum Mol Genet. 2003 Dec 1 ; 12(23):3181 -94). As the expression of specific plectin isoforms was found to be dependent on cell type (tissue) and stage of development (Fuchs P, Zorer M, Rezniczek GA, Spazierer D, Oehler S, Castanon MJ, Hauptmann R, Wiche G.
  • a further preferred polymorphism in PLEC is a SNP, preferably at a position selected from the group consisting of nt 145047578 of chromosome 8, nt 145006118 of chromosome 8, nt 145003969 of chromosome 8, nt 144999661 of chromosome 8, nt 144999622 of chromosome 8, nt 144999517 of chromosome 8, nt 144998936 of chromosome 8, nt 144998621 of chromosome 8, nt 144998416 of chromosome 8, nt 144997960 of chromosome 8, nt 144996823 of chromosome 8, nt 144996548 of chromosome 8, nt 144996061 of chromosome 8, nt 144995948 of chromosome 8, nt 144994985 of chromosome 8, nt 144994802 of chromosome 8, nt
  • the presence one or more nucleotide at a position selected from said group causes the transcript to encode a different amino acid at the corresponding position, preferably a different amino acid than listed in Table 2 as "aa Ref for the for the corresponding position in SEQ ID NO: l 1 and SEQ ID NO: 12, respectively.
  • the polymorphism is preferably within the coding sequence (CDS).
  • the one or more polymorphism preferably is located in the CDS of NM 001146334 (SEQ ID NO: 13).
  • the one or more polymorphism in NACAD is located in the sequence of SEQ ID NO: 13.
  • the one or more polymorphism in NACAD is preferably located in the region of nt 68 to nt 4072 of SEQ ID NO: 13.
  • the presence one or more nucleotide at a position selected from said group causes the transcript to encode a different amino acid at the corresponding position, preferably a different amino acid than listed in Table 2 as "aa Ref for the for the corresponding position in SEQ ID NO: 14.
  • the present invention relates a method for diagnosing dilated cardiomyopathy (DCM) in a subject or for assessing the risk of a subject to acquire DCM or to predict the risk of a subject for heart failure comprising: (i) determining in a sample of a subject to be diagnosed the sequence of one or more polymorphisms in UNC13B (ENSG00000198722); (ii) comparing the determined sequence to the sequence of said polymorphism in a control derived from a control subject (control sequence), the control subject not suffering from dilated cardiomyopathy, (iii) attributing the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure to said subject to be diagnosed if one or more determined sequences differ from the respective sequence in said control sequence.
  • DCM dilated cardiomyopathy
  • the one or more polymorphism in UNC13B is preferably located in a region selected from the group consisting of nt 35375124 to nt 35375198 of chromosome 9, nt 35376025 to nt 35376244 of chromosome 9, nt 35381097 to nt 35381212 of chromosome 9, nt 35382354 to nt 35382504 of chromosome 9, nt 35397164 to nt 35397307 of chromosome 9, nt 35397632 to nt 35397709 of chromosome 9, nt 35398879 to nt 35399031 of chromosome 9, nt 35403437 to nt 35403596 of chromosome 9, and nt 35403745 to nt 35405332 of chromosome 9.
  • the sequences of the polymorphisms on chromosome 9 are as outlined herein for UNC13B refer to the positive strand of chro
  • the present invention relates a method for diagnosing dilated cardiomyopathy (DCM) in a subject or for assessing the risk of a subject to acquire DCM or to predict the risk of a subject for heart failure comprising: (i) determining in a sample of a subject to be diagnosed the sequence of one or more polymorphisms in VWF (ENSG00000110799); (ii) comparing the determined sequence to the sequence of said polymorphism in a control derived from a control subject (control sequence), the control subject not suffering from dilated cardiomyopathy, (iii) attributing the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure to said subject to be diagnosed if one or more determined sequences differ from the respective sequence in said control sequence.
  • DCM dilated cardiomyopathy
  • the presence one or more nucleotide at a position selected from said group causes the transcript to encode a different amino acid at the corresponding position, preferably a different amino acid than listed in Table 2 as "aa Ref for the for the corresponding position in SEQ ID NO:26.
  • a further preferred polymorphism in LAMA5 is a SNP, preferably at a position selected from the group consisting of nt 60912702 of chromosome 20, nt 60911480 of chromosome 20, nt 60909672 of chromosome 20, nt 60902342 of chromosome 20, nt 60900389 of chromosome 20, nt 60898539 of chromosome 20, nt 60897722 of chromosome 20, nt 60897372 of chromosome 20, nt 60891954 of chromosome 20, nt 60890155 of chromosome 20, nt 60889715 of chromosome 20, nt 60886335 of chromosome 20, nt 60885808 of chromosome 20, and nt 60885046 of chromosome 20.
  • the present invention relates a method for diagnosing dilated cardiomyopathy (DCM) in a subject or for assessing the risk of a subject to acquire DCM or to predict the risk of a subject for heart failure comprising: (i) determining in a sample of a subject to be diagnosed the sequence of one or more polymorphisms in KIAA0284 (ENSG00000099814)); (ii) comparing the determined sequence to the sequence of said polymorphism in a control derived from a control subject (control sequence), the control subject not suffering from dilated cardiomyopathy, (iii) attributing the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure to said subject to be diagnosed if one or more determined sequences differ from the respective sequence in said control sequence.
  • DCM dilated cardiomyopathy
  • the one or more polymorphism in KIAA0284 is preferably located in a region selected from the group consisting of nt 105350168 to nt 105350886 of chromosome 14, and nt 105352612 to nt 105354315 of chromosome 14.
  • the sequences of the polymorphisms on chromosome 14 are as outlined herein for KIAA0284 refer to the positive strand of chromosome 14 but may likewise be detected on the complementary strand.
  • a further preferred polymorphism in KIAA0284 is a SNP, preferably at a position selected from the group consisting of nt 105350189 of chromosome 14, nt 105350270 of chromosome 14, nt 105350674 of chromosome 14, nt 105350800 of chromosome 14, nt 105352635 of chromosome 14, nt 105352992 of chromosome 14, nt 105353017 of chromosome 14, nt 105353074 of chromosome 14, nt 105353674 of chromosome 14, and nt 105353689 of chromosome 14.
  • the presence of a different nucleotide than listed in Table 2 as "CDS Ref for one or more positions selected from the group consisting of nt 863 of SEQ ID NO:41, nt 944 of SEQ ID NO:41, nt 1348 of SEQ ID NO:41 , nt 1474 of SEQ ID NO:41 , nt 1849 of SEQ ID NO:41, nt 2206 of SEQ ID NO:41 , nt 2231 of SEQ ID NO:41 , nt 2288 of SEQ ID NO:41, nt 2888 of SEQ ID NO:41 , and nt 2903 of SEQ ID NO:41 at the respective position is attributed to the presence of DCM in the patient to be diagnosed or the risk of acquiring DCM.
  • PRR14L is SNP at a position selected from the group consisting nt 385 of SEQ ID NO:43, nt 2153 of SEQ ID NO:43, nt 2351 of SEQ ID NO:43, nt 3126 of SEQ ID NO:43, nt 3191 of SEQ ID NO:43, nt 4093 of SEQ ID NO:43, nt 4181 of SEQ ID NO:43, and nt 5791 of SEQ ID NO:43.
  • Table 2 summarizes preferred SNP positions according to the present invention. Therein preferred control sequences are given.
  • Table 2 summarizes preferred SNP positions according to the present invention. Therein preferred control sequences are given. As outlined herein, the inventors found that a sequence differing from the respective control sequence is indicative for DCM or for the risk of a subject to acquire DCM or for the risk of a subject for heart failure.
  • the EPG5 gene encodes for an ectopic P-granules autophagy protein 5 homolog (C. elegans) of unknown function.
  • the present inventors however found that alterations within its sequence, in particular those altering the sequence of the encoded protein, are connected with the presence or the risk of acquiring DCM or the risk of heart failure in a patient.
  • the present invention relates a method for diagnosing dilated cardiomyopathy (DCM) in a subject or for assessing the risk of a subject to acquire DCM or to predict the risk of a subject for heart failure comprising: (i) determining in a sample of a subject to be diagnosed the sequence of one or more polymorphisms in EPG5 (ENSG00000152223); (ii) comparing the determined sequence to the sequence of said polymorphism in a control derived from a control subject (control sequence), the control subject not suffering from dilated cardiomyopathy, (iii) attributing the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure to said subject to be diagnosed if one or more determined sequences differ from the respective sequence in said control sequence.
  • DCM dilated cardiomyopathy
  • the polymorphism is preferably within the coding sequence (CDS).
  • the one or more polymorphism preferably is located in the CDS of NM 020964 (SEQ ID NO:53).
  • the one or more polymorphism in EPG5 is located in the sequence of SEQ ID NO:53.
  • a further preferred polymorphism in MLL3 is a SNP, preferably at a position selected from the group consisting of nt 152055723 of chromosome 7, nt 152027687 of chromosome 7, nt 151917716 of chromosome 7, nt 151878035 of chromosome 7, nt 151874751 of chromosome 7, nt 151860796 of chromosome 7, nt 151859939 of chromosome 7, nt 151859765 of chromosome 7, nt 151856090 of chromosome 7, and nt 151853076 of chromosome 7.
  • the present invention relates a method for diagnosing dilated cardiomyopathy (DCM) in a subject or for assessing the risk of a subject to acquire DCM or to predict the risk of a subject for heart failure comprising: (i) determining in a sample of a subject to be diagnosed the sequence of one or more polymorphisms in DCHS1 (ENSG00000166341); (ii) comparing the determined sequence to the sequence of said polymorphism in a control derived from a control subject (control sequence), the control subject not suffering from dilated cardiomyopathy, (iii) attributing the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure to said subject to be diagnosed if one or more determined sequences differ from the respective sequence in said control sequence.
  • DCM dilated cardiomyopathy
  • Preferred control sequences (Ref) of the SNPs and preferred sequences of the SNPs attributed to the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure are given in Table 2.
  • Further preferred polymorphisms in DCHSl are SNPs at a position selected from the group consisting of nt 1457 of SEQ ID NO:57, nt 3176 of SEQ ID NO:57, nt 3185 of SEQ ID NO:57, nt 4252 of SEQ ID NO:57, nt 4448 of SEQ ID NO:57, nt 4835 of SEQ ID NO:57, nt 5972 of SEQ ID NO:57, nt 8186 of SEQ ID NO:57, and nt 8269 of SEQ ID NO:57.
  • the presence one or more nucleotide at a position selected from said group causes the transcript to encode a different amino acid at the corresponding position, preferably a different amino acid than listed in Table 2 as "aa Ref for the for the corresponding position in SEQ ID NO:58.
  • the polymorphism is preferably within the coding sequence (CDS).
  • the one or more polymorphism preferably is located in the CDS of NM 007110 (SEQ K) NO:59).
  • the one or more polymorphism in TEPl is located in the sequence of SEQ ID NO:59.
  • the one or more polymorphism in TEPl is preferably located in a region selected from the group consisting of nt 17 to nt 607 of SEQ ID NO:59, nt 776 to nt 910 of SEQ ID NO:59, nt 1432 to nt 1589 of SEQ ID NO:59, nt 1969 to nt 2137 of SEQ ID NO:59, nt 3262 to nt 3379 of SEQ ID NO:59, nt 3575 to nt 3750 of SEQ ID NO:59, nt 3751 to nt 3907 of SEQ ID NO:59 nt 5168 to nt 5292 of SEQ ID NO:59, nt 5393 to nt 5548 of SEQ ID NO:59, nt 6129 to nt 6289 of SEQ ID NO:59.
  • the presence one or more nucleotide at a position selected from said group causes the transcript to encode a different amino acid at the corresponding position, preferably a different amino acid than listed in Table 2 as "aa Ref for the for the corresponding position in SEQ ID NO:60.
  • the one or more polymorphism in LRP4 is preferably located in a region selected from the group consisting of nt 46907642 to nt 46907723 of chromosome 11, nt 46900458 to nt 46900589 of chromosome 11, nt 46898017 to nt 46898188 of chromosome 11, nt 46894926 to nt 46895144 of chromosome 11, nt 46890151to nt 46890264 of chromosome 11, nt46889530 to nt 46889665 of chromosome 11, nt 46885999 to nt 46886086 of chromosome 11, and nt 46878268 to nt 46880866 of chromosome 11.
  • the sequences of the polymorphisms on chromosome 11 are as outlined herein for LRP4 refer to the positive strand of chromosome 11 but may likewise be detected on the complementary strand.
  • a further preferred polymorphism in LRP4 is a SNP, preferably at a position selected from the group consisting of nt 46907678 of chromosome 11 , nt 46900560 of chromosome 11 , nt 46898069 of chromosome 11 , nt 46894995 of chromosome 11, nt 46890202 of chromosome 11 , nt 46889554 of chromosome 11 , nt 46886060 of chromosome 11, nt 46880599 of chromosome 11.
  • a further preferred polymorphism in CRIPAK is a SNP, preferably at a position selected from the group consisting of nt 1388597 of chromosome 4, nt 1388724 of chromosome 4, nt 1389180 of chromosome 4, nt 1389399 of chromosome 4, nt 1389629 of chromosome 4.
  • Preferred control sequences (Ref) of the SNPs and preferred sequences of the SNPs attributed to the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure are given in Table 2.
  • the one or more polymorphism in CEP290 is preferably located in a region selected from the group consisting of nt 88486458 to nt 88486609 of chromosome 12, nt 88482809 to nt 88483264 of chromosome 12, nt 88481557 to nt 88481721 of chromosome 12, nt 88478363 nt to 88478629 of chromosome 12, nt 88472869 to nt 88473006 of chromosome 12, nt 88449353to nt 88449494 of chromosome 12.
  • the sequences of the polymorphisms on chromosome 12 are as outlined herein for CEP290 refer to the positive strand of chromosome 12 but may likewise be detected on the complementary strand.
  • the polymorphism is preferably within the coding sequence (CDS).
  • the one or more polymorphism preferably is located in the CDS of NM 025114 (SEQ ID NO:65).
  • the one or more polymorphism in CEP290 is located in the sequence of SEQ ID NO:65.
  • COBW domain containing 6 gene (CBWD6) (ENSG00000204790) encodes a protein of unknown function.
  • CBWD6 COBW domain containing 6 gene
  • the present inventors found that alterations within its sequence, in particular those altering the sequence of the encoded protein, are connected with the presence or the risk of acquiring DCM or the risk of heart failure in a patient.
  • the present invention relates a method for diagnosing dilated cardiomyopathy (DCM) in a subject or for assessing the risk of a subject to acquire DCM or to predict the risk of a subject for heart failure comprising: (i) determining in a sample of a subject to be diagnosed the sequence of one or more polymorphisms in CBWD6 (ENSG00000204790); (ii) comparing the determined sequence to the sequence of said polymorphism in a control derived from a control subject (control sequence), the control subject not suffering from dilated cardiomyopathy, (iii) attributing the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure to said subject to be diagnosed if one or more determined sequences differ from the respective sequence in said control sequence.
  • DCM dilated cardiomyopathy
  • the one or more polymorphism in CBWD6 is preferably located in a region selected from the group consisting of nt 261 to nt 347 of SEQ ID NO:71 , nt 348 to nt 444 of SEQ ID NO:71 , nt 871 to nt 922 of SEQ ID NO:71 , nt 923 to nt 991 of SEQ ID NO:71 , and nt 1058 to nt 1187 of SEQ ID NO:71.
  • the presence of a different nucleotide than listed in Table 2 as "CDS Ref ' for one or more positions selected from the group consisting of nt 233 of SEQ ID NO:71, nt 316 of SEQ ID NO:71, nt 799 of SEQ ID NO:71, nt 824 of SEQ ID NO:71 , and nt 1076 of SEQ ID NO:71 at the respective position is attributed to the presence of DCM in the patient to be diagnosed or the risk of acquiring DCM.
  • the one or more polymorphism in SEC16A is preferably located in a region selected from the group consisting of nt 241 to nt 3876 of SEQ ID NO:73, nt 3877 to nt 4013 of SEQ ID NO:73, nt 4014 to nt 4111 of SEQ ID NO:73, nt 7007 to nt 7101 of SEQ ID NO:73, and nt 7177 to nt 7236 of SEQ ID NO:73.
  • the presence of one or more nucleotide causing the respective transcript to encode for an amino acid as listed in Table 2 as "aa Alt” for the corresponding position in SEQ ID NO:74 is attributed to the presence of DCM in the patient to be diagnosed or the risk of acquiring DCM.
  • the protein encoded by SCARF 1 is a scavenger receptor that is expressed in endothelial cells. It regulates the uptake of chemically modified low density lipoproteins, including acetylated low density lipoprotein (Ac-LDL), and it may be involved in atherogenesis. This gene is regulated by the transcription factors ZNF444/EZF-2 and SP1. Alternative splicing results in multiple transcript variants. The present inventors however found that alterations within its sequence, in particular those altering the sequence of the encoded protein, are connected with the presence or the risk of acquiring DCM or the risk of heart failure in a patient.
  • a further preferred polymorphism in SCARF 1 is a SNP, preferably at a position selected from the group consisting of nt 1547094 of chromosome 17, nt 1546809 of chromosome 17, nt 1546743 of chromosome 17, nt 1540288 of chromosome 17, nt 1538417 of chromosome 17, and nt 1538179 of chromosome 17.
  • Preferred control sequences (Ref) of the SNPs and preferred sequences of the SNPs attributed to the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure are given in Table 2.
  • the presence of one or more nucleotide causing the respective transcript to encode for an amino acid as listed in Table 2 as "aa Alt” for the corresponding position in SEQ ID NO:77 and SEQ ID NO:78, respectively, is attributed to the presence of DCM in the patient to be diagnosed or the risk of acquiring DCM.
  • SNRNP200 is SNPs at a position selected from the group consisting of nt 995 of SEQ ID NO:79, nt 1936 of SEQ ID NO:79, nt 2150 of SEQ ID NO:79, nt 2879 of SEQ ID NO:79, nt 5432 of SEQ ID NO:79, nt 5894 of SEQ ID NO:79, and nt 5983 of SEQ ID NO:79.
  • Table 2 summarizes preferred SNP positions according to the present invention. Therein preferred control sequences are given.
  • the presence one or more nucleotide at a position selected from said group causes the transcript to encode a different amino acid at the corresponding position, preferably a different amino acid than listed in Table 2 as "aa Ref ' for the for the corresponding position in SEQ ID NO:82.
  • the presence of a different nucleotide than listed in Table 2 as "CDS Ref for one or more positions selected from the group consisting of nt 142 of SEQ ID NO:83, nt 2119 of SEQ ID NO:83, nt 2267 of SEQ ID NO:83, nt 3332 of SEQ ID NO:83, nt 3422 of SEQ ID NO:83, nt 3688 of SEQ ID NO:83, and nt 4384 of SEQ ID NO:83 at the respective position is attributed to the presence of DCM in the patient to be diagnosed or the risk of acquiring DCM.
  • Further preferred polymorphisms in PTPN14 are SNPs at a position selected from the group consisting of nt 664 of SEQ ID NO:85, nt 1019 of SEQ ID NO:85, nt 1586 of SEQ ID NO:85, nt 2133 of SEQ ID NO:85, nt 2325 of SEQ ID NO:85, nt 2326 of SEQ ID NO:85, and nt 2390 of SEQ ID NO:85.
  • Table 2 summarizes preferred SNP positions according to the present invention. Therein preferred control sequences are given. As outlined herein, the inventors found that a sequence differing from the respective control sequence is indicative for DCM or for the risk of a subject to acquire DCM or for the risk of a subject for heart failure.
  • sequences may differ due to naturally occurring polymorphisms.
  • control sequence it is meant that the determined sequence does not have a sequence occurring in healthy subjects. It will moreover be acknowledged that it may be the case that also in subjects of the healthy control group a sequence occurs that is attributed to a disease.
  • the inventors found that all determined sequences in DCM patients are rare variations, e.g. occurring in at most 0.04 % of all subject, i.e. in the general population
  • the skilled person is aware of statistical method to determine whether a certain variation with respect to a control allows the diagnosis.
  • a value of 1 indicates that a positive result is equally likely among subjects in both the "diseased” and “control” groups; a value greater than 1 indicates that a positive result is more likely in the diseased group; and a value less than 1 indicates that a positive result is more likely in the control group.
  • a value of 1 indicates that a negative result is equally likely among subjects in both the "diseased” and “control” groups; a value greater than 1 indicates that a negative result is more likely in the test group; and a value less than 1 indicates that a negative result is more likely in the control group.
  • Preferred confidence intervals of the invention are 90%, 95%, 97.5%, 98%, 99%, 99.5%, 99.9% and 99.99%, while preferred p values are 0.1 , 0.05, 0.025, 0.02, 0.01 , 0.005, 0.001, and 0.0001.
  • Suitable threshold numbers for the diagnosis can be determined done by grouping a reference population of patients according to their number of differing polymorphisms into certain quantiles, e.g. quartiles, quintiles or even according to suitable percentiles. For each of the quantiles or groups above and below certain percentiles, hazard ratios can be calculated comparing the risk for an adverse outcome, i.e. an "DCM" or a "heart failure", e.g.
  • dilated cardiomyopathy in a subject or for assessing the risk of a subject to acquire DCM or to predict the risk of a subject for heart failure comprising: (i) determining in a sample of a subject to be diagnosed the sequence of one or more polymorphisms in each of the genes of a combination selected from the group consisting of the combinations listed in Table 3; (ii) comparing the determined sequence to the sequence of said polymorphisms in a control derived from a control subject (control sequence), the control subject not suffering from dilated cardiomyopathy, (iii) attributing the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure to said subject to be diagnosed if one or more determined sequences for each of said genes differ from the respective sequence in said control sequence.
  • DCM dilated cardiomyopathy
  • the present invention relates to method for diagnosing dilated cardiomyopathy (DCM) in a subject or for assessing the risk of a subject to acquire DCM or to predict the risk of a subject for heart failure comprising: (i) determining in a sample of a subject to be diagnosed the sequence of one or more polymorphisms in each of the transcripts of a combination selected from the group consisting of the combinations of transcripts listed in Table 4; (ii) comparing the determined sequence to the sequence of said polymorphisms in a control derived from a control subject (control sequence), the control subject not suffering from dilated cardiomyopathy, (iii) attributing the presence of dilated cardiomyopathy or the risk of acquiring DCM or the risk of heart failure to said subject to be diagnosed if one or more determined sequences for each of said genes differ from the respective sequence in said control sequence.
  • DCM dilated cardiomyopathy
  • TTN TTN
  • VPS 13 A SCN5A, SYNE1, DSC2, LMNA, LAMA2, ACTN2, FKTN, RBM20, PSEN1 , TMPO, LDB3, MYH6, DMD, VCL, NEBL, MYH7, DSP, FLT1, TNNC1 , MYBPC3, MYPN, TPM1, ANKRD1 , ILK, SGCD, MURC, TCAP, DOLK, and CHRM2.
  • the presence of DCM or the risk of acquiring DCM is attributed to said subject if said determined sequences of polymorphisms in two or more genes of the two panels of genes differ from the respective control sequence.
  • SCN5A (ENSGOOOOO 183873) is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene are a cause of long QT syndrome type 3 (LQT3), an autosomal dominant cardiac disease. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
  • the dystrophin gene is highly complex, containing at least eight independent, tissue-specific promoters and two polyA-addition sites. Furthermore, dystrophin RNA is differentially spliced, producing a range of different transcripts, encoding a large set of protein isoforms.
  • Dystrophin (as encoded by the Dp427 transcripts) is a large, rod-like cytoskeletal protein which is found at the inner surface of muscle fibers. Dystrophin is part of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton (F-actin) and the extra-cellular matrix, [provided by RefSeq, Jul 2008]
  • Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits.
  • MYH7 (ENSG00000092054) encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing early-onset distal myopathy, [provided by RefSeq, Jul 2008]
  • the FLT1 gene encodes a member of the vascular endothelial growth factor receptor (VEGFR) family.
  • VEGFR family members are receptor tyrosine kinases (RTKs), which contain an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and a tyrosine kinase (TK) domain within the cytoplasmic domain.
  • RTKs receptor tyrosine kinases
  • This protein binds to VEGFR-A, VEGFR-B and placental growth factor and plays an important role in angiogenesis and vasculogenesis. Expression of this receptor is found in vascular endothelial cells, placental trophoblast cells and peripheral blood monocytes.
  • Isoforms include a full-length transmembrane receptor isoform and shortened, soluble isoforms.
  • the soluble isoforms are associated with the onset of pre-eclampsia. [provided by RefSeq, May 2009]
  • Troponin is a central regulatory protein of striated muscle contraction, and together with tropomyosin, is located on the actin filament.
  • Troponin consists of 3 subunits: Tnl, which is the inhibitor of actomyosin ATPase; TnT, which contains the binding site for tropomyosin; and TnC, the protein encoded by the TNNCl gene (ENSGOOOOOl 14854).
  • Tnl which is the inhibitor of actomyosin ATPase
  • TnT which contains the binding site for tropomyosin
  • TnC the protein encoded by the TNNCl gene (ENSGOOOOOl 14854).
  • the binding of calcium to TnC abolishes the inhibitory action of Tnl, thus allowing the interaction of actin with myosin, the hydrolysis of ATP, and the generation of tension. Mutations in this gene are associated with cardiomyopathy dilated type 1Z. [provided by RefSeq, Oct
  • Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently.
  • Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function.
  • MYPN ENSGOOOOOl 38347 encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin.
  • this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function.
  • Alternative splicing results in multiple transcript variants, [provided by RefSeq, Dec 2011]
  • ILK encodes a protein with a kinase-like domain and four ankyrin-like repeats.
  • the encoded protein associates at the cell membrane with the cytoplasmic domain of beta integrins, where it regulates integrin-mediated signal transduction.
  • Activity of this protein is important in the epithelial to mesenchymal transition, and over-expression of this gene is implicated in tumor growth and metastasis.
  • Alternative splicing results in multiple transcript variants, [provided by RefSeq, Jun 2013]

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Abstract

La présente invention concerne une méthode de diagnostic d'une cardiomyopathie dilatée (CMD) chez un sujet ou d'évaluation du risque pour un sujet de développer une CMD ou une insuffisance cardiaque. Ladite méthode comprend les étapes consistant : (i) à déterminer, dans un échantillon prélevé chez un sujet devant faire l'objet d'un diagnostic, la séquence d'un ou de plusieurs polymorphismes dans un (premier) panel de gènes comprenant les gènes du groupe constitué de PIEZO1, PLEC, HELZ2, NACAD, PKD1, IGSF10, TNRC18, UNC13B, VWF et XIRP2 ; (ii) à comparer la séquence ainsi déterminée à la séquence dudit polymorphisme dans un échantillon témoin prélevé chez un sujet témoin (séquence témoin), le sujet témoin ne souffrant pas d'une cardiomyopathie dilatée ; et (iii) à confirmer la présence d'une cardiomyopathie dilatée ou du risque de développer une CMD ou une insuffisance cardiaque chez ledit sujet devant faire l'objet du diagnostic si une ou plusieurs séquences ainsi déterminées diffèrent de la séquence correspondante dans ladite séquence témoin. De plus, l'invention concerne un nécessaire ou une puce permettant de diagnostiquer une cardiomyopathie dilatée (CMD) chez un sujet ou d'évaluer le risque pour un sujet de développer une CMD, ledit nécessaire ou ladite puce comprenant des moyens permettant de déterminer la séquence d'un ou de plusieurs polymorphismes dans un (premier) panel de gènes et comprenant des sondes permettant de détecter un ou plusieurs polymorphismes mononucléotidiques à l'intérieur de chaque gène du premier panel de gènes.
PCT/EP2015/065890 2014-07-10 2015-07-10 Nouveau panel de gènes utilisable en vue du diagnostic d'une cardiomyopathie dilatée Ceased WO2016005589A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106435002A (zh) * 2016-12-12 2017-02-22 北京泱深生物信息技术有限公司 口腔鳞状细胞癌生物标记物及其应用
CN107287317A (zh) * 2017-07-10 2017-10-24 中国人民解放军第四军医大学 Myh7‑a934v突变基因用于制备诊断肥厚型心肌病试剂盒的应用

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* Cited by examiner, † Cited by third party
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WO2012107580A1 (fr) * 2011-02-10 2012-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédé de diagnostic in vitro pour prédire une prédisposition à la cardiomyopathie

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106435002A (zh) * 2016-12-12 2017-02-22 北京泱深生物信息技术有限公司 口腔鳞状细胞癌生物标记物及其应用
CN106435002B (zh) * 2016-12-12 2019-07-12 北京泱深生物信息技术有限公司 口腔鳞状细胞癌生物标记物及其应用
CN107287317A (zh) * 2017-07-10 2017-10-24 中国人民解放军第四军医大学 Myh7‑a934v突变基因用于制备诊断肥厚型心肌病试剂盒的应用

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