{"id":1574,"date":"2018-11-11T14:21:58","date_gmt":"2018-11-11T13:21:58","guid":{"rendered":"http:\/\/www.newslab.sk\/2018\/11\/11\/diagnostika-cystickej-fibrozy-so-zameranim-na-molekularnogeneticku-analyzu-cftr-genu\/"},"modified":"2018-11-11T14:26:14","modified_gmt":"2018-11-11T13:26:14","slug":"diagnostika-cystickej-fibrozy-so-zameranim-na-molekularnogeneticku-analyzu-cftr-genu","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/diagnostika-cystickej-fibrozy-so-zameranim-na-molekularnogeneticku-analyzu-cftr-genu\/","title":{"rendered":"Trends in cystic fibrosis diagnostic with focus on the molecular analysis of CFTR gene"},"content":{"rendered":"

*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/span><\/strong><\/p>\n

 <\/p>\n

Prv\u00e9 historick\u00e9 zmienky o tomto ochoren\u00ed siahaj\u00fa do stredoveku, ke\u010f sa slan\u00fd pot u det\u00ed sp\u00e1jal s poruchami pankreasu a rizikom v\u010dasn\u00e9ho \u00famrtia a tieto deti boli pova\u017eovan\u00e9 za obete bosor\u00e1ctva. Exaktn\u00fd medic\u00ednsky poh\u013ead na cystick\u00fa fibr\u00f3zu medzi prv\u00fdmi priniesla americk\u00e1 patologi\u010dka a pediatri\u010dka Dorothy Andersenov\u00e1 v roku 1938, ke\u010f op\u00edsala toto ochorenie v pitevnom n\u00e1leze ako \u201ecystick\u00fa fibr\u00f3zu pankreasu\u201c. Pre diagnostiku CF bol d\u00f4le\u017eit\u00fd objav zv\u00fd\u0161enej koncentr\u00e1cie chloridov v pote Paulom di Sant\u2019 Agnesom, ktor\u00fd sa stal z\u00e1kladom dodnes pou\u017e\u00edvan\u00e9ho potn\u00e9ho testu zaveden\u00e9ho v roku 1953.<\/p>\n

O desa\u0165 rokov sa Dr. Andersenov\u00e1 podie\u013eala aj na v\u00fdvoji potn\u00e9ho testu, ktor\u00fd m\u00e1 odvtedy nezastupite\u013en\u00e9 miesto\u00a0 v diagnostike CF. \u010eal\u0161\u00edmi v\u00fdznamn\u00fdmi m\u00ed\u013enikmi bola identifik\u00e1cia poruchy chloridov\u00e9ho kan\u00e1la ako z\u00e1kladn\u00e9ho patofyziologick\u00e9ho mechanizmu (1983) a n\u00e1sledne objav CFTR <\/em>g\u00e9nu (1989). Odvtedy sa diagnostika a klinick\u00fd mana\u017ement CF rozv\u00edja m\u00ed\u013eov\u00fdmi krokmi, \u010do sa odrazilo na v\u00fdraznom zlep\u0161en\u00ed kvality a pred\u013a\u017een\u00ed \u017eivota. Medi\u00e1n veku vo vyspel\u00fdch krajin\u00e1ch aktu\u00e1lne dosahuje 37 rokov(1).<\/p>\n

 <\/p>\n

Novorodeneck\u00fd skr\u00edning CF na Slovensku<\/h1>\n

Skr\u00edning cystickej fibr\u00f3zy sa na Slovensku zaviedol od +.9. 2009. Princ\u00edpom met\u00f3dy je stanovenie imunoreakt\u00edvneho trypsinog\u00e9nu (IRT) v suchej kvapke krvi pod\u013ea algoritmu IRT\/IRT, teda dvojstup\u0148ov\u00e9ho stanovovania hladiny IRT. Trypsinog\u00e9n je pankreatick\u00fd prote\u00edn \u2013 neakt\u00edvny prekurzor tryps\u00ednu, ktor\u00fd sa v d\u00f4sledku ob\u0161trukcie pankreatick\u00fdch kan\u00e1likov pri CF dost\u00e1va do krvn\u00e9ho obehu. Hrani\u010dn\u00fd limit (cut-off) pre prv\u00fd odber (IRT\/1) vo vzorke odobratej v 72. \u2013 96. hodine \u017eivota je 70 ng\/ml (99. percentil) a pre druh\u00fd odber (IRT\/2) medzi 14. \u2013 21. d\u0148om \u017eivota hodnota 60 ng\/ml. Pri celoplo\u0161nom novorodeneckom skr\u00edningu CF mus\u00ed by\u0165 zoh\u013ead\u0148ovan\u00fd aj etnick\u00fd p\u00f4vod die\u0165a\u0165a. Sk\u00fasenosti z n\u00e1rodn\u00e9ho referen\u010dn\u00e9ho skr\u00edningov\u00e9ho centra preuk\u00e1zali, \u017ee novorodenci r\u00f3mskeho etnika maj\u00fa \u010dasto falo\u0161ne pozit\u00edvne v\u00fdsledky skr\u00edningu a signifikantne vy\u0161\u0161ie hladiny IRT (a\u017e o 34 %) v porovnan\u00ed s majoritnou popul\u00e1ciou. Pre r\u00f3mske etnikum sa preto zv\u00fd\u0161ila hrani\u010dn\u00e1 hodnota IRT\/1 na 84 ng\/ml a IRT\/2 na 72 ng\/ml(4). Podobn\u00e1 situ\u00e1cia je dokumentovan\u00e1 v USA u det\u00ed afro-ameri\u010danov.<\/p>\n

Celosvetovo sa pri skr\u00edningu cystickej fibr\u00f3zy uv\u00e1dza falo\u0161n\u00e1 negativita 5 a\u017e 9 %(2,3), preto pri zodpovedaj\u00facom klinickom n\u00e1leze je potrebn\u00e9 zv\u00e1\u017ei\u0165 mo\u017enos\u0165 CF aj u det\u00ed, ktor\u00e9 absolvovali novorodeneck\u00fd skr\u00edning s negat\u00edvnym v\u00fdsledkom. Ne\u0161pecifick\u00e9 zv\u00fd\u0161enie hladiny IRT je op\u00edsan\u00e9 u novorodencov s perinat\u00e1lnou asfyxiou a m\u00f4\u017ee vies\u0165 k falo\u0161nej pozitivite. V\u010faka novorodeneck\u00e9mu skr\u00edningu sa priemern\u00fd vek pri diagnostike ochorenia zn\u00ed\u017eil na 6 a\u017e 8 t\u00fd\u017ed\u0148ov oproti 14 mesiacom pred zaveden\u00edm skr\u00edningu(3). Identifik\u00e1cia pacientov s CF novorodeneck\u00fdm skr\u00edningom a skor\u00e1 lie\u010dba ved\u00fa k v\u00fdznamne lep\u0161ej progn\u00f3ze.<\/p>\n

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Klinick\u00e9 prejavy cystickej fibr\u00f3zy<\/h1>\n

CF je multiorg\u00e1nov\u00e9 ochorenie, pr\u00edznaky ochorenia m\u00f4\u017eu by\u0165 u ka\u017ed\u00e9ho pacienta vyjadren\u00e9 v r\u00f4znej intenzite a postihova\u0165 rozli\u010dn\u00e9 org\u00e1ny. V novorodeneckom veku je asi u 1\/5 det\u00ed s CF pr\u00edtomn\u00fd tzv. mek\u00f3niov\u00fd ileus. Typick\u00e9 sinopulmon\u00e1lne pr\u00edznaky s\u00fa chronick\u00e1 rinos\u00ednusit\u00edda, nosn\u00e1 polyp\u00f3za, atelekt\u00e1zy, bronchiekt\u00e1zie, pali\u010dkovit\u00e9 prsty, perzistuj\u00face infekcie patog\u00e9nmi typick\u00fdmi pre CF a p\u013e\u00facne mykobakteri\u00f3zy, pneumotorax, hemopt\u00fdza a alergick\u00e1 bronchopulmon\u00e1lna aspergil\u00f3za. Z prejavov mimo respira\u010dn\u00e9ho traktu potom dominuj\u00fa poruchy tr\u00e1viaceho traktu: mek\u00f3niov\u00fd ileus, insuficiencia exokrinn\u00e9ho pankreasu a recidivuj\u00face pankreatit\u00eddy, diabetes mellitus, gastroezof\u00e1gov\u00fd reflux, syndr\u00f3m ob\u0161trukcie dist\u00e1lneho \u010dreva, bili\u00e1rna cirh\u00f3za a\u017e cirh\u00f3za pe\u010dene, choleliti\u00e1za, malnutr\u00edcia, metabolick\u00e1 kostn\u00e1 choroba a de- ficit vitam\u00ednov rozpustn\u00fdch v tukoch (A, D, E, K). Abnormality v mineralograme a acidob\u00e1zickej rovnov\u00e1he s\u00fa d\u00f4le\u017eit\u00fdmi pr\u00edznakmi CF. Pri ak\u00fatnej hyponatriemickej dehydrat\u00e1cii doch\u00e1dza k anorexii, vracaniu, hmotnostn\u00e9mu \u00fabytku s rizikom rozvoja poruchy vedomia a k\u0155\u010dov. Chronick\u00e1 metabolick\u00e1 alkal\u00f3za s hypokali\u00e9miou bola op\u00edsan\u00e1 u dospel\u00e9ho pacienta ako prv\u00fd pr\u00edznak cystickej fibr\u00f3zy(5).<\/p>\n

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Diagnostika CF<\/h1>\n

Pri klinickej suspekcii alebo pozit\u00edvnom\/hrani\u010dom v\u00fdsledku novorodeneck\u00e9ho skr\u00edningu je indikovan\u00fd potn\u00fd test. Ten- to test je zalo\u017een\u00fd na stanoven\u00ed koncentr\u00e1cie chloridov v pote pilokarp\u00ednovou ionofor\u00e9zou a m\u00e1 senzitivitu asi 95 %. Hodnoty nad 60 mmol\/l s\u00fa diagnostick\u00e9 pre CF, hodnoty 30 \u2013 59 mmol\/l s\u00fa ozna\u010dovan\u00e9 ako hrani\u010dn\u00e9 a diagn\u00f3za CF je mo\u017en\u00e1, pri hodnot\u00e1ch pod 30 mmol\/l je CF nepravdepodobn\u00e1. Test a jeho laborat\u00f3rne vyhodnotenie musia prebieha\u0165 pod\u013ea stanoven\u00fdch minim\u00e1lnych \u0161tandardov(1). N\u00e1sledne je indikovan\u00e9 molekul\u00e1rnogenetick\u00e9 vy\u0161etrenie CFTR <\/em>g\u00e9nu, \u0161tandardne sa v prvom kroku vy\u0161etruje panel mut\u00e1ci\u00ed naj\u010dastej\u0161\u00edch v danej popul\u00e1cii (tabu\u013eka 1)<\/em><\/strong>.<\/p>\n

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Ochorenia pr\u00edbuzn\u00e9 CFTR<\/em><\/h1>\n

Klinick\u00e9 jednotky s dysfunkciou CFTR<\/em>, ktor\u00e9 nesp\u013a\u0148aj\u00fa klinick\u00e9 krit\u00e9ri\u00e1 pre cystick\u00fa fibr\u00f3zu, s\u00fa s\u00fahrnne ozna\u010dovan\u00e9 ako poruchy pr\u00edbuzn\u00e9 CFTR <\/em>(CFTR<\/em>-related disorders, CFTR<\/em>-Rds)(6). Pod\u013ea aktu\u00e1lne platn\u00fdch odpor\u00fa\u010dan\u00ed Nad\u00e1cie pre cystick\u00fa fibr\u00f3zu (Cystic Fibrosis Foundation) z roku 2017 s\u00fa definovan\u00e9 tri poruchy pr\u00edbuzn\u00e9 CFTR<\/em>: rekurentn\u00e1 pankreatit\u00edda, kongenit\u00e1lna bilater\u00e1lna agen\u00e9za vas deferens (CBAVD) a chronick\u00e9 z\u00edskan\u00e9 bronchiekt\u00e1zie(7).<\/p>\n

Pre pr\u00edpady pozit\u00edvneho novorodeneck\u00e9ho skr\u00edningu a intermedi\u00e1rnych hodn\u00f4t potn\u00e9ho testu sa v USA pou\u017e\u00edva pojem metabolick\u00fd syndr\u00f3m pr\u00edbuzn\u00fd CFTR <\/em>(CF transmembrane conductance regulator-related metabolic syndrome, CRMS), ktor\u00fd sa prekr\u00fdva s jednotkou pozit\u00edvny skr\u00edning CF, nejednozna\u010dn\u00e1 diagn\u00f3za (CF screen positive, inconclusive diagnosis, CFSPID), pou\u017e\u00edvanou v ostatn\u00fdch krajin\u00e1ch. U v\u00e4\u010d\u0161iny det\u00ed s poruchami pr\u00edbuzn\u00fdmi CFTR <\/em>sa v prv\u00fdch rokoch \u017eivota nerozvinie obraz cystickej fibr\u00f3zy. V malej \u010dasti sa v\u0161ak rozv\u00edja CF a zatia\u013e nie s\u00fa dostupn\u00e9 \u00fadaje o dlhodobej progn\u00f3ze t\u00fdchto pacientov(8,9).<\/p>\n

CFTR<\/em>-RDs a CRMS\/CFSPID nahr\u00e1dzaj\u00fa nejasn\u00e9 ozna\u010denia atypick\u00e1, neklasick\u00e1 alebo neskor\u00e1 CF pou\u017e\u00edvan\u00e9 v minulosti.<\/p>\n

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G\u00e9n CFTR<\/em><\/strong><\/p>\n

G\u00e9n zodpovedn\u00fd za CF je ozna\u010dovan\u00fd ako CFTR <\/em>(Cystic Fibrosis Transmembrane Conductance Regulator). Je lokalizovan\u00fd na 7q31.2, dlh\u00fd 250 kb, zlo\u017een\u00fd z 27 ex\u00f3nov dlh\u00fdch 38 bp a\u017e 724 bp(10). G\u00e9n k\u00f3duje mRNA dlh\u00fa 6,5 kb, ktor\u00e1 je prepisovan\u00e1 do polypeptidu zlo\u017een\u00e9ho z 1 480 aminokysel\u00edn.<\/p>\n

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Prote\u00edn CFTR, \u0161trukt\u00fara a funkcia<\/h1>\n

Za fyziologick\u00fdch okolnost\u00ed je CFTR <\/em>transmembr\u00e1nov\u00fd prote\u00edn funguj\u00faci ako chloridov\u00fd kan\u00e1l s regula\u010dnou funkciou pre niektor\u00e9 \u010fal\u0161ie i\u00f3nov\u00e9 kan\u00e1ly. Je zlo\u017een\u00fd z piatich funk\u010dn\u00fdch dom\u00e9n, a to z dvoch transmembr\u00e1nov\u00fdch dom\u00e9n TMD1 a TMD2, dvoch dom\u00e9n NBD1 a NBD2 via\u017eucich ATP a jednej ve\u013ekej regula\u010dnej dom\u00e9ny R, ktor\u00e1 sp\u00e1ja obe polovice polypeptidu. Prote\u00edn CFTR je zakotven\u00fd v lipidickej dvojvrstve sekretorick\u00fdch buniek, orientovan\u00fd je do cytoplazmy (obr\u00e1zok 1)<\/em><\/strong>.<\/p>\n

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Varianty v g\u00e9ne CFTR<\/em><\/h1>\n

V s\u00fa\u010dasnosti je op\u00edsan\u00fdch takmer 2 000 variantov v g\u00e9ne CFTR<\/em>, z toho viac ne\u017e 1 200 patog\u00e9nnych. Datab\u00e1za Cystic Fibrosis Genetic Analysis Consortium Database CFGAC (http:\/\/www.genet.sickkids.on.ca\/cftr)<\/a> obsahuje aktu\u00e1lny stav variantov CFTR<\/em>. Jednozna\u010dn\u00e1 v\u00e4\u010d\u0161ina variantov je ve\u013emi zriedkav\u00e1 a ich v\u00fdskyt je obmedzen\u00fd na mal\u00e9 izolovan\u00e9 popul\u00e1cie. Len 30 variantov v g\u00e9ne CFTR <\/em>sa vyskytuje s podielom viac ne\u017e 0,1 %.
\nNaj\u010dastej\u0161\u00edm variantom v g\u00e9ne CFTR <\/em>a prv\u00fdm identifikovan\u00fdm(12) je F508del (ozna\u010dovan\u00fd aj ako delta-F508, skr\u00e1tene \u2206F508). Je sp\u00f4soben\u00fd del\u00e9ciou troch b\u00e1z v 11. ex\u00f3ne g\u00e9nu CFTR<\/em>, \u010doho d\u00f4sledkom je strata jednej aminokyseliny \u2013 fenylalan\u00ednu v prote\u00edne CFTR na poz\u00edcii 508. V\u00fdsledn\u00fd prote\u00edn je nefunk\u010dn\u00fd. Podiel tohto variantu predstavuje na Slovensku od 59,4 do 66,8 %(13).<\/p>\n

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Molekul\u00e1rna patol\u00f3gia<\/h1>\n

Zast\u00fapenie r\u00f4znych variantov v jednotliv\u00fdch funk\u010dn\u00fdch dom\u00e9nach CFTR <\/em>je nerovnomern\u00e9. Zv\u00fd\u0161en\u00e9 mno\u017estvo variantov bolo pozorovan\u00e9 v dom\u00e9ne R a NBD1. R\u00f4zne typy variantov maj\u00fa r\u00f4zny efekt na priebeh ochorenia. D\u00f4sledkom\u00a0\u0161irokej \u0161k\u00e1ly variantov v g\u00e9ne CFTR <\/em>je ve\u013ek\u00e1 fenotypov\u00e1 variabilita CF, ku ktorej prispieva aj vplyv vonkaj\u0161ieho prostredia a genetick\u00e9ho pozadia jedinca.<\/p>\n

Mechanizmy vplyvu r\u00f4znych variantov na funk\u010dnos\u0165 prote\u00ednu CFTR m\u00f4\u017eeme rozdeli\u0165 do 5 skup\u00edn:<\/p>\n

    \n
  1. Netvor\u00ed sa \u017eiaden prote\u00edn CFTR alebo len zanedbate\u013en\u00e9 mno\u017estvo z d\u00f4vodu pred\u010dasnej termin\u00e1cie transl\u00e1cie z d\u00f4vodu pred\u010dasn\u00fdch stop kod\u00f3nov: G542X, 621+1G>T, 390insT.<\/li>\n
  2. Poruchy posttransla\u010dn\u00fdch \u00faprav, v ktor\u00fdch d\u00f4sledku doch\u00e1dza k pred\u010dasnej degrad\u00e1cii polypeptidov: napr. F508del, N1303K,<\/li>\n
  3. Poruchy v regul\u00e1cii sp\u00f4soben\u00e9 konforma\u010dn\u00fdmi zmenami prote\u00ednu CFTR: G551D, G551S, S1255P.<\/li>\n
  4. Porucha vodivosti chloridov\u00e9ho kan\u00e1la: napr. R117H, R334W,<\/li>\n
  5. Zn\u00ed\u017een\u00e1 hladina transkriptu mRNA a n\u00e1sledne aj prote\u00ednu: 3849+10kbC>T, 1811+1,6kbA>C<\/li>\n<\/ol>\n

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    Molekul\u00e1rno-genetick\u00e1 anal\u00fdza g\u00e9nu CFTR<\/em><\/h1>\n

    Molekulovo-genetick\u00e1 anal\u00fdza sa realizuje zo vzorky perif\u00e9rnej krvi odobratej do sterilnej sk\u00famavky s EDTA. Molekul\u00e1rna diagnostika CF je zalo\u017een\u00e1 na identifik\u00e1cii kauz\u00e1lnych variantov, ale existencia takmer 2 000 variantov rozpt\u00fdlen\u00fdch po celom g\u00e9ne CFTR <\/em>m\u00f4\u017ee sp\u00f4sobi\u0165 falo\u0161ne negat\u00edvny v\u00fdsledok. Met\u00f3dou multiplexnej alelovo \u0161pecifickej PCR sa vy\u0161etruje 67 variantov v CFTR <\/em>g\u00e9ne, ktor\u00e9 predstavuj\u00fa v na\u0161ej popul\u00e1cii viac ako 90 % v\u0161etk\u00fdch CF variantov (tabu\u013eka 1)<\/em><\/strong>.<\/p>\n

    Na anal\u00fdzu cel\u00e9ho g\u00e9nu CFTR <\/em>sa vyu\u017e\u00edvaj\u00fa met\u00f3dy ako dHPLC (denaturing high performance liquid chromatography), HRM (high resolution melting) alebo celog\u00e9nov\u00e9 sekvenovanie.<\/p>\n

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    Indik\u00e1cie na testovanie CFTR <\/em>g\u00e9nu<\/h1>\n

    Indik\u00e1cie na molekul\u00e1rnogenetick\u00fa anal\u00fdzu CFTR <\/em>g\u00e9nu(upraven\u00e9 pod\u013ea 14):<\/p>\n

      \n
    1. Diagnostick\u00e9 testovanie pri typick\u00fdch prejavoch CF, pri atypick\u00fdch klinick\u00fdch prejavoch a\/alebo hrani\u010dn\u00fdch hodnot\u00e1ch potn\u00e9ho testu, pri mu\u017eskej infertilite s CBAVD a pri ostatn\u00fdch CFTR<\/em>-RDs u dospel\u00fdch.<\/li>\n
    2. Prenat\u00e1lna diagnostika (napr. v pr\u00edpade nosi\u010dstva mut\u00e1ci\u00ed CFTR<\/em>, pri gravidite s verifikovanou CF u jedn\u00e9ho z rodi\u010dov alebo u plodu s hyperechog\u00e9nnym \u010drevom a\/alebo dilat\u00e1ciou \u010drevn\u00fdch k\u013eu\u010diek).<\/li>\n
    3. Testovanie nosi\u010dstva pre CF u jedincov s pozit\u00edvnou rodinnou anamn\u00e9zou. V niektor\u00fdch krajin\u00e1ch je testovanie nosi\u010dstva pre CF zaveden\u00e9 aj u jedincov bez pozit\u00edvnej rodinnej anamn\u00e9zy v r\u00e1mci vy\u0161etrovania nosi\u010dstva pre naj\u010dastej\u0161ie genetick\u00e9 ochorenia alebo u neplodn\u00fdch p\u00e1rov (neplat\u00ed pre SR).<\/li>\n<\/ol>\n

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      Z\u00e1ver<\/h1>\n

      Genetika v s\u00fa\u010dasnej dobe predstavuje odbor, ktor\u00fd v\u00fdrazne men\u00ed n\u00e1\u0161 poh\u013ead na patofyziol\u00f3giu ochoren\u00ed. Cystick\u00e1 fibr\u00f3za, ako relat\u00edvne \u010dast\u00e9 ochorenie, je ve\u013emi podrobne pre\u0161tudovan\u00e1 z molekulovo-genetick\u00e9ho poh\u013eadu. Od samotn\u00e9ho potvrdenia klinickej diagn\u00f3zy sa dost\u00e1vame k novorodeneck\u00e9mu skr\u00edningu, prenat\u00e1lnej diagnostike, ur\u010dovania nosi\u010dstva u asymptomatick\u00fdch jedincov, \u010di predimplanta\u010dnej diagnostike embry\u00ed. Navy\u0161e, ur\u010denie pr\u00edtomnosti konkr\u00e9tnych mut\u00e1ci\u00ed n\u00e1m umo\u017e\u0148uje zvoli\u0165 najefekt\u00edvnej\u0161iu lie\u010dbu. Cystick\u00e1 fibr\u00f3za sa takto st\u00e1va modelov\u00fdm ochoren\u00edm a ukazuje n\u00e1m potenci\u00e1l genetickej diagnostiky aj u menej \u010dast\u00fdch monog\u00e9nov\u00fdch ochoren\u00ed.<\/p>\n

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       <\/p>\n

      LITERAT\u00daRA<\/strong><\/p>\n

        \n
      1. Castellania C, Duff AJA, Belle SC, et ECFS best practice guidelines: the 2018 revision. J Cyst Fibros 2018; 17: 153-178.<\/li>\n
      2. Dluholuck\u00fd S, Knapkov\u00e1 M. Ro\u010dn\u00e1 spr\u00e1va novorodeneck\u00e9ho skr\u00edni gu za rok Monitor medic\u00edny SLS 2014; (3-4): 20-24.<\/li>\n
      3. Lysinov\u00e1 M, Knapkov\u00e1 M, Dluholuck\u00fd S. Novorodeneck\u00fd skr\u00edning v s\u00fa\u010dasnosti. Pediat prax 2015; 16(5): 188-191.<\/li>\n
      4. Urbanov\u00e1 V, Feketeov\u00e1 A, Podrack\u00e1 \u013d. Pseudo-Bartterov syndr\u00f3m ako prv\u00fd prejav cystickej fibr\u00f3zy. \u010ces-slov Pediat 2015; 70(1): 33-36.<\/li>\n
      5. Fila Cystick\u00e1 fibr\u00f3za u dosp\u011bl\u00fdch. Intern\u00ed Med 2014; 16(2): 54-60.<\/li>\n
      6. Bombieri C, Claustres M, De Boeck K, et Recommendations for the classification of diseases as CFTR<\/em>-related disorders. J Cyst Fibros 2011; 10: S86-S102.<\/li>\n
      7. Farrell PM, Terry White, et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017; 181S: S4-15.<\/li>\n
      8. Ren CL, <\/a>Borowitz DS, <\/a>Gonska T<\/a>. Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive J Pediatr 2017; 181: S45-S51.<\/li>\n
      9. De Boeck K, <\/a>Vermeulen F<\/a>, Dupont <\/a> The diagnosis of cystic fibrosis. Presse Med <\/a>2017; 46: e97-e108.<\/li>\n
      10. Zielanski J, Bozon D, Kerem BS, et Identification of mutations in exons 1 through 8 of the Cystic Transmembrane Conductance Regulator (CFTR<\/em>) gene. Genomics 1991; 10: 229-235.<\/li>\n
      11. Rowe SM, Miller S, Sorscher EJ. Cystic Fibrosis. The New England Journal of Medicine 2005; 352: 1992-2001.<\/li>\n
      12. Kerem BS, Rommens JM, Buchanan JA et Identification of the cystic fibrosis gene: Genetic analysis. Science 1989; 245: 1073-1080.<\/li>\n
      13. K\u00e1dasi \u013d, Pol\u00e1kov\u00e1 H, Za\u0165kov\u00e1 A, et Distribution of 9 common mutations in the CFTR <\/em>gene in Slovak cystic fibrosis patients. Gene Geogr 1997; 11: 51-56.<\/li>\n
      14. Dequeker E, Stuhrmann M, Morris MA, et Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR<\/em>-related disorders \u2013 updated European recommendations. European Journal of Human Genetics 2009; 17: 51-65.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

        *All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.   Prv\u00e9 historick\u00e9 zmienky o tomto ochoren\u00ed siahaj\u00fa do stredoveku, ke\u010f sa slan\u00fd pot u det\u00ed sp\u00e1jal s poruchami pankreasu a rizikom v\u010dasn\u00e9ho \u00famrtia a tieto deti boli pova\u017eovan\u00e9 za<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[290],"tags":[1020,1021,1022,1023,1024,1025],"class_list":["post-1574","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-cftr-en","tag-cysticka-fibroza-en","tag-imunoreaktivny-trypsinogen-en","tag-irt-en","tag-molekularna-diagnostika-en","tag-novorodenecky-skrining-en","typ_clanku-review-article"],"acf":{"abstrakt":"

        Cystic fibrosis (CF), one of the most frequent genetic diseases, is rationally the subject of research resulting in permanent improvement in diagnostic and therapy. In the last decade, the most important improvement in clinical management of CF patients has been the early diagnosis in newborns by extensive newborn screening in many countries. In addition, routine genetic diagnostics allows development and implementation of mutation-specific therapy.<\/p>\n

        Keywords:<\/strong> CFTR, cystic fibrosis, molecular diagnostics, newborn screening, IRT, immunoreactive trypsinogen.<\/p>\n","casopis":[{"ID":1513,"post_author":"7","post_date":"2018-11-05 11:53:53","post_date_gmt":"2018-11-05 10:53:53","post_content":"

          \r\n \t
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        • Laboratory diagnostic possibilities for Clostridium difficile infections<\/li>\r\n \t
        • Chorangiosis of Placenta - Disorder of Unclear Etiology (Case Report and Overview of Current Knowledge)<\/li>\r\n \t
        • Circulating tumor DNA and its utilization as marker with prognostic, predictive and diagnostic value in patients with oncological diseases<\/li>\r\n<\/ul>","post_title":"newsLab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-2","to_ping":"","pinged":"","post_modified":"2018-11-05 11:57:18","post_modified_gmt":"2018-11-05 10:57:18","post_content_filtered":"","post_parent":0,"guid":"http:\/\/www.newslab.sk\/casopis\/newslab-2\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"98","upload_clanok":{"ID":1572,"id":1572,"title":"Diagnostika cystickej fibr\u00f3zy so zameran\u00edm na molekul\u00e1rnogenetick\u00fa","filename":"Diagnostika-cystickej-fibr\u00f3zy-so-zameran\u00edm-na-molekul\u00e1rnogenetick\u00fa.pdf","filesize":290543,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2018\/11\/Diagnostika-cystickej-fibr\u00f3zy-so-zameran\u00edm-na-molekul\u00e1rnogenetick\u00fa.pdf","link":"https:\/\/www.newslab.sk\/en\/diagnostika-cystickej-fibrozy-so-zameranim-na-molekularnogeneticku-analyzu-cftr-genu\/diagnostika-cystickej-fibrozy-so-zameranim-na-molekularnogeneticku-2\/","alt":"","author":"7","description":"","caption":"","name":"diagnostika-cystickej-fibrozy-so-zameranim-na-molekularnogeneticku-2","status":"inherit","uploaded_to":1574,"date":"2018-11-11 13:12:39","modified":"2018-11-11 13:12:39","menu_order":0,"mime_type":"application\/pdf","type":"application","subtype":"pdf","icon":"https:\/\/www.newslab.sk\/wp-includes\/images\/media\/document.png"}},"_links":{"self":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1574","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/comments?post=1574"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1574\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1574"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1574"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1574"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}