Patent Publication Number: US-2018032673-A1

Title: Pathology determination assistance device, method and storage medium

Description:
TECHNICAL FIELD 
     The present invention relates to a device for assisting determination of the pathology of a test subject, more specifically to a device for assisting determination of the pathology of a test subject by displaying a list containing information on gene mutation based on the gene sequences of the test subject, and various items of medical information in connection with the gene mutation stored in public databases and the like. 
     BACKGROUND ART 
     In recent research with regard to gene-mutation-related diseases, studies of the relationship between diseases and gene mutations have been actively carried out, typically by analyzing the genetic information of patients. For example, with respect to polycystic kidney diseases (PKD), which are known as highly frequent hereditary kidney diseases that are also refractory diseases, PKD1 gene and PKD2 gene have been identified as genes causing autosomal dominant polycystic kidney disease (ADPKD). In ADPKD, about 85% of the gene mutation is due to abnormality of PKD1 gene, and about 15% is due to abnormality of PKD2 gene. It has been reported that the progression of the disease is accelerated by the abnormality of PKD1 gene. The Sanger sequence method (Non-patent Document 1) and the next-generation sequence analysis method (Patent Document 1 and Non-patent Document 2) have been publicly known as methods for detecting gene matations, and mutations of PKD1 gene and PKD2 gene can be detected by these methods. 
     Additionally, in recent years, various public databases have disclosed study results regarding the relationship between diseases and gene mutations. For example, the Polycystic Kidney Disease (PKD) Foundation website discloses a database, regarding pathogenic mutations, that is provided by the Mayo Clinic (this database is hereinafter referred to as the “Mayo database”). Fuxther, GenBank, which is run by the National Center for Biotechnology Information (NCBI) in the United States, discloses a database regarding various sequences. Thus, medical information regarding gene mutations can be obtained from these public databases. 
     CITATION LIST 
     Patent Documents 
     Patent Document 1: JP2009-11230A 
     Non-Patent Documents 
     
         
         Non-patent Document. 1: F. Sanger et al., “A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase,” Journal of Molecular Biology, April 1975, Volume 94, p. 411-446 
         Non-patent Document 2: “Next generation DNA sequencer—applications and the prospects for the clinical medicine,” Junko Sugano-Mishima et al., Modern Media, Piken Chemical Co., Ltd., August 2011, 57th edition, No. 8, p. 1-5 
       
    
     SUMMARY OF INVENTION 
     Technical Problem 
     In order to specify a pathogenic gene mutation that induces the pathology of a patient using detected gene mutation information, it is necessary to obtain various types of information, from a medical standpoint, regarding the gene mutation. Therefore, sufficient information to accurately specify a pathogenic gene mutation cannot be acquired by referring to only one public database. Further, when several to several tens of gene mutations are detected from a singie patient, it is necessary to refer to a plurality of public databases and previously published academic papers for each of these several to several tens of gene mutations individually. This is significantly time-consuming; further, it is not possible to sufficiently specify a pathogenic gene mutation without databases of healthy subjects. 
     The present invention was made to solve the above problems, and an object thereof is to provide, for example, a device for assisting determination of pathology that enables easier specification of a pathogenic gene mutation of a test subject by displaying a list containing gene mutation information based on the gene sequences of a test subject, and various items of medical information regarding gene mutation stored in public databases or the like; the device also refers to a database of gene mutations (polymorphism) of healthy subjects that is uniquely constructed. 
     Solution to Problem 
     A pathology determination assistance device of the pre gent invention for achieving the above object is a pathology determination assistance device for assisting determination of the pathology of a polycystic kidney disease. The device comprises an extraction means for extracting information on gene mutation in a region related to polycystic kidney disease using sequence data showing a gene sequence of a test subject; an acquisition means for acquiring, using the extracted information on gene mutation, medical information corresponding to the extracted gene mutation from a plurality of databases in which gene mutation and medical information are associated with each other; and a list display means for displaying a list containing the extracted information on gene mutation and the obtained medical information. 
     The pathology determination assistance device of the present invention preferably comprises a storage unit in which the databases are stored. 
     It is preferable that the information on gene mutation is chromosome position-based information, which includes a chromosome number, the position of mutation, and the kind of the base after mutation. 
     Further, a pathology determination assistance method of the present invention is a pathology determination assistance method for assisting determination of the pathology of a polycystic kidney disease. The method comprises an extraction step for extracting information on gene mutation in a region related to polycystic kidney disease using sequence data showing a gene sequence of a test subject; an acquisition step for acquiring, using the extracted information on gene mutation, medical information corresponding to the extracted gene mutation from a plurality of databases in which gene mutation and medical information are associated with each other; and a list display step for displaying a list containing the extracted information on gene mutation and the obtained medical information. 
     Further, a program of the present invention is a program for causing a computer to function as the extraction means, the acquisition means, and the list display means of the pathology determination assistance device of the present invention. 
     Further, a computer-readable storage medium of the present invention is a medium in which the above program of the present invention is stored. 
     Advantageous Effects of Invention 
     The present invention enables display of a list of gene mutation information obtained by a test subject, as well as various items of medical information regarding the gene mutation stored in public databases or the like, thereby exhaustively providing, as a list, various kinds of information required in determining the pathology of a test subject based on gene mutation information. 
     Further, the present invention provides, as the list exhaustively showing information, not only information from existing public databases, but also information from a database regarding gene mutation (polymorphism) of healthy subjects; more specifically, by performing sequence analyses of a predetermined number of healthy subjects and constructing a new unique database of healthy subjects, and referring to the thus-uniquely constructed gene mutation (polymorphism) database of healthy subjects, the present invention enables a comparison with normal gene mutations (polymorphism) observed in healthy subjects, and thereby excludes the normal gene mutations from several to several tens of detected gene mutations of a single patient, thus more easily detecting a pathogenic gene mutation in a test subject. Although patients with polycystic kidney disease have kidney cysts at birth, they often have no symptoms until they are in their 30s to 40s. Therefore, in the creation of a genetic polymorphism database of healthy subjects, it is important to select healthy subjects who are not younger than 35 years old and who were confirmed by ultrasonography to be free of kidney cysts in both kidneys. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a block diagram showing a schematic structure of a pathology determination assistance device according to an embodiment of the present invention. 
         FIG. 2  is a block diagram showing functions of a pathology determination assistance device according to an embodiment of the present invention. 
         FIG. 3  is a flow chart showing a flow of data processing performed by a pathology determination assistance device according to an embodiment of the present invention. 
     
    
    
     DESCRIPTION OF EMBODIMENTS 
     Hereinafter, an embodiment of the present invention is specifically explained with reference to the attached drawings. In the explanations and drawings below, the same reference numbers refer to the same or similar constituents, and a detailed explanation of the same or similar constituents will be omitted. 
     For ease of explanation, polycystic kidney disease (PKD) is used as the target disease in the pathology determination below. 
       FIG. 1  is a block diagram showing a schematic structure of a pathology determination assistance device  1  according to an embodiment of the present invention. In this embodiment, the pathology determination assistance device  1  is embodied as a computer system. 
     The pathology determination assistance device  1  (hereinafter may simply be referred to as a “device  1 ”) comprises a CPU  10  for performing data processing described later; a memory  11  serving as a working memory for data processing; a storage unit  12  for storing processed data; a bus  13  for transmitting data between the respective units; and an interface unit  14  (hereinafter referred to as an “I/F unit”) for performing data input and output between the device  1  and external devices. Although it is not shown in  FIG. 1 , the pathology determination assistance device  1  also comprises various general means provided in a computer, such as an operating means (e.g., a keyboard) or a display means (e.g., a display). 
     In the storage unit  12 , internal databases  12   a  are stored beforehand; in each of internal databases  12   a,  gene mutation information about the target disease (polycystic kidney disease (PKD)) and medical information regarding the gene mutation are associated with each other. 
     Further, the device  1  may also be connected to various public databases  3  via an internet  2 ; in this case, the internal databases  12   a  may store medical information regarding gene mutation that is acquired from the public databases  3 , as well as gene mutation information about the target disease that is obtained by querying the public databases  3 ; these information items are associated with each other. 
       FIG. 2  is a block diagram showing functions of the device  1  according to an embodiment of the present invention. The device  1  comprises an extraction unit  21 , an acquisition unit  22 , and a list display unit  23 . These functional blocks are embodied by installing the program of the present invention to the device  1 . These functions are described later. 
     1) Gene Mutation Information 
     In the embodiment of the present invention, the gene mutation information is expressed based on information on chromosome position. The gene mutation information includes a chromosome number, the position (start position and end position) of the mutation in the chromosome having this number, and the type of the base after mutation. Table 1 shows an example of gene mutation information with regard to polycystic kidney disease (PKD). It is known that, in the case of PKD, PKD1 gene abnormality is present in the 16th chromosome (chr 16), and PKD2 gene abnormality is present in the fourth chromosome (chr 4). 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Contig 
                 Start pos 
                 End pos 
                 Ref value 
                 Actual value 
               
               
                   
               
             
            
               
                 chr16 
                  2143 657. 
                  2143 657. 
                 G 
                 T 
               
               
                 chr16 
                  2154 478. 
                  2154 478. 
                 A 
                 G 
               
               
                 chr16 
                  2160 494. 
                  2160 494. 
                 C 
                 T 
               
               
                 chr16 
                  2164 808. 
                  2164 808. 
                 C 
                 T 
               
               
                 chr16 
                  2166 672. 
                  2166 672. 
                 G 
                 A 
               
               
                 chr16 
                  2167 874. 
                  2167 874. 
                 G 
                 A 
               
               
                 chr4 
                 88929 305. 
                 88929 305. 
                 G 
                 A 
               
               
                 chr4 
                 88959 381. 
                 88959 381. 
                 G 
                 A 
               
               
                 chr4 
                 88979 196. 
                 88979 196. 
                 C 
                 T 
               
               
                 chr4 
                 88997 102. 
                 88997 102. 
                 C 
                 T 
               
               
                   
               
            
           
         
       
     
     In Table 1, the Contig column shows a chromosome number, the Start pos and End pos columns show the position of mutation (start position and end position), and the Actual value column shows the type of the base after mutation. The Ref value column shows the normal base, i.e., the type of the base before mutation, at the position. 
     2) Internal Databases 
     Six kinds of databases are described below as examples of various internal databases  12   a  that are prepared beforehand. 
     Database of Healthy Japanese Subjects 
     Samples (e.g., blood samples) were obtained from a predetermined number (e.g., 140 subjects) of healthy Japanese subjects not younger than a predetermined age (e.g., 35 years old) having no cysts in both of their kidneys; the samples were subjected to sequence analysis by a known method, and information on the position of the detected gene mutation (for example, single nucleotide polymorphism, SNP) is converted into position information based on chromosome position information; the resulting information is stored as an internal database  12   a.    
     When a query is given to this database, and if the gene mutation matching the query is stored in the database as a record, information as to how many subjects out of the predetermined number of subjects have the corresponding gene mutation is returned as the query result. 
     Cons Paper Database 
     If genes of different species derived from a common ancestor were changed in the course of evolution, the proteins derived from the genes often have a common function. Such a region having a high homology between different species is called a “conserved region”. The conserved region is considered important in the function of the proteins. The Cons paper (Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genome. Genome ReS2005 15: 1034-1050), published by Adam Siepel et al., shows a method of expressing a state of gene region conservation using values. By quantifying the conservation states of the respective bases of the PKD1 gene region and the PKD2 gene region in the Cons paper into Cons scores, and associating the Cons scores with the position information based on the chromosome position information, the resulting information is stored as an internal database  12   a.    
     When a query is given to this database, and if the gene mutation matching the query is stored in the database as a record, the Cons score returned as the query result from the database. The Cons score is a real number in the range of 0 to 1, and serves as an index showing that, as the score is closer to 1, the region is more conserved, and that the presence of mutation in the base indicates a high pathogenicity. 
     Mayo Database 
     The data of pathogenic mutations regarding PKD1 mutation and PKD2 mutation disclosed in the Mayo database is associated with position information based on chromosome position information, and is stored as an internal database  12   a.    
     When a query is given to this database, and if the gene mutation matching the query is stored in the database as a record, a classification of determination used in the PKD foundation is returned. Examples of the classifications include “Definitely Pathogenic” and “Highly Likely Pathogenic.” 
     PubMed ID Database 
     PubMed is a database of document information created by the U.S. National Center for Biotechnology Information (NCBI). Information of pathogenic gene mutations is extracted beforehand from the hitherto-published academic papers and the like accumulated in PubMed, and is associated with the position information based on the chromosome position information. The resulting information is stored as an internal database  12   a.    
     When a query is given to this database, and if the gene mutation matching the query is stored in the database as a record, PubMed ID is returned. PubMed ID refers to unique ID numbers of documents accumulated in PubMed. 
     Pseudogene Sequence Database 
     Pseudogene sequences PKD1P1, PKD1P2, PKD1P3, PKD1P4, PKD1P5, and PKD1P6, which are known pseudogene sequences with respect to PhD gene, are obtained from various public databases and are compared with PKD1 gene. The mutation sites that differ between the pseudogenes and the normal gene PKD 1  are extracted, and are associated with the position information based on the chromosome position. The resulting information is stored as an internal database  12   a.    
     When a query is given to this database, and if the gene mutation matching the query is stored in the database as a record, a result indicating that the gene mutation matching the query is a mutation derived from a pseudogene is returned as the query result from the database. When a plurality of gene mutations derived from these pseudogenes is extracted, it is likely that the pseudogenes were amplified by long-range PCR, which is described later. This serves as an index of accuracy management in gene examinations. 
     GenBank Database 
     The information regarding the position of gene mutations of PKD1 gene and PKD2 gene obtained from GenBank database are converted to the position information based on the chromosome position information, and are stored as an internal database  12   a.    
     When a query is given to this database, and if the gene mutation matching the query is stored in the database as a record, the rs# number is returned as a query result from the database. The rs# number refers to a reference SNP ID number, which is a universal SNP ID number defined for each SNP by the NCBI. 
     3) Performance of the Pathology Determination Assistance Device 
     In the explanation below, a process performed by the device  1  means a process performed by the CPU  10  of the device  1  unless otherwise specified. The CPU  10  temporarily stores necessary data (such as intermediate data being processed) in a memory  11  that serves as a working memory, and stores the data that are stored for a long period of time, such as calculation results, in the storage unit  12  as necessary. Further, in order to carry out steps S 1  to S 4  described below, the device  1  stores the program of the present invention in the storage unit  12  beforehand, for example, in an executable format (for example, a form in which the program can be produced by being converted from a programming language such as C language using a compiler). The device  1  carries out processing using the program stored in the storage unit  12 . The program may also be installed to the device from a computer-readable storage medium such as a CD-ROM; otherwise, the device  1  may be connected to the internet  2  to download the program code of the program via the internet  2 . 
       FIG. 3  is a flow chart showing a flow of data processing performed by a pathology determination assistance device according to an embodiment of the present invention. The data processing performed by the pathology determination assistance device according to the embodiment of the present invention is described in detail below based on the flow chart shown in  FIG. 3 . 
     In step S 1 , sequence data of a test subject is read into the device. The sequence data is created, for example, as FASTQ format data or VCF data beforehand, for example, from a sample enabling gene analysis, such as blood of the test subject, using a commercially available sequencer device, and is stored in the storage unit  12  beforehand. Alternatively, the sequence data may be acquired and read from an external device via the I/F unit  14  or the internet  2 . 
     Creation of sequence data is explained below. In the case of polycystic kidney disease (PKD) that is used as the target disease in the determination in this embodiment, PKD1 gene and PKD2 gene have a relatively large size; therefore, a sequencer device using a next-generation sequence analysis method is more preferable, as the sequencer device for performing the detection of gene mutation, than a sequencer device using the Sanger method. 
     The Sanger method is a method for determining base sequence using the principle that when dideoxynucleotide is captured during the DNA replication in a sequencing reaction, the nucleic acid elongation reaction is stopped. The Sanger method ensures sufficient sensitivity for point mutation; however, the method has a problem such that if mutation other than point mutation such as deletion or insertion of the bases is present, the base sequences after the corresponding site cannot be read. Further, in the method using the Sanger method, determination of base sequence by a single kind of sequence primer is possible only for a limited chain length (up to about 500 bp). Therefore, even if only PKD1 is to be detected, it is necessary to use 90 kinds of primers for each specimen, thereby requiring a large number of processes, and thus significantly increasing the costs. 
     In contrast, in the analysis method called a next-generation sequence analysis method, first, exon of PKD1 gene is amplified by long-range PCR using a genomic DNA as a template, and a library of fragments of 35 bp to 400 bp is prepared. Thereafter, the base sequence is determined using a commercially available sequencer device. The next-generation sequence analysis method is capable of mass sequencing and is suitable for many kinds of analyses such as exome analysis or sequencing of genes having relatively a large size, such as PKD1 gene and PKD2 gene. 
     In this embodiment, the sequence data is created beforehand, for example, by a sequencer device using a next-generation sequence analysis method. 
     In step S 2  (extraction step), the extraction unit  21  shown in  FIG. 2  performs mapping and alignment of the sequence fragment length of the read sequence data (FASTQ format), thereby extracting gene mutation from the sequence data. As a specific means for extracting gene mutation, for example, known software for extracting SNP (single nucleotide polymorphism) may be used. 
     The extracted gene mutation information is expressed based on the information on chromosome position, which includes a chromosome number, the position (start position and end position) of the mutation in the chromosome having this number, and the type of the base after mutation. At this point in time, the extracted gene mutations include a synonymous mutation that has a mutation but has the same amino acid coded by the gene and the same protein function as those before the mutation, as well as gene mutations (polymorphism) other than the pathogenic gene mutation of polycystic kidney disease (PKD), which is the target disease in the determination. 
     Compared with the sequence fragment length in prior art that was about 75 bp, the sequence fragment length in this embodiment, which is set upon the extraction of gene mutation, is longer (about 400 bp) than the amplification range and amplification cross section in long-range PCR, thereby increasing the detection rate (correlation rate with respect to the ADPKD patients) from 63% to 89%. 
     In step S 3  (acquisition step), the acquisition unit  22  shown in  FIG. 2  acquires medical information regarding the gene mutation from a plurality of internal databases  12   a  using the extracted gene mutation information extracted in step S 2 . More specifically, using gene mutation information, i.e., a chromosome number, the position of mutation in the chromosome having this number, and the type of the base after mutation as search queries, the acquisition unit  22  queries each of the plurality of internal databases  12   a  to find any records that match the search queries. If there are any records that match the search queries in the internal databases  12   a,  information defined in each internal database  12   a  is returned as a query result. 
     For example, when a query regarding the presence or absence of records about mutation “T” present in position 2160494 in the 16th chromosome is given to the internal databases  12   a,  the gene mutation information of this query is “Contig=chr 16, Startpos=2160494, Endpos=2160494, Actual value=T.” For example, in the case of the Mayo database, the device  1  determines whether the Mayo database has any records of this gene mutation information. When the records are stored in the database, the device  1  acquires a classification “Likely Neutral,” which is medical information associated with the gene mutation information “Contig=chr 16, Startpos=2160494, Endpos=2160494, Actual value=T,” as a query result from the internal database  12   a.  When there are no records in the database, the device  1  acquires information indicating that no records are stored (for example, NULL). 
     As in the Mayo database, for other internal databases  12   a  as well, the acquisition unit  22  determines whether any records of gene mutation information represented by “Contig=chr 16, Startpos=2160494, Endpos=2160494, Actual value=T” is stored in each internal database  12   a.  When the database has any records, the device  1  acquires medical information associated with the gene mutation. For example, in the case of the healthy Japanese subjects database, the medical information corresponds to information as to how many subjects out of the predetermined number of subjects have the gene mutation. Similarly, in the case of the Cons paper database, the medical information corresponds to the Cons score; in the case of the GenBank database, the medical information corresponds to the rs# number; and in the case of the PubMed ID database, the medical information corresponds to the PubMed ID. 
     In step S 4  (list display step), the list display unit  24  shown in  FIG. 2  displays a list containing gene mutation information extracted in step S 2  and medical information obtained in step S 3 . Table 2 shows an example of items in the list. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                   
                   
                   
                   
                   
                 Actual 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Ref  
                 Actual  
                 DB #1 
                 DB #2 
                 DB #3 
                 DB #4 
                 DB #5 
               
               
                 Contig 
                 Start pos 
                 End pos 
                 value 
                 value 
                 Mayo Classification 
                 Id 
                 Jap Ref 
                 Cons 
                 PMID 
               
               
                   
               
               
                 chr16 
                  2143 657. 
                  2143 657. 
                 G 
                 T 
                   
                   
                   
                 0 
                   
               
               
                 chr16 
                  2154 478. 
                  2154 478. 
                 A 
                 G 
                 Likely Neutral 
                 rs4786209 
                 100/140 
                 0 
                   
               
               
                 chr16 
                  2160 494. 
                  2160 494. 
                 C 
                 T 
                 Likely Neutral 
                 rs79884128 
                  54/140 
                 0.023622 
                 22185115 
               
               
                 chr16 
                  2164 808. 
                  2164 808. 
                 C 
                 T 
                   
                 rs40433 
                  24/140 
                 0 
                   
               
               
                 chr16 
                  2166 672. 
                  2166 672. 
                 G 
                 A 
                 Likely Neutral 
                 rs4787158 
                  15/140 
                 0 
                   
               
               
                 chr16 
                  2167 874. 
                  2167 874. 
                 G 
                 A 
                 Likely Neutral 
                   
                   
                 0 
                   
               
               
                 chr4 
                 88929 305. 
                 88929 305. 
                 G 
                 A 
                 Likely Neutral 
                 rs2728118 
                  90/140 
                 0.267717 
                 22008521 
               
               
                 chr4 
                 88959 381. 
                 88959 381. 
                 G 
                 A 
                   
                 rs2725221 
                 122/140 
                 0 
                 22008521 
               
               
                 chr4 
                 88979 196. 
                 89979 196. 
                 C 
                 T 
                 Definitely Pathogenic 
                 rs146396414 
                   
                 1—Likely pathogenic 
                   
               
               
                 chr4 
                 88997 102. 
                 88997 102. 
                 C 
                 T 
                   
                 rs2728121 
                 101/140 
                 0 
               
               
                   
               
            
           
         
       
     
     In Table 2, the Contig column shows a chromosome number, the Start pos and End pos columns show the position (start position and end position) of mutation, and the Actual value column shows the type of the base after mutation. The Ref value column shows the normal base, i.e., the type of the base before mutation, at the position. The “Actual” and “DB #1” to “DB #5” columns show medical information obtained from the internal databases  12   a.  These columns show, from left to right, classification according to the Mayo database, the rs# number according to the GenBank database, the number of gene mutation carriers according to the healthy Japanese subjects database, the Cons score according to the Cons paper database, and the PubMed ID according to the PubMed ID database. 
     For example, referring to Table 2 regarding mutation “T” in position 2160494 in the 16th chromosome, the row specified by “Contig=chr 16, Startpos=2160494, Endpos=2160494, Actual value=T” shows, as a list, classification (Likely Neutral) according to the Mayo database, the rs# number (rs 79884128), the number of gene mutation carriers among Japanese (54/140), the Cons score (0.023622), and the PubMed ID (22185115). 
     Further, Table 2 shows one to several tens of gene mutations extracted from the sequence data of the test subject. Each of the extracted gene mutations is displayed while being individually associated with medical information acquired from the internal databases  12   a.  The information items exhaustively listed in Table 2 are various kinds of information, from a medical standpoint, required to determine the pathology of the patient. 
     As described above, the present invention enables display of a list containing gene mutation information obtained from a test subject and various items of medical information regarding the gene mutation stored in public databases or the like, thereby exhaustively providing, in the form of a list, various items of information required to determine the pathology of the test subject based on gene mutation information. Therefore, with the present invention, it becomes unnecessary to individually refer to a plurality of public databases or academic papers and the like for the individual gene mutations, thereby reducing the labor required for the pathology determination of the test subject. 
     Further, since these information items required for the determination are exhaustively displayed, it becomes unnecessary to stop the determination work in each step of referring to a plurality of public databases or academic papers and the like, thereby allowing the user to focus more on the determination work. 
     An embodiment of the present invention has been explained above; however, the present invention is not limited to the embodiment above. 
     Although a list of gene mutation information extracted in step S 2  and medical information obtained in step S 3  are displayed in step S 4  in the embodiment described above, the items of gene mutation information in the list may be different from those in this embodiment. In addition to these information items, any items required for the determination may be suitably selected from various items, such as effects of mutation (Effect), discrimination between PKD1 gene and PKD2 gene (Region), codon mutation (Codon), amino acid mutation (Aa), nucleotide mutation (Nuc ch), and protein change (Prot ch), to be added to the list. Table 3 shows an example of a list including these additional items. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
             
            
               
                   
                   
                   
                   
                   
                 Actual 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Ref  
                 Actual  
                   
                   
                   
                   
               
               
                 Contig 
                 Start pos 
                 End pos 
                 value 
                 value 
                 Effect 
                 Region 
                 Codon 
                 Aa 
               
               
                   
               
               
                 chr16 
                  2143 657. 
                  2143 657. 
                 G 
                 T 
                 Non syn cod 
                 PKD1 
                 gCt/gAt 
                 A3635D 
               
               
                 chr16 
                  2154 478. 
                  2154 478. 
                 A 
                 G 
                 Intron 
                 PKD1 
                   
                   
               
               
                 chr16 
                  2160 494. 
                  2160 494. 
                 C 
                 T 
                 Syn coding 
                 PKD1 
                 acG/acA 
                 T1558T 
               
               
                 chr16 
                  2164 808. 
                  2164 808. 
                 C 
                 T 
                 Non syn cod 
                 PKD1 
                 cCg/cAg 
                 R739Q 
               
               
                 chr16 
                  2166 672. 
                  2166 672. 
                 G 
                 A 
                 Intron 
                 PKD1 
                   
                   
               
               
                 chr16 
                  2167 874. 
                  2167 874. 
                 G 
                 A 
                 Syn coding 
                 PKD1 
                 ctC/ctT 
                 L373L 
               
               
                 chr4 
                 88929 305. 
                 88929 305. 
                 G 
                 A 
                 Syn coding 
                 PKD2 
                 ggG/ggA 
                 G140G 
               
               
                 chr4 
                 88959 381. 
                 88959 381. 
                 G 
                 A 
                 Intron 
                 PKD2 
                   
                   
               
               
                 chr4 
                 88979 196. 
                 89979 196. 
                 C 
                 T 
                 Stop gained 
                 PKD2 
                 Cga/Tga 
                 R654* 
               
               
                 chr4 
                 88997 102. 
                 88997 102. 
                 C 
                 T 
                 Utr3 prime 
                 PKD2 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Actual 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 DB #1 
                 DB #2 
                 DB #3 
                 DB #4 
                 DB #5 
               
               
                 Contig 
                 Nuc ch 
                 Prot ch 
                 Mayo Classification 
                 Id 
                 Jap Ref 
                 Cons 
                 PMID 
               
               
                   
               
               
                 chr16 
                   
                   
                   
                   
                   
                 0 
                   
               
               
                 chr16 
                 8161 + 21T &gt; C 
                 Likely Silent  
                 Likely Neutral 
                 rs4786209 
                 100/140 
                 0 
                   
               
               
                 chr16 
                 4674G &gt; A 
                 Thr1558Thr 
                 Likely Neutral 
                 rs79884128 
                  54/140 
                 0.023622 
                 22185115 
               
               
                 chr16 
                   
                   
                   
                 rs40433 
                  24/140 
                 0 
                   
               
               
                 chr16 
                 1607 − 27C &gt; T 
                 Likely Silent 
                 Likely Neutral 
                 rs4787158 
                  15/140 
                 0 
                   
               
               
                 chr16 
                 1119C &gt; T 
                 Leu373Leu 
                 Likely Neutral 
                   
                   
                 0 
                   
               
               
                 chr4 
                  420G &gt; A 
                 Gly140Gly 
                 Likely Neutral 
                 rs2728118 
                  90/140 
                 0.267717 
                 22008521 
               
               
                 chr4 
                   
                   
                   
                 rs2725221 
                 122/140 
                 0 
                 22008521 
               
               
                 chr4 
                 1960C &gt; T 
                 Arg654X 
                 Definitely Pathogenic 
                 rs146396414 
                   
                 1—Likely pathooenic 
                   
               
               
                 chr4 
                   
                   
                   
                 rs2728121 
                 101/140 
                 0 
               
               
                   
               
            
           
         
       
     
     Further, although the data processing shown in  FIG. 3  is performed by the CPU  10  in the embodiment described above, the data processing may also be performed in such a manner that the processing performed by the CPU  10  is first divided to separate functions, a dedicated electronic circuit is created for each function, and these electronic circuits execute the divided steps of the data processing in  FIG. 3 . 
     Further, although a stand-alone system in which the internal databases  12   a  are stored in the storage unit  12  of the device  1  is used in the embodiment described above, the storage for storing the internal databases  12   a  is not limited to the storage unit  12 . For example, a network-type system may be used in which the internal databases  12   a  are stored in another computer device separated from the device  1 , and obtained by accessing the other computer device through the internet  3 . 
     Further, in the embodiment described above, the information on gene mutation with respect to the target disease and the medical information in connection with the gene mutation are associated with each other and stored in the internal databases  12   a  beforehand; however, it is not necessary to fix the information items in the internal database  12   a;  instead, the information items may be dynamically and regularly updated, for example, through the internet  3 . Examples of the means for dynamically updating the contents of the internal databases  12   a  includes creation of an automation program in which update procedures are written in a script language. In this case, the automation program is stored in the storage unit  12  in the device  1 , and is regularly booted to automatically access the public databases  3  so as to automatically collect information required for the update of the internal databases  12   a  from the public databases  3 , thereby updating the contents of the internal databases  12   a.    
     Further, although the operating means and the display means are described as separate structures in the embodiment described above, the operating means and the display means may be unified to form a touch-panel-type structure. 
     Further, in the embodiment described above, text information is displayed in step S 4  as the information items to be displayed as a list; however, it may also be configured such that predetermined processing associated with the text information is suitably executed. For example, it may be configured such that, when a list of PubMed ID is displayed, by specifying a PubMed ID number using, for example, an operating means (mouse), the data files of academic papers associated with the ID number are displayed. 
     DESCRIPTION OF REFERENCE NUMERALS 
     
         
           1 . Pathology determination assistance device 
           2 . Internet. 
           3 . Public database 
           10 . CPU 
           11 . Memory 
           12 . Storage unit 
           12   a.  Internal database 
           13 . Bus 
           14 . Interface unit 
           21 . Extraction unit (extraction means) 
           22 . Acquisition unit (acquisition means) 
           23 . List display unit (list display means)