$aGenesAlreadyMappedTo[] = $aTranscript['gene'];
}
} else {
// We don't have the gene that this transcript belongs to in the database yet.
// Save it for now, we may need to add it later on if the variant can't be mapped to something that already exists in LOVD.
$aGenesWeCanMapTo[] = $aTranscript['gene'];
}
}
}
$aGenesWeCanMapTo = array_unique($aGenesWeCanMapTo);
if ($aVariant['mapping_flags'] & MAPPING_ALLOW_CREATE_GENES && count($aGenesWeCanMapTo)) {
// We may add extra genes to map this variant to. $aGenes contains genes we can map to.
// Try the genes one by one.
foreach ($aGenesWeCanMapTo as $sGene) {
// Get information from HGNC.
$aGeneInfoFromHgnc = lovd_getGeneInfoFromHgncOld($sGene, array('gd_hgnc_id', 'gd_app_sym', 'gd_app_name', 'gd_pub_chrom_map', 'gd_locus_type', 'gd_pub_eg_id', 'md_mim_id', 'gd_pub_refseq_ids', 'md_refseq_id'), true);
if (empty($aGeneInfoFromHgnc)) {
// Couldn't find this gene. Try the next.
continue;
}
list($sHgncID, $sSymbol, $sGeneName, $sChromLocation, $sLocusType, $sEntrez, $sOmim, $sRefseq1, $sRefseq2) = array_values($aGeneInfoFromHgnc);
// Get LRG if it exists.
if (!($sRefseqGenomic = lovd_getLRGbyGeneSymbol($sSymbol))) {
// No LRG, get NG if it exists.
if (!($sRefseqGenomic = lovd_getNGbyGeneSymbol($sSymbol))) {
// Also no NG, use the NC instead.
$sRefseqGenomic = $_SETT['human_builds'][$_CONF['refseq_build']]['ncbi_sequences'][$sChromosome];
}
}
// Get UD.
try {
function lovd_getGeneInfoFromHgncOld($sHgncId, $aCols, $bRecursion = false)
{
// Downloads gene information from the HGNC website. The specified columns will be retrieved.
// The first argument can be an HGNC accession number, an HGNC approved gene symbol, or boolean true to retrieve ALL genes.
// The results will be returned as an associative array; in case all genes have been loaded an array of arrays is returned with gene symbols as keys.
// If $bRecursion == true, this function automatically handles deprecated HGNC entries.
// On error, this function calls lovd_errorAdd if inc-lib-form.php was included. It always returns false on failure.
// Process columns.
$aColumns = $aCols;
// $aColumns will be extended with more information, whereas $aCols is used for the return value and as such should not be changed.
$sColumns = '';
foreach ($aCols as $sColumn) {
$sColumns .= 'col=' . $sColumn . '&';
}
// Make sure we request the right data.
if ($sHgncId === true) {
// Boolean true; return bulk data.
$sWhere = '';
// Using approved symbols as array keys, so we need to get them from the HGNC.
if (!in_array('gd_app_sym', $aCols)) {
$sColumns .= 'col=gd_app_sym&';
$aColumns[] = 'gd_app_sym';
}
} else {
if (ctype_digit($sHgncId)) {
// HGNC database ID.
$sWhere = 'gd_hgnc_id%3D' . $sHgncId;
} else {
// FIXME; implement proper check on gene symbol.
// Gene symbol; also match SYMBOL~withdrawn to be able to use a deprecated symbol as search key.
$sWhere = rawurlencode('gd_app_sym IN ("' . $sHgncId . '", "' . $sHgncId . '~withdrawn")');
}
// We also surely need gd_app_name to check for and handle withdrawn or deprecated entries.
if (!in_array('gd_app_name', $aCols)) {
$sColumns .= 'col=gd_app_name&';
$aColumns[] = 'gd_app_name';
}
}
$aHgncFile = lovd_php_file('http://www.genenames.org/cgi-bin/download?' . $sColumns . 'status_opt=2&where=' . $sWhere . '&order_by=gd_app_sym_sort&limit=&format=text&submit=submit');
// If the HGNC is having database problems, we get an HTML page.
if (empty($aHgncFile) || stripos(implode($aHgncFile), '<html') !== false) {
if (function_exists('lovd_errorAdd')) {
lovd_errorAdd('', 'Couldn\'t get gene information, probably because the HGNC is having database problems.');
}
return false;
}
if ($sHgncId === true) {
// Got bulk data.
$aHGNCgenes = array();
array_shift($aHgncFile);
foreach ($aHgncFile as $sGene) {
$aGene = array_combine($aColumns, explode("\t", $sGene));
$sSymbol = str_replace('~withdrawn', '', $aGene['gd_app_sym']);
if (!empty($aHGNCgenes[$sSymbol]) && $sSymbol != $aGene['gd_app_sym']) {
// Symbol has been deprecated and then reassigned to another gene, don't overwrite that one.
continue;
}
$aHGNCgenes[$sSymbol] = $aGene;
foreach (array_diff($aColumns, $aCols) as $sUnwantedColumn) {
// Don't return columns the caller hasn't asked for.
unset($aHGNCgenes[$sSymbol][$sUnwantedColumn]);
}
}
return $aHGNCgenes;
}
// Requested single entry.
if (isset($aHgncFile[1])) {
// Looks like we've got valid data here.
$aGene = array_combine($aColumns, explode("\t", $aHgncFile[1]));
// We might encorporate one or more of these locus types excludes later, so that we can throw an error without first calling mutalyzer a number of times.
//$aBadLocusTypes = array('RNA, cluster', 'RNA, transfer', 'RNA, ribosomal', 'transposable element', 'virus integration site', 'phenotype only', 'unknown', 'region', 'complex locus constituent', 'endogenous retrovirus', 'fragile site', 'T cell receptor gene', 'T cell receptor pseudogene');
$aBadLocusTypes = array('phenotype only');
if ($aGene['gd_app_name'] == 'entry withdrawn') {
if (function_exists('lovd_errorAdd')) {
lovd_errorAdd('hgnc_id', 'Entry ' . htmlspecialchars($sHgncId) . ' no longer exists in the HGNC database.');
}
return false;
} elseif (preg_match('/^symbol withdrawn, see (.+)$/', $aGene['gd_app_name'], $aRegs)) {
if ($bRecursion) {
return lovd_getGeneInfoFromHgncOld($aRegs[1], $aCols);
} elseif (function_exists('lovd_errorAdd')) {
lovd_errorAdd('hgnc_id', 'Entry ' . htmlspecialchars($sHgncId) . ' is deprecated according to the HGNC, please use ' . $aRegs[1] . '.');
}
return false;
} elseif (in_array('gd_pub_chrom_map', $aCols) && $aGene['gd_pub_chrom_map'] == 'reserved') {
if (function_exists('lovd_errorAdd')) {
lovd_errorAdd('hgnc_id', 'Entry ' . htmlspecialchars($sHgncId) . ' does not yet have a public association with a chromosomal location');
}
return false;
} elseif (in_array('gd_locus_type', $aCols) && in_array($aGene['gd_locus_type'], $aBadLocusTypes)) {
if (function_exists('lovd_errorAdd')) {
lovd_errorAdd('hgnc_id', 'LOVD cannot process this type of gene entry ' . htmlspecialchars($sHgncId) . ' (Locus Type: ' . $aGene['gd_locus_type'] . ').');
}
return false;
}
foreach (array_diff($aColumns, $aCols) as $sUnwantedColumn) {
// Don't return columns the caller hasn't asked for.
unset($aGene[$sUnwantedColumn]);
}
// 2016-09-14; 3.0-17; HGNC can return multiple OMIM IDs.
if (isset($aGene['md_mim_id']) && preg_match('/^(\\d+), /', $aGene['md_mim_id'], $aRegs)) {
// Just trim the other(s) off.
$aGene['md_mim_id'] = $aRegs[1];
}
return $aGene;
} elseif (function_exists('lovd_errorAdd')) {
// No math found, start looking for alias. We could have included an OR in the original search, but I am not
// sure if that would maybe have other genes pop up while the official gene is then ignored.
// We only do this search, if we can report if of course (hence the check for lovd_errorAdd()).
// Replace WHERE.
$sWhere = rawurlencode('CONCAT(" ", gd_aliases, ",") LIKE "% ' . $sHgncId . ',%"');
$aHgncFile = lovd_php_file('http://www.genenames.org/cgi-bin/download?' . $sColumns . 'status_opt=2&where=' . $sWhere . '&order_by=gd_app_sym_sort&limit=&format=text&submit=submit');
// Just quick check if we have a match now...
if (!empty($aHgncFile) && stripos(implode($aHgncFile), '<html') === false) {
unset($aHgncFile[0]);
$sSymbolList = '';
foreach ($aHgncFile as $sLine) {
$aGene = array_combine($aColumns, explode("\t", $sLine));
$sSymbolList .= (!$sSymbolList ? '' : ', ') . $aGene['gd_app_sym'];
}
if ($sSymbolList) {
// "Prettify" the output by replacing the last , by an "or".
$sSymbolList = preg_replace('/, ([^ ]+)$/', " or \$1", $sSymbolList);
lovd_errorAdd('hgnc_id', 'Entry ' . htmlspecialchars($sHgncId) . ' was not found, perhaps you are referring to ' . $sSymbolList . '?');
} else {
lovd_errorAdd('hgnc_id', 'Entry ' . htmlspecialchars($sHgncId) . ' was not found in the HGNC database.');
}
}
}
return false;
}
// Now that we've parsed the transcript accession number, let's see if we need to do anything with its gene.
if ($sSymbol != 'none' && empty($aGenesChecked[$sSymbol])) {
// We haven't seen this gene before in this upload.
// First try to get this gene from the database.
if ($aGene = $_DB->query('SELECT g.refseq_UD, g.name, IF(IFNULL(t.position_g_mrna_start, 0) = IFNULL(t.position_g_mrna_end, 0), NULL, IF(t.position_g_mrna_start < t.position_g_mrna_end, "+", "-")) AS strand
FROM ' . TABLE_GENES . ' AS g LEFT JOIN ' . TABLE_TRANSCRIPTS . ' AS t ON (g.id = t.geneid) WHERE g.id = ? ORDER BY t.id ASC LIMIT 1', array($sSymbol))->fetchAssoc()) {
// We've got it in the database. Check its columns.
$aGene['columns'] = $_DB->query('SELECT colid FROM ' . TABLE_SHARED_COLS . ' WHERE geneid = ? AND colid IN("' . implode('", "', $aVOTCols) . '")', array($sSymbol))->fetchAllColumn();
$aGenesChecked[$sSymbol] = $aGene;
} elseif (strpos($_POST['autocreate'], 'g') !== false) {
// We don't have this gene in the database yet. Try to add it instead.
$_BAR->setMessage('Loading gene information for ' . $sSymbol . '...', 'done');
if (empty($aGeneInfo)) {
// Getting all gene information from the HGNC takes a few seconds.
$_BAR->setMessage('Loading gene data...', 'done');
$aGeneInfo = lovd_getGeneInfoFromHgncOld(true, array('gd_hgnc_id', 'gd_app_sym', 'gd_app_name', 'gd_pub_chrom_map', 'gd_locus_type', 'gd_pub_eg_id', 'md_mim_id'));
if (empty($aGeneInfo)) {
// We can't gene information from the HGNC, so we can't add them.
// This is a major problem and we can't just continue; the user will have to give permission not to create new gene entries.
ob_start();
lovd_showInfoTable('Could not get any gene information from the HGNC database! If this problem persists, consider importing the file without creating new gene entries. ' . 'If this is not an option for you, please try again later.', 'stop');
$_BAR->setMessage(ob_get_clean(), 'done');
exit('</BODY></HTML>');
}
// Remove the Loading gene data...' message again.
$_BAR->setMessage('Loading gene information for ' . $sSymbol . '...', 'done');
}
// Get HGNC data for this gene.
while (true) {
if (empty($aGeneInfo[$sSymbol]) || $aGeneInfo[$sSymbol]['gd_app_name'] == 'entry withdrawn' || $aGeneInfo[$sSymbol]['gd_pub_chrom_map'] == 'reserved') {
// Can't use this symbol.
