Vaimse arengu mahajäämuse geneetilised põhjused: X-liiteline vaimse arengu mahajäämus

Üheks kõige sagedasemaks raske puude põhjuseks lastel ja noortel on vaimse arengu mahajäämus (VAM). Vaatamata sellele, et välja on töötatud palju erinevaid uurimis meetodeid, jääb enamik neist patsientidest praegugi veel täpse diagnoosita. Viimastel aastatel on uuringute tähelepanu keskpunkti tõusnud X-kromosoom, kuna on leitud, et võrreldes autosoomidega esineb X-kromosoomis märgatavalt rohkem geene, mis muteerununa põhjustavad VAMi. Artiklis on kirjeldatud teadaolevalt sagedasemaid X-liitelise vaimse arengu mahajäämuse sündroome ning toodud välja autismi seni leitud seosed X-liitelise VAMiga. Eesti Arst 2007; 86 (4): 239–24

Fragiilse X-i sündroom Eestis: patsientide ja premutatsiooni kandjate kliinilised ja sotsiaalsed probleemid

Fragiilse X-i sündroom (FXS) on kõige sagedasem X-liiteline monogeenne haigus ning monogeense päriliku vaimse arengu mahajäämuse põhjus. FMR1 geeni täismutatsioon põhjustab FXSi fenotüüpi, premutatsiooniga naistel on suurenenud enneaegse ovariaalse puudulikkuse risk. Artiklis kirjeldatud uuringu teostamisel võeti aluseks aastatel 1997–2006 Tartu Ülikooli Kliinikumi ühendlabori geneetikakeskuses tehtud FXSi positiivsete DNA-analüüside tulemused, mille hulgast tehti kindlaks FXSi põhjustav täismutatsioon nii mees- kui ka naissoost patsientidel, samuti premutatsioon, mida leiti vaid naissoost patsientidel. Kliiniliste andmete analüüs tehti kõigil täismutatsiooniga FXS-patsientidel ning 14 premutatsiooni kandval naisel. Eesti Arst 2008; 87(7−8):500−50

Vaimse arengu mahajäämuse geneetilised põhjused Eestis: fragiilne X sündroom ja kreatiini transporteri defekt

The present study was initiated to characterize two most common X-linked MR disorders: fragile X syndrome (FXS) and creatine transporter deficiency in Estonia. Within years 1997 to 2006 in the Department of Genetics of United Laboratories of Tartu University Hospital there were 676 patients (516 children and 160 adults) investigated for FXS. The prevalence of FXS among the MR population in Estonia was 2.7%, which was similar to the results of previously reported studies that were performed on Caucasian males. Furthermore, the overall live-birth prevalence rate of FXS from 1984 to 2005 was 1:27,115. The clinical phenotype of the boys with FXS was similar to previously reported cases. The main clinical feature of the females with FXS premutation was premature ovarian insufficiency or irregular menstruation (43%). In collaboration with Department of Genetics of United Laboratories of Tartu University Hospital, Children’s Clinic of Tartu University Hospital, and Tallinn Children’s Hospital DNA material and phenotype data from 83 Estonian families were collected. From this study group familial XLMR group that consist 49 families where probands in the families were mainly boys were chosen. The prevalence of creatine transporter deficiency among investigated families with suspicion of XLMR was found to be 2 %. In three related brothers and their mother a missense mutation – c.1271G>A (p.Gly424Asp) was identified. This mutation has not been previously reported. The phenotype of patients with creatine transporter defect was somewhat different from published cases and the clinical expression varied widely among affected brothers. In addition, our aim was to evaluate the correlation between clinical features and molecular finding in cases of rare submicroscopic chromosomal aberration, which causes MR in complicated dysmorphic patients. In this study, two patients with submicroscopic copy number variation in chromosomes X and 17q were being described. Uuringus analüüsitakse kahte sagedasemat X-liitelise vaimse arengu mahajäämuse sündroomi – fragiilse X sündroomi (FXS) ja kreatiini transporteri defekti. FXS uuringu teostamisel võeti aluseks 1997-2006 aastal SA Tartu Ülikooli Kliinikumi Ühendlabori geneetikakeskuses teostatud FXS-i positiivsete DNA analüüside tulemused. Sel ajavahemikul oli Eestis FXS uuring teostatud 676 patsiendil (516 lapsel ja 160 täiskasvanul). FXS esinemissageduseks Eesti vaimse arengu mahajäämusega patsientide hulgas oli 2,7%, mis sarnanes esinemissagedusega vaimse arengu mahajäämusega patsientide populatsiooni kohta publitseeritud tulemustega Kaukaasia rassi meestel. Lisaks leiti FXS üldlevimus Eestis aastatel 1984-2005. See oli 1:27,115 elusalt sündinud vastsündinu kohta, mis on madalam kirjanduses publitseeritud andmetest. FXS-ga poiste kliiniline pilt oli sarnane eelnevalt kirjeldatud juhtudele. FXS premutatsiooniga naispatsientide peamiseks kliiniliseks avaldumiseks oli enneaegne ovariaalne puudulikkus või ebaregulaarsed menstruatsioonid (43%). Koostöös SA Tartu Ülikooli Kliinikumi Ühendlabori geneetikakeskuse, Tartu Ülikooli Lastekliinikumi ja Tallinna Lastehaigla Geeneetikateenistusega koguti DNA materjal ja kliinilised andmed 83-st Eesti perest. Sellest grupist valiti 49 peret kelle perekonna anamnees viitas pärilikule X-liitelisele vaimse arengu mahajäämusele. Kreatiini transporteri defekt leiti X-liitelise vaimse arengu mahajäämuse kahtlusega perekondade seast 2%-l. Leiti üks hemisügootne punktmutatsioon – c.1271G>A (p.Gly424Asp) ühe perekonna kolmel vennal ja nende emal. Seda mutatsiooni ei ole varasemalt kirjeldatud. Selle haiguse kliiniline väljendumine oli väga erinev ühe perekonna haigestunud vendade seas ning see fenotüüp oli erinev eelnevalt publitseeritud juhtudest. Seoses submikroskoopiliste koopiaarvu muutuste uurimisega 83-s eelnevalt mainitud Eesti peres, kirjeldatakse selles töös kahte harvaesinevat kromosomaalset muutust – kompleksset X-kromosoomi aberratsiooni ja deletsiooni 17 kromosoomi pikas õlas, ning neid muutusi kandvate patsientide kliinilist fenotüüpi

Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability

The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability. This discovery was made possible by systematic and unbiased X chromosome exome resequencing.Cheryl Shoubridge... Jozef Gécz... et al

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease