{"id":2285,"date":"2021-09-20T10:46:26","date_gmt":"2021-09-20T08:46:26","guid":{"rendered":"https:\/\/www.newslab.sk\/molekularna-diagnostika-vrodenej-neutropenie\/"},"modified":"2021-09-20T10:48:03","modified_gmt":"2021-09-20T08:48:03","slug":"molecular-diagnosis-of-congenital-neutropenia","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/molecular-diagnosis-of-congenital-neutropenia\/","title":{"rendered":"Molecular diagnosis of congenital neutropenia"},"content":{"rendered":"

*A rare case of autochthonous human dirofilariasis with the manifestation of pseudotumor of the epididymis caused by helminth Dirofilaria repens<\/strong><\/span><\/p>\n

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\u00davod<\/strong><\/h3>\n

Molekul\u00e1rna diagnostika zriedkav\u00fdch vroden\u00fdch ochoren\u00ed sa ka\u017ed\u00fd rok zlep\u0161uje, k \u010domu najm\u00e4 posledn\u00e9 desa\u0165ro\u010die prispievaj\u00fa techniky sekvenovania novej gener\u00e1cie (NGS, next generation sequencing<\/em>). Napriek tomu efektivita alebo tzv. diagnostick\u00fd \u00fa\u010dinok dosahuje celkovo pri mnoh\u00fdch vroden\u00fdch ochoreniach aj s vyu\u017eit\u00edm NGS asi len 25 %(1). Vroden\u00e9 poruchy imunity s\u00fa skupinou ochoren\u00ed, kde sa NGS vzh\u013eadom na genetick\u00fa variabilitu vyu\u017e\u00edva \u010dasto. Do tejto skupiny ochoren\u00ed patr\u00ed i vroden\u00e1 neutrop\u00e9nia, ktor\u00e1 je charakterizovan\u00e1 redukciou absol\u00fatneho po\u010dtu neutrofilov (ANC, absolute neutrophil count<\/em>) v perif\u00e9rnej krvi, ktor\u00fa rad\u00edme k poruch\u00e1m fagocytov. Neutrop\u00e9nia je \u010dasto klinicky asymptomatick\u00e1 a\u017e do momentu, ke\u010f sa u pacienta za\u010dne prejavova\u0165 rekurentn\u00fdmi infekciami, ktor\u00e9 mnohokr\u00e1t ved\u00fa k chronick\u00fdm, z\u00e1va\u017en\u00fdm a\u017e \u017eivot ohrozuj\u00facim stavom(2).<\/p>\n

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Vroden\u00e1 neutrop\u00e9nia<\/h3>\n

Neutrop\u00e9nia je relat\u00edvne \u010dast\u00fdm n\u00e1lezom u pribli\u017ene 1 % popul\u00e1cie, pri\u010dom v niektor\u00fdch popul\u00e1ci\u00e1ch m\u00f4\u017ee jej v\u00fdskyt dosahova\u0165 a\u017e 8 %. Vroden\u00e1 forma neutrop\u00e9nie sa vyskytuje u menej ako 1\/100 000 \u013eud\u00ed, \u010do tvor\u00ed pribli\u017ene 1 z 1 000 pr\u00edpadov v\u0161etk\u00fdch neutrop\u00e9ni\u00ed(3). Z anal\u00fdzy d\u00e1t zozbieran\u00fdch Medzin\u00e1rodn\u00fdm registrom z\u00e1va\u017en\u00fdch chronick\u00fdch neutrop\u00e9ni\u00ed (SCNIR, Severe Chronic Neutropenia International Registry<\/em>) sa prevalencia vrodenej a idiopatickej neutrop\u00e9nie pohybovala v \u0161t\u00e1toch prispievaj\u00facich do registra v rozmedz\u00ed od 0,006 a\u017e po 8,5 pr\u00edpadu na mili\u00f3n obyvate\u013eov s priemerom 1,65. Slovensko v tom \u010dase do registra neprispievalo i ke\u010f v s\u00fa\u010dasnosti je partnerom tejto organiz\u00e1cie(3). Monog\u00e9nov\u00e1 kongenit\u00e1lna neutrop\u00e9nia predstavuje klinicky a geneticky ve\u013emi heterog\u00e9nnu skupinu, pri\u010dom toto ozna\u010denie sa vz\u0165ahuje na chronick\u00fa z\u00e1va\u017en\u00fa neutrop\u00e9niu bez in\u00fdch abnormal\u00edt, tzv. izolovan\u00fa, nesyndr\u00f3mov\u00fa neutrop\u00e9niu, ako aj na syndr\u00f3mov\u00e9 genetick\u00e9 ochorenia spojen\u00e9 s r\u00f4znymi extrahematologick\u00fdmi fenotypov\u00fdmi prejavmi(4). Neutrop\u00e9nia sa z\u00e1rove\u0148 m\u00f4\u017ee vyskytova\u0165 pri in\u00fdch ochoreniach imunitn\u00e9ho syst\u00e9mu postihuj\u00facich napr\u00edklad z\u00edskan\u00fa imunitu ako ich pridru\u017een\u00fd prejav alebo ako s\u00fa\u010das\u0165 klinick\u00e9ho obrazu zlyhania kostnej drene(5).<\/p>\n

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Genetika vrodenej neutrop\u00e9nie<\/h3>\n

Z\u00e1va\u017en\u00e1 kongenit\u00e1lna neutrop\u00e9nia (SCN, severe congenital neutropenia<\/em>) sa prejavuje ako chronick\u00e9 alebo intermitentn\u00e9 ochorenie, pri\u010dom pacienti, ktor\u00ed \u0148ou trpia, maj\u00fa z\u00e1rove\u0148 sklon k rozvoju ak\u00fatnej myeloidnej leuk\u00e9mie (AML) a myelodyspl\u00e1zie (MDS)(6). S izolovanou formou ochorenia je doposia\u013e spojen\u00fdch viacero g\u00e9nov (tabu\u013eka 1)<\/strong>, z ktor\u00fdch najv\u00fdznamnej\u0161\u00ed je g\u00e9n ELANE, <\/em>ktor\u00e9ho mut\u00e1cie s\u00fa zodpovedn\u00e9 pribli\u017ene a\u017e za 40 % pr\u00edpadov \u0165a\u017ekej vrodenej neutrop\u00e9nie (ob<\/strong>r\u00e1zok 1) <\/strong>a vy\u0161e 50 % pr\u00edpadov cyklickej neutrop\u00e9nie charakterizovanej oscil\u00e1ciou po\u010dtu neutrofilov zvy\u010dajne v 21-d\u0148ov\u00fdch cykloch(7). V s\u00fa\u010dasnosti je zn\u00e1mych takmer 200 r\u00f4znych mut\u00e1ci\u00ed v tomto g\u00e9ne(8) a ka\u017ed\u00fd rok prib\u00fadaj\u00fa nov\u00e9 varianty vr\u00e1tane variantov vo forme mozaiky(9). \u010eal\u0161\u00edm z asociovan\u00fdch g\u00e9nov je HAX1<\/em>, ktor\u00e9ho mut\u00e1cie sp\u00f4sobuj\u00fa vznik autozom\u00e1lne reces\u00edvnej formy SCN, naz\u00fdvanej aj Kostmannov syndr\u00f3m, ktor\u00fd bol prv\u00fdkr\u00e1t zaznamenan\u00fd u \u0161v\u00e9dskej konsangvina\u010dnej rodiny(10). Aj ke\u010f je v\u00fdskyt zriedkav\u00e9ho Kostmannovho syndr\u00f3mu \u010dastej\u0161\u00ed u pacientov z konsangvina\u010dn\u00fdch rod\u00edn, nie je na ne obmedzen\u00fd a jeho incidencia je vzh\u013eadom na autozom\u00e1lne reces\u00edvny charakter a r\u00f4znu frekvenciu HAX1 <\/em>mut\u00e1ci\u00ed geograficky a etnicky z\u00e1visl\u00e1. V popul\u00e1ci\u00e1ch s vy\u0161\u0161ou mierou konsangvina\u010dn\u00fdch man\u017eelstiev m\u00f4\u017eu by\u0165 HAX1 <\/em>varianty zodpovedn\u00e9 dokonca za viac SCN pr\u00edpadov ako ELANE. <\/em>Mut\u00e1cie v in\u00fdch g\u00e9noch s\u00fa vo vz\u0165ahu k vzniku izolovanej kongenit\u00e1lnej neutrop\u00e9nie identifikovan\u00e9 vo v\u00fdrazne men\u0161ej miere (obr\u00e1zok 1)<\/strong>. Navy\u0161e g\u00e9ny, ktor\u00fdch varianty sp\u00f4sobuj\u00fa r\u00f4zne mierne alebo adultn\u00e9 formy ochorenia, ako je napr\u00edklad adultn\u00e1 neutrop\u00e9nia s monocyt\u00f3zou(11), zni\u017euj\u00fa z\u00e1chytnos\u0165 samotn\u00e9ho ochorenia a t\u00fdm aj mo\u017enos\u0165 identifik\u00e1cie molekul\u00e1rnej pr\u00ed\u010diny.<\/p>\n

Syndr\u00f3mov\u00e9 neutrop\u00e9nie s\u00fa ochorenia spojen\u00e9 s poruchami metabolizmu, vezikulov\u00e9ho transportu, imunologick\u00fdch funkci\u00ed \u010di s riboz\u00f3movou dysfunkciou, ktor\u00fdch spolo\u010dn\u00fdm prejavom je neutrop\u00e9nia(12). Ide o monog\u00e9novo podmienen\u00e9 syndr\u00f3my s r\u00f4znym typom dedi\u010dnosti a ich vznik je sp\u00e1jan\u00fd s variantmi vo viac ako 30 r\u00f4znych g\u00e9noch (tabu\u013eka 1)<\/strong>. Naj\u010dastej\u0161ie sa vyskytuj\u00facou syndr\u00f3movou neutrop\u00e9niou je Shwachmanov-Diamondov syndr\u00f3m (SDS), multiorg\u00e1nov\u00e9 ochorenie sp\u00f4soben\u00e9 variantmi v g\u00e9ne SBDS<\/em>. Varianty v tomto g\u00e9ne s\u00fa z\u00e1rove\u0148 po mut\u00e1ci\u00e1ch v g\u00e9ne ELANE <\/em>druhou naj\u010dastej\u0161ou pr\u00ed\u010dinou z\u00e1va\u017enej kongenit\u00e1lnej neutrop\u00e9nie (izolovanej i syndr\u00f3movej) a s\u00fa zodpovedn\u00e9 za 14 % \u0165a\u017ek\u00fdch vroden\u00fdch neutrop\u00e9ni\u00ed (obr\u00e1zok 1)<\/strong>(13). Vznik z\u00e1va\u017enej vrodenej neutrop\u00e9nie je v\u00fdrazne sp\u00e1jan\u00fd aj s variantmi v g\u00e9ne SLC37A4 <\/em>sp\u00f4sobuj\u00facimi vznik glykogen\u00f3zy(14), variantmi v TAZ <\/em>sp\u00f4sobuj\u00facimi vznik Barthovho syndr\u00f3mu \u010di variantmi v g\u00e9ne CXCR4I <\/em>asociovan\u00fdmi so vznikom syndr\u00f3mu WHIM. Ostatn\u00e9 syndr\u00f3mov\u00e9 poruchy s prejavmi SCN s\u00fa menej \u010dast\u00e9 a predstavuj\u00fa len mal\u00fa \u010das\u0165 vroden\u00fdch neutrop\u00e9ni\u00ed(13). Rovnako je to pri neutrop\u00e9ni\u00e1ch pozorovan\u00fdch pri in\u00fdch imunodeficienci\u00e1ch, ktor\u00e9 spolo\u010dne so zlyhaniami kostnej drene, ako je Fanconiho an\u00e9mia \u010di Dyskeratosis congenita(15), prispievaj\u00fa k celkov\u00e9mu po\u010dtu neutrop\u00e9ni\u00ed iba minim\u00e1lne. Aj ke\u010f je doposia\u013e zn\u00e1mych viac ako 50 g\u00e9nov asociovan\u00fdch so vznikom niektorej z foriem SCN, pre v\u00e4\u010d\u0161inu plat\u00ed, \u017ee ich mut\u00e1cie s\u00fa ve\u013emi zriedkav\u00e9(5).<\/p>\n

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Molekul\u00e1rna diagnostika<\/h3>\n

Genetick\u00e9 testovanie s identifik\u00e1ciou kauz\u00e1lneho variantu by malo by\u0165 \u0161tandardnou strat\u00e9giou u pacientov s neutrop\u00e9niou, ke\u010f\u017ee identifik\u00e1cia g\u00e9nu m\u00f4\u017ee napr\u00edklad predikova\u0165 reakciu na terapiu faktorom stimuluj\u00facim kol\u00f3nie granulocytov (G-CSF) aj identifikova\u0165 pacientov s rizikom zlyhania kostnej drene, predispoz\u00edciou na vznik AML, MDS alebo vz\u00e1cnej ak\u00fatnej lymfoblastickej leuk\u00e9mie(6). Molekul\u00e1rna diagnostika je \u010doraz d\u00f4le\u017eitej\u0161ia aj vzh\u013eadom na r\u00fdchle napredovanie pr\u00edstupov g\u00e9novej terapie, a to obzvl\u00e1\u0161\u0165 pri ochoreniach imunitn\u00e9ho syst\u00e9mu. Wiskottov-Aldrichov syndr\u00f3m je jedno z ochoren\u00ed, kde je g\u00e9nov\u00e1 terapia u\u017e v \u0161t\u00e1diu klinick\u00e9ho testovania a \u00faspe\u0161ne bola podan\u00e1 viacer\u00fdm pacientom(16).<\/p>\n

Identifik\u00e1cia kauz\u00e1lneho g\u00e9nov\u00e9ho variantu zodpovedn\u00e9ho za vznik neutrop\u00e9nie je komplexn\u00fd proces, kde prvotn\u00e9 zhodnotenie le\u017e\u00ed na klinickej diagnostike, pri ktorej je potrebn\u00e9 vyl\u00fa\u010denie z\u00edskanej formy ochorenia. Pr\u00edstup Sangerovho sekvenovania je vyu\u017eite\u013en\u00fd v pr\u00edpade izolovanej alebo cyklickej neutrop\u00e9nie, pri ktorej je predpoklad pr\u00edtomnosti variantov v g\u00e9ne ELANE <\/em>(13). V pr\u00edpade potvrdenej cyklickej formy SCN je kandid\u00e1tnym g\u00e9nom GFI1<\/em>(11), sekvenovanie kandid\u00e1tneho g\u00e9nu HAX1 <\/em>je mo\u017en\u00e9 najm\u00e4 v pr\u00edpade konsangvinity rodi\u010dov. Ak je neutrop\u00e9nia s\u00fa\u010das\u0165ou syndr\u00f3mu, identifik\u00e1cia pr\u00ed\u010diny sa \u010dasto opiera o ostatn\u00e9 sympt\u00f3my, ktor\u00e9 s\u00fa typick\u00e9 pre <\/em>dan\u00e9 ochorenie. Ani pr\u00edtomnos\u0165 <\/em>extrahematologick\u00fdch znakov v\u0161ak nemus\u00ed v\u017edy jednozna\u010dne ukazova\u0165 na konkr\u00e9tny syndr\u00f3m a rozsiahle testovanie viacer\u00fdch g\u00e9nov Sangerov\u00fdm sekvenovan\u00edm je \u010dasovo a finan\u010dne neefekt\u00edvne, pri\u010dom pacient \u010dasto zost\u00e1va bez genetickej diagn\u00f3zy. Aj z n\u00e1\u0161ho pozorovania m\u00f4\u017eeme poveda\u0165, \u017ee priame sekvenovanie je \u00fa\u010dinn\u00e9 len u pacientov s mut\u00e1ciou v g\u00e9ne ELANE<\/em>. Dokonca ani u pacientov s fenotypom \u0161pecifick\u00e9ho syndr\u00f3mu, napr\u00edklad klinicky diagnostikovan\u00fdm Shwachmanov\u00fdm-Diamondov\u00fdm syndr\u00f3mom, \u010dasto nedoch\u00e1dza k identifik\u00e1cii molekul\u00e1rnej pr\u00ed\u010diny ochorenia. Pomocou Sangerovho sekvenovania z\u00e1rove\u0148 nemo\u017eno odhali\u0165 vari\u00e1cie po\u010dtu k\u00f3pi\u00ed (CNV, copy number variant) a <\/em>del\u00e9cie na \u00farovni ex\u00f3nov \u010di cel\u00e9ho g\u00e9nu.<\/p>\n

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Panel, ex\u00f3m \u010di gen\u00f3m?<\/h3>\n

Sangerovo sekvenovanie je pri tak\u00fdchto geneticky r\u00f4znorod\u00fdch ochoreniach ne\u00fa\u010dinn\u00e9 a v diagnostickom procese sa \u010doraz \u010dastej\u0161ie pristupuje k technik\u00e1m mas\u00edvneho paraleln\u00e9ho sekvenovania novej gener\u00e1cie vo forme g\u00e9nov\u00fdch panelov, celoex\u00f3mov\u00e9ho (WES, whole exome sequencing<\/em>) alebo celogen\u00f3mov\u00e9ho (WGS, whole genome sequencing<\/em>) sekvenovania. G\u00e9nov\u00e9 panely sa zameriavaj\u00fa na zn\u00e1me g\u00e9ny sp\u00e1jan\u00e9 so vznikom izolovanej a syndr\u00f3movej SCN aj na g\u00e9ny asociovan\u00e9 so vznikom AML a MDS(13). V porovnan\u00ed s WES alebo WGS pr\u00edstupmi panelov\u00e9 testovanie redukuje n\u00e1hodn\u00e9 n\u00e1lezy, poskytuj\u00fa lep\u0161ie pokrytie a v\u00fdhodou je i \u013eah\u0161ia interpret\u00e1cia v\u00fdsledkov a ni\u017e\u0161ia cena(17). Na druhej strane panely g\u00e9nov vy\u017eaduj\u00fa \u010dast\u00fa aktualiz\u00e1ciu vzh\u013eadom na neust\u00e1le prib\u00fadaj\u00face poznatky o nov\u00fdch kauz\u00e1lnych g\u00e9noch. Len za posledn\u00e9 \u0161tyri roky bolo v\u010faka NGS pr\u00edstupom identifikovan\u00fdch viacero nov\u00fdch g\u00e9nov (EFL1<\/em>, HYOU1<\/em>, SRP54<\/em>, SMAR- CD2<\/em>) asociovan\u00fdch so vznikom SCN a m\u00f4\u017eeme predpoklada\u0165, \u017ee ich po\u010det bude narasta\u0165 aj v bud\u00facnosti(4,18). V\u00e4\u010d\u0161ina komer\u010dne dostupn\u00fdch panelov neposkytuje sekvenovanie viac ako 30 g\u00e9nov (Invitae Corporation, PreventionGenetics, Blueprint Genetics Oy., Fulgent Genetics a in\u00e9), a preto ciele<\/em>n\u00e9 <\/em>sekvenovanie nemus\u00ed odhali\u0165 pr\u00ed\u010dinu ochorenia a\u017e u 40 % pacientov(4), pri\u010dom toto \u010d\u00edslo m\u00f4\u017ee by\u0165 vy\u0161\u0161ie v pr\u00edpade, \u017ee panelov\u00e9 sekvenovanie sa vykon\u00e1 len u ELANE <\/em>negat\u00edvnych pacientov. V s\u00fa\u010dasnosti v\u0161ak ch\u00fdba dostatok \u0161t\u00fadi\u00ed, ktor\u00e9 by porovn\u00e1vali diagnostick\u00fa \u00fa\u010dinnos\u0165 panelov\u00e9ho sekvenovania a jednotliv\u00fdch panelov u pacientov s neutrop\u00e9niou.<\/p>\n

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Z h\u013eadiska identifik\u00e1cie kauz\u00e1lneho variantu, ako aj identifik\u00e1cie nov\u00fdch g\u00e9nov asociovan\u00fdch s SCN je najlep\u0161ou vo\u013ebou pr\u00edstup WES alebo WGS. Tie sa v s\u00fa\u010dasnosti vyu\u017e\u00edvaj\u00fa najm\u00e4 na v\u00fdskumn\u00e9 \u00fa\u010dely, ale postupne si h\u013eadaj\u00fa cestu aj do be\u017en\u00e9ho diagnostick\u00e9ho procesu. V diagnostike vroden\u00fdch por\u00fach imunity m\u00f4\u017eu dan\u00e9 pr\u00edstupy dosahova\u0165 diagnostick\u00fa \u00fa\u010dinnos\u0165 od 10 a\u017e po takmer 90 %(19,20). WGS poskytuje uniformn\u00e9 pokrytie gen\u00f3mu so v\u0161etk\u00fdmi k\u00f3duj\u00facimi i regula\u010dn\u00fdmi sekvenciami, intrag\u00e9nov\u00fdmi regi\u00f3nmi aj identifik\u00e1ciu CNV, ale za vy\u0161\u0161iu cenu a celkovo zv\u00fd\u0161en\u00fa n\u00e1ro\u010dnos\u0165 anal\u00fdzy. WES predstavuje ak\u00fdsi kompromis medzi panelov\u00fdm sekvenovan\u00edm a WGS a jeho pou\u017eitie na za\u010diatku diagnostick\u00e9ho procesu m\u00f4\u017ee strojn\u00e1sobi\u0165 po\u010det pacientov s molekul\u00e1rnou diagn\u00f3zou za tretinu celkov\u00fdch n\u00e1kladov(21). WES v\u0161ak nemus\u00ed zabezpe\u010di\u0165 posta\u010duj\u00face pokrytie v\u0161etk\u00fdch po\u017eadovan\u00fdch sekvenci\u00ed a interpret\u00e1cia jednotliv\u00fdch detegovan\u00fdch variantov, najm\u00e4 variantov neistej signifikancie, je v s\u00fa\u010dasnosti st\u00e1le v\u00fdzvou. Interpret\u00e1ciu variantov z\u00edskan\u00fdch pomocou NGS v\u00fdrazne zjednodu\u0161uje trio sekvenovanie probanda a oboch rodi\u010dov, naj\u010dastej\u0161ie vo forme WES, ktor\u00e9 umo\u017e\u0148uje sledova\u0165 dedi\u010dnos\u0165 variantov od bezpr\u00edznakov\u00fdch rodi\u010dov a najm\u00e4 vznik de novo <\/em>variantov(15). Trio sekvenovanie v\u0161ak zna\u010dne zvy\u0161uje cenu diagnostick\u00e9ho procesu. Na zhodnotenie efektivity jednotliv\u00fdch pr\u00edstupov v molekul\u00e1rnej diagnostike <\/em>neutrop\u00e9nie v s\u00fa\u010dasnosti nie je dostatok \u0161t\u00fadi\u00ed, \u010do je <\/em>sp\u00f4soben\u00e9 n\u00edzkou <\/em>incidenciou ochorenia a teda mal\u00fdm po\u010dtom pacientov. D\u00f4le\u017eit\u00e9 v\u0161ak je ku ka\u017ed\u00e9mu pacientovi pri- stupova\u0165 individu\u00e1lne, a z\u00e1rove\u0148 tak, aby bola zachovan\u00e1 vysok\u00e1 diagnostick\u00e1 \u00fa\u010dinnos\u0165 pri s\u00fa\u010dasne efekt\u00edvne vyu\u017eit\u00fdch zdrojoch.<\/p>\n

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Po\u010fakovanie<\/em><\/strong><\/p>\n

Pr\u00e1ca bola finan\u010dne podporen\u00e1 Vedeckou grantovou agent\u00farou Ministerstva \u0161kolstva, vedy, v\u00fdskumu a \u0161portu Slovenskej <\/em>republiky a Slovenskej akad\u00e9mie vied (VEGA 1\/0190\/19) a Ministerstvom zdravotn\u00edctva Slovenskej republiky (MZSR_2018\/46-SAV-5).<\/em><\/p>\n

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

    \n
  1. Hartman P, Beckman K, Silverstein K, et Next generation sequencing for clinical diagnostics: Five year experience of an academic laboratory. Mol Genet Metab Reports<\/em>. 2019;19:100464.<\/li>\n
  2. Arceci RJ, Hann IM, Smith OP, et P<\/em>ediatric<\/em> He<\/em>mat<\/em>ology<\/em>. Blackwell Publishing Ltd; 2006.<\/li>\n
  3. Donadieu J, \u00a0Beaupain \u00a0B, \u00a0Mahlaoui \u00a0N, \u00a0Bellann\u00e9-Chantelot \u00a0C. \u00a0Epidemiology of Congenital Neutropenia. Hematol Oncol Clin North Am<\/em>. 2013;27(1):1-17.<\/li>\n
  4. Donadieu J, Beaupain B, Fenneteau O, Bellann\u00e9-Chantelot Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br J Haematol<\/em>. 2017;179(4):557-574.<\/li>\n
  5. Tangye SG, Al-Herz W, Bousfiha A, et Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol<\/em>. 2020;40(1):24- 64.<\/li>\n
  6. Mehta HM, Malandra M, Corey G-CSF and GM-CSF in Neutropenia. J Immunol<\/em>. 2015;195(4):1341-1349.<\/li>\n<\/ol>\n
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    1. Dale DC, Bolyard AA, Aprikyan Cyclic neutropenia. Semin Hematol<\/em>. 2002;39(2):89-94.<\/li>\n<\/ol>\n
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      1. Germeshausen M, Deerberg S, Peter Y, Reimer C, Kratz CP, Ballmaier M. The Spectrum of ELANE Mutations and their Implications in Severe Congenital and Cyclic Hum Mutat<\/em>. 2013;34(6):905-914.<\/li>\n
      2. Liu Q, Zhang L, Shu Z, et al. Two paternal mosaicism of mutation in ELANE causing severe congenital neutropenia exhibit normal neutrophil morphology and ROS Clin Immunol<\/em>. 2019;203:53-58.<\/li>\n
      3. Kostmann Infantile Genetic Agranulocytosis (Agranulocytosis infantilis hereditaria) A New Recessive Lethal Disease in Man. Acta Paedi- <\/em>atr<\/em>. 1956;45(3):309-310.<\/li>\n
      4. Armistead PM, Wieder E, Akande O, et correspondence: Cyclic neutropenia associated with T cell immunity to granulocyte proteases and a double de novo mutation in GFI1, a transcriptional regulator of ELANE. Br <\/em>J Haematol<\/em>. 2010;150(6):716-719.<\/li>\n
      5. Boxer LA, Newburger PE. A molecular classification of congenital neutropenia Pediatr Blood Cancer<\/em>. 2007;49(5):609-614.<\/li>\n
      6. Skokowa J, Dale DC, Touw IP, et Severe congenital neutropenias. Nat Rev Dis Prim<\/em>. 2017;3:17032.<\/li>\n
      7. Chou JY, Jun HS, Mansfield B Type I glycogen storage diseases: disorders of the glucose-6-phosphatase\/glucose-6-phosphate transporter complexes. J Inherit Metab Dis<\/em>. 2015;38(3):511-519.<\/li>\n
      8. Furutani E, Newburger PE, Shimamura Neutropenia in the age of genetic testing: Advances and challenges. Am J Hematol<\/em>. 2019;94(3):384- 393.<\/li>\n
      9. Ferrua F, Marangoni F, Aiuti A, et Paradigms and perspectives Gene therapy for Wiskott-Aldrich syndrome: History, new vectors, future directions. J Allergy Clin Immunol<\/em>. 2020;146:262-265.<\/li>\n
      10. Bean LJH, Funke B, Carlston CM, et al. Diagnostic gene sequencing panels: from design to report\u2014a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med<\/em>. 2020;22(3):453-461.<\/li>\n
      11. Carapito R, Konantz M, Paillard C, et al. Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like J Clin Invest<\/em>. 2017;127(11):4090-4103.<\/li>\n
      12. Al-Herz W, Chou J, Delmonte OM, et Comprehensive genetic results for primary immunodeficiency disorders in a highly consanguineous population. Front Immunol<\/em>. 2019;10(JAN):3146.<\/li>\n
      13. Chinn IK, Orange JS. A 2020 update on the use of genetic testing for patients with primary immunodeficiency. Expert Rev Clin Immunol<\/em>. 2020;16(9):897-909.<\/li>\n
      14. Stark Z, Schofield D, Alam K, et al. Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet Med<\/em>. 2017;19(8):867-874.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

        *A rare case of autochthonous human dirofilariasis with the manifestation of pseudotumor of the epididymis caused by helminth Dirofilaria repens   \u00davod Molekul\u00e1rna diagnostika zriedkav\u00fdch vroden\u00fdch ochoren\u00ed sa ka\u017ed\u00fd rok zlep\u0161uje, k \u010domu najm\u00e4 posledn\u00e9 desa\u0165ro\u010die prispievaj\u00fa techniky sekvenovania novej gener\u00e1cie (NGS, next generation sequencing). Napriek tomu efektivita alebo tzv. diagnostick\u00fd \u00fa\u010dinok dosahuje celkovo pri<\/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":[1773,1777,1775,374,1776],"class_list":["post-2285","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-elane-en","tag-molecular-genetics","tag-neutropenia-en","tag-next-generation-sequencing-en","tag-wes-en","typ_clanku-review-article"],"acf":{"abstrakt":"

        Congenital neutropenia is a group of primary immunodeficiency disorders characterized by a low neutrophil count, which may be syndromic with the presence of various extrahematological features. Due to the clinical and genetic heterogeneity of congenital neutropenia, currently associated with more than 50 genes, next-generation sequencing techniques are at the forefront of the molecular diagnosis of neutropenia. In the form of panel, whole exome or whole genome sequencing, these techniques enable cost-effective and time-efficient diagnostics and the identification of new genes associated with the development of neutropenia. Although there are not enough data to compare the diagnostic yield of these approaches, available studies currently show it as the most effective diagnostic approach for genotypic and phenotypic heterogeneous diseases, such as neutropenia.<\/p>\n

        Keywords: <\/strong>neutropenia, molecular genetics, ELANE<\/em>, next-generation sequencing, WES<\/p>\n","casopis":[{"ID":2233,"post_author":"7","post_date":"2021-09-19 22:32:27","post_date_gmt":"2021-09-19 20:32:27","post_content":"We\u2019re bringing you this year\u2019s 1st<\/sup> issue of newslab, the scientific journal<\/strong>\r\n\r\n \r\n

          \r\n \t
        • Genomic variability of virus Sars-CoV-2<\/li>\r\n \t
        • Contribution of immunohistochemistry to histomorphological diagnostics of COVID-19 pneumonia<\/li>\r\n \t
        • Detection of microsatellite instability in Lynch syndrome-associated tumours<\/li>\r\n \t
        • Comparison of platelet glycoprotein analysis in the wholeh blood and plasma rich in platelets<\/li>\r\n \t
        • Tspan1 expression in prostatic adenocarcinoma<\/li>\r\n<\/ul>","post_title":"newslab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-8","to_ping":"","pinged":"","post_modified":"2021-09-19 22:36:56","post_modified_gmt":"2021-09-19 20:36:56","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.newslab.sk\/casopis\/newslab-8\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"32 - 36","upload_clanok":{"ID":2283,"id":2283,"title":"NEWSLAB 1-2021_Medova","filename":"NEWSLAB-1-2021_Medova.pdf","filesize":312852,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2021\/09\/NEWSLAB-1-2021_Medova.pdf","link":"https:\/\/www.newslab.sk\/en\/molecular-diagnosis-of-congenital-neutropenia\/newslab-1-2021_medova-2\/","alt":"","author":"7","description":"","caption":"","name":"newslab-1-2021_medova-2","status":"inherit","uploaded_to":2285,"date":"2021-09-20 08:35:18","modified":"2021-09-20 08:35:18","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\/2285","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=2285"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/2285\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=2285"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=2285"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=2285"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}