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Introduction Heterozygous pathogenic and likely pathogenic sequence variants in the RUNX1 (Runt-related Transcription Factor 1) gene are a common genetic cause of decreased platelet count and/or platelet dysfunction and an increased risk of developing myelodysplasia and acute myeloid leukemia. The majority of causative variants are substitutions, which rarely occur de novo. The aim of this case report is to present a patient with congenital thrombocytopenia caused by a deletion variant in exon 9 in the RUNX1 gene. Case report A one-month-old male infant was admitted to the Clinical Hospital Center Rijeka because of anemia and thrombocytopenia verified in the course of an acute viral infection. During follow-up, he occasionally had petechiae and ecchymoses on the lower extremities after mild trauma, with no other symptoms. The patient had persistent slightly decreased values of platelets with normal morphology, but with pathological aggregation with adrenaline and adenosine diphosphate. Due to the unclear etiology of persistent mild thrombocytopenia, he was referred for genetic testing at the age of five. Genomic DNA was isolated from the patient’s peripheral blood and whole-exome sequencing was performed using the next-generation sequencing method. A heterozygous frameshift variant, c.1160delG (NM_001754.4), was identified in exon 9. The variant is classified as likely pathogenic. Conclusion To the best of our knowledge, the heterozygous variant c.1160delG in the RUNX1 gene was first described in our patient. Although pathogenic variants in the RUNX1 genes are very rare, persistently low platelet counts of unclear etiology should raise suspicion of an underlying genetic disorder.

Medicinska genetika je medicinska specijalizacija u kojoj se primjenjuju principi i znanja o nasljeđivanju u prepoznavanju, dijagnostici, prevenciji i liječenju bolesti te unaprjeđivanju zdravlja. Uloga medicinskog genetičara je organizacija skrbi za pacijente s genetičkim poremećajima, što uključuje prepoznavanje indikacija za genetičko testiranje, provođenje genetičkog testiranja i organizaciju cjeloživotne skrbi. S obzirom na to da je medicinska genetika izuzetno multidisciplinarna specijalizacija, medicinski genetičari koordiniraju skrb za pacijenta s drugim specijalistima, logopedima, psiholozima, udrugama pacijenata. Medicinska genetika i logopedija izrazito su isprepletene brojnim poveznicama, od činjenice da je ljudska vrsta jedinstvena po postojanju jezika, koji je barem djelomično genetički kodiran, do toga da su pacijenti s genetičkim uzrocima razvojnih govorno-jezičnih poremećaja neizbježno uključeni u zajedničku skrb obiju vrsti stručnjaka. Stoga je izuzetno važno osvijestiti ulogu logopeda u području medicinske genetike, koja uključuje, s jedne strane, povezivanje nalaza genetičkog testiranja s očekivanim kliničkim obilježjima i ispravnim pristupom pacijentu s potvrđenim genetičkim uzrokom razvojnog govorno-jezičnog poremećaja te, s druge strane, prepoznavanje pacijenata s mogućim genetičkim uzrokom razvojnog govorno-jezičnog poremećaja. Priručnik Osnove medicinske genetike za studente logopedije obvezna je literatura za obvezni kolegij Osnove medicinske genetike na drugoj godini studija Logopedija. Osnovni su ciljevi priručnika i kolegija opisati i objasniti (1) osnovne pojmove iz genetike čovjeka potrebne za razumijevanje nastajanja i nasljeđivanja genetičkih poremećaja, (2) genetičke uzroke razvojnih govorno-jezičnih poremećaja te (3) osnove interpretacije nalaza genetičkog testiranja u kontekstu povezivanja s očekivanim kliničkim obilježjima i ispravnim pristupom pacijentu s razvojnim govorno-jezičnim poremećajem. Ovaj priručnik nastao je kao odgovor na nekoliko činjeničnih stanja u području medicinske genetike u svijetu, posebice u njezinu spoju s logopedijom. Prije svega, osnovna vizija i ideja za čitav kolegij bila je da se, s ciljem stjecanja specifičnih znanja, vještina i vrijednosti/stavova, svi oblici nastave (predavanja, seminari i vježbe) provode kroz metode aktivnog učenja temeljene na problemskom i iskustvenom učenju, potičući razvijanje otvorenog, analitičkog i kritičkog razmišljanja. Ovakvim pristupom učenju i poučavanju, obrnutnim od klasičnog načina, potiče se jednostavnije i svrhovitije savladavanje i primjena osnovnih teorijskih znanja, kao i razmišljanje o pacijentu u obrascima kliničkih obilježja. Nadalje, u postojećoj literaturi trenutno nema sličnih nastavnih priručnika koji bi omogućili učenje medicinske genetike u području logopedije, pa je navedeni koncept aktivnog učenja ključan za simulaciju stvarnog oblika djelovanja u kliničkoj praksi. U priručniku se nalaze brojni zadatci za savladavanje različitih razina znanja (kognitivna domena), vještina (psihomotorna domena) i vrijednosti i stavova (afektivna domena). Zadatci omogućavaju timski ili samostalni rad, vođenu argumentiranu raspravu i istraživanje rješenja problema, što osim postavljenih ishoda učenja za kolegij omogućava razvijanje i općih kompetencija, poput znanja i vještina za praksu te osjećaj samostalnosti i uvažavanja kolega. Naposljetku, s obzirom na to da je medicinska genetika jedna od najbrže razvijajućih medicinskih specijalizacija, pa većina gradiva u udžbenicima zastarijeva već prilikom njihova izdavanja, ovaj priručnik omogućava brzu prilagodbu i nadopunjavanje najnovijim spoznajama kroz jednostavne promjene sadržaja. Nastavnici polaznike tijekom nastave cijelo vrijeme strukturirano vode kroz priručnik na predavanjima, seminarima i vježbama. Predavanja, seminari i vježbe su u priručniku označeni različitim bojama naslova, što uvelike pridonosi brzom snalaženju i preglednosti. U prvom dijelu priručnika i nastave, gradivo je posvećeno osnovama genetike čovjeka, a drugi dio osnovama medicinske genetike, uz posebnu pažnju usmjerenu na analizu slučajeva. Primjeri genetičkih bolesti i poremećaja koji su prikazani u priručniku isključivo su oni s kojima se logopedi najčešće susreću po završenom studiju. Naposljetku, tijekom kolegija Osnove medicinske genetike poseban je naglasak stavljen na razvijanje afektivne domene, jer je ključno da, osim navedenih specifičnih znanja i vještina, budući logopedi razviju osviještenost za multidimenzionalnost genetičkih bolesti i poremećaja, kao i važnosti djelovanja u multidisciplinarnom timu, za dobrobit pacijenata s razvojnim govorno-jezičnim poremećajima.

To examine the knowledge, behavior, and attitudes toward medical genetics among obstetrics and gynecology, pediatrics, and neurology residents and specialists. The cross-sectional study involved 182 non-genetic residents and specialists in the Republic of Croatia, who completed a validated online questionnaire anonymously and voluntarily. The questionnaire consisted of five groups of questions: general information, knowledge, behavior in practice, attitude toward genetic testing, and additional education in medical genetics. The median score for overall knowledge of medical genetics was 70.2% among obstetrician- gynecologists, 80.5% among pediatricians, and 76.7% among neurologists (P

Small supernumerary marker chromosome (sSMC) is a structurally abnormal chromosome. It is an additional chromosome mainly detected, but rarely identifiable by conventional cytogenetic analysis. To identify the origin and composition of a specific sSMC, the application of a molecular cytogenetic method is essential. Despite the recent escalation of high-throughput methods, fluorescence in situ hybridization (FISH), as a powerful and sensitive technique with simple and inexpensive laboratory procedure, is still the method of choice in the characterization of sSMC structure. The aim of this study was to analyze the sSMC collected since 2009 in our Laboratory and to direct attention to the value of the FISH method in determining the origin of sSMC in prenatal diagnosis. A combination of conventional karyotyping and FISH were performed on cultured amniocytes as an effective utilization strategy in sSMC detection. The overall frequency of sSMCs was 0.24% (6/2456). Indications for prenatal diagnosis in those six cases were maternal age (2/6), first- trimester combined screening test (2/6) and ultrasound finding (2/6). Mosaic karyotypes were present in 66.67% (4/6) cases. FISH analyses revealed that the majority of sSMCs (50.00%) originate from chromosome 15. They were found to be dicentric (15), isochromosomes (12, 18) and centric minute (19). De novo origin of sSMC was detected in most of the cases (83.33%), except one dicentric 15, which was inherited from the mother. Gained experience in the field of molecular cytogenetics allows us to conclude that FISH remains to be a gold standard in the identification of sSMCs in prenatal diagnostics.

Introduction: The deficiency of vitamin D has been associated with premature birth. The effects of vitamin D are mediated by its receptor (VDR), which is encoded by the VDR gene. Both VDR gene polymorphisms and DNA methylation play important roles during normal and pathological pregnancy. The aim of this study was to evaluate whether maternal VDR gene polymorphisms and long interspersed nucleotide elements 1 (LINE-1) DNA methylation, alone or in combination, are a risk factor for idiopathic spontaneous preterm birth (ISPTB) in Croatian and Slovenian women. Material and methods: This case-control study included 50 women who delivered spontaneously early preterm (23-336/7 weeks of gestation) and 50 control women who delivered at term. The FokI (rs2228570), ApaI (rs7975232), Bsml (rs1544410), TaqI (rs 731236), and Cdx2 (rs11568820) single nucleotide polymorphisms (SNPs) in the VDR gene were identified using the combination of polymerase chain reaction and restriction fragment length polymorphism. Quantification of LINE-1 DNA methylation was determined using the MethyLight method. Results: There was no significant difference observed in genotype and allele frequencies of VDR gene polymorphism between women with ISPTB and control women (P > 0.050). Moreover, no significant differences were found in inheritance models between groups of subjects. The values of LINE-1 DNA methylation in patients with ISPTB did not significantly differ compared to the control group (P = 0.767). Additionally, no association was observed in DNA methylation between any of the analyzed genotypes of VDR gene polymorphisms (P > 0.050). Conclusion: The results of our study indicate that VDR gene polymorphisms are not associated with the occurrence of ISPTB. In addition, based on the LINE-1 quantification, DNA methylation is not associated with ISPTB nor with VDR gene polymorphisms. Considering the number of patients enrolled, further research is needed to detect and clarify the role of DNA methylation and VDR gene polymorphisms in ISPTB.

"Slagalica nasljeđa" - priručnik za opismenjavanje iz medicinske genetike ima tri namjene. Prije svega, on je edukativna slikovnica za studente, liječnike i pacijente, ali i druge zainteresirane pojedince jer su u njoj kroz ilustracije objašnjene osnove genetike čovjeka, kao i osnove medicinske genetike. Od toga kako prepoznati osobu s genetičkim poremećajem, kako nastaju i koje vrste genetičkih poremećaja postoje pa sve do toga na koji ih način možemo dijagnosticirati. Nadalje, nakon svake ilustracije na pojedinoj stranici nalaze se definicije 79 pojmova iz medicinske genetike koje čine tezaurus za studente, liječnike i pacijente koji se na bilo koji način susreću s genetičkim poremećajima. Naposljetku, ova knjiga sadrži i primjere rečenica u koje su ubačeni stručni pojmovi iz medicinske genetike, a koji su namijenjeni studentima prilikom savladavanja komunikacijskih vještina na kolegiju Medicinska genetika, ali i liječnicima prilikom informiranja svojih pacijenata o (mogućem) genetičkom poremećaju. Uz kreatoricu ideje i urednicu izdanja, doc. dr. sc. Ninu Perezu, autori izdanja su studenti šeste godine Integriranog preddiplomskog i diplomskog sveučilišnog studija Medicina i prof. dr. sc. Saša Ostojić.

Genetic variation in the maternal vitamin D receptor FokI gene as a risk factor for recurrent pregnancy loss

Background: Pallister-Killian syndrome (PKS) is a sporadic, rare chromosomal disorder, caused by tissue-limited mosaicism for an isochromosome 12p (i12p). Prenatal diagnosis of PKS is generally incidental at karyotyping in case of fetal anomaly detection or advanced maternal age. Although clinical presentation of PKS varies, cytogenetic findings are constant, and include a tetrasomy of chromosome 12p diagnosed by chorionic villus sampling, amniocentesis or cordocentesis. We report a case of prenatally diagnosed PKS with unique dysmorphic feature: bifid cardiac apex, a type of morphology that has not been documented ever before in the literature. Case report:. Our patient is the 38-year-old pregnant woman who underwent amniocentesis at 18 weeks and 1 days’ gestation upon of an ultrasonographic imaging of fetal cleft lip and advanced maternal age. Cytogenetic analysis of amniotic fluid detected a male mosaic karyotype with a supernumerary chromosome (SMC) in 18/28 (64%) of fetal amniocytes. To determine the chromosomal origin of SMC, fluorescence in situ hybridization (FISH) was performed on metaphase spread chromosomes and mosaicism of tetrasomy 12p was confirmed: mos 47, XY, +mar[18]/46, XY[10].ish i(12p)(8M16/SP6++, CEP12+, VIJyRM2196-). Ultrasound examination showed a male fetus with abnormal facial profile, an echogenic focus in the left ventricle of the heart and shortened fetal long bones. After receiving a genetic counseling for established diagnosis of PKS, the woman requested a termination of pregnancy due to medical reasons. A postmortem inspection and autopsy of the fetus revealed a complex heart anomaly that includes bifid cardiac apex and ventricular septal defect. Conclusion: This report expands the clinical manifestations of PKS with a unique feature of bifid cardiac apex, and highlights the targeted diagnosis of Pallister-Killian syndrome in a second and third trimester of pregnancy if specific ultrasound markers are present.

Goal: Preterm birth (PTB) is defined as birth before the 37th completed week of gestation and is the leading cause of neonatal mortality and morbidity. Although up to 25% of PTBs are medically induced, the majority is initiated spontaneously (SPTB or idiopathic PTB), accounting for approximately 50 % of all cases. Tumor necrosis factor α (TNFα) is a critical proinflammatory cytokine involved in the remodeling of cervix and fetal membranes by promoting collagen degradation. The aim of our study was to evaluate the potential association of TNFα rs361525 -238 G/A and TNFα rs1800629 -308 G/A gene polymorphisms with SPTB in Slavic women, and their contribution to clinical characteristics of women with SPTB. Material and methods: A total of 138 women with SPTB and 139 women with term delivery were included in a case-control study. All women with SPTB had singleton pregnancies following natural conception and spontaneous initiation of PTB before the 37th week of gestation. None of the women had known risk factors for PTB, including diabetes, hypertension, kidney disease, autoimmune conditions, allergic diseases, birth canal infections, in vitro fertilization and complications of pregnancy. The control group consisted of 139 women who had a term birth of a singleton baby after an uncomplicated pregnancy and were of the same age and parity as patients. Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: We found a statistically significant higher frequency of the TNFα -238 AG genotype (X2=7.32 ; P=0.025) and A allele (X2=7.48 ; P=0.006) in women with SPTB compared to controls. Additionally, the odds for SPTB in women were increased under the dominant genetic model (AA+AGvsGG: OR=3.20 ; 95% CI=1.30- 7.83 ; P=0.011). There were no statistically significant differences in genotype and allele frequencies of TNFα -308 G/A between SPTB patients and controls. Moreover, no significant associations of the TNFα -308 G/A and SPTB occurred. None of the polymorphisms contributed to the clinical characteristics of women with SPTB. Conclusion: Our results indicate that maternal TNFα rs361525 -238 G/A might be susceptibility factor for SPTB.

Low back pain is and will continue to be one of the leading causes of disability, absence from work and thus costs for individuals and societies. It can be expected that lifetime prevalence of the low back pain will continue to increase with increasing sedentary lifestyle across the globe in developing and already developed countries. Diagnosing low back pain patients or their differentiation from healthy subjects is thus an interesting task. One of the means for diagnostics arise from properties of surface EMG signals which provide information about complex changes occurring within low back muscles during fatiguing contractions. So far, studies of the surface EMG based classification models of low back pain patients have been directed only to their differentiation from healthy subjects. This thesis deepens the knowledge on surface EMG based classification models and introduces differentiation of low back pain patients with radiculopathy from nonspecific chronic low back pain patients and healthy subjects. The measurement protocol is simplified, and number of classification features is reduced only to one. Surface EMG signals were measured above low back muscles: m. erector spinae at L1-L2 interspace and m. erector spinae at L4-L5 interspace. A variant of the Roman chair was used to perform static contractions and subject’s own upper body weight was used to induce muscle fatigue in low back muscles. The time-frequency method called Hilbert-Huang transformation (HHT) was utilized to estimate power spectrum from recorded surface EMG signals above lower back. As a descriptor of surface EMG spectral changes, the regression line of slope of the median frequency of the power spectrum was calculated to form classification feature for the decision tree classification. Two splitting criterions were evaluated, Gini diversity index and Maximum deviance reduction. The results show that regression line slope of the median frequency derived from HHT based power spectrum estimate is significantly different between low back pain patients with radiculopathy and other two groups, being chronic low back pain patients and control subjects. There was no significant difference between chronic low back pain patients and control subjects. The proposed classification feature and model enabled differential electromyographic diagnostics of low back pain and radiculopathy.

Aim: The aim of this study was to evaluate the potential association between spontaneous or idiopathic PTB (SPTB) and DNMT3B gene polymorphisms in Slavic women, and their contribution to clinical characteristics of women with SPTB and their new-borns (family history of PTB, maternal smoking before pregnancy, maternal age, gestational week at delivery and fetal birth weight). Patients and methods: A total of 162 women with SPTB and 162 women with term delivery were included in a case-control study. Genotyping of DNMT3B rs1569686 and DNMT3B rs2424913 single nucleotide polymorphisms was performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: DNMT3B rs1569686 and rs2424913 minor alleles (T) were significantly more frequent in women with familial PTB than non-familial PTB, and contributed to a 3.30 and 3.54 increased odds for familial PTB under dominant genetic models (95 % CI = 1.53-7.14, P = 0.003 and 95 % CI = 1.56-8.01, P = 0.002). Furthermore, the DNMT3B rs1569686 and rs2424913 T alleles were significantly more frequent in women with SPTB who smoked before pregnancy, reaching the most significant association under additive genetic models (OR = 6.86, 95 % CI = 2.25-20.86, P ˂ 0.001 and OR = 3.77, 95 % CI = 1.36-10.52, P = 0.011). Conclusion: The DNMT3B rs1569686 and rs2424913 gene polymorphisms in Slavic women might be associated with a positive family history of PTB and smoking status before pregnancy.

Low back pain is one of the leading causes of absence from work. Diagnosing low back pain patients or mere differentiation from healthy subjects is therefore an interesting problem. One way to diagnose comes from properties of surface EMG signals to reflect complex changes occurring within skeletal muscles during fatiguing static contractions. This doctoral work introduces differentiation of low back pain patients with radiculopathy from chronic nonspecific low back pain patients and from healthy subjects based only on four surface EMG signals. The measurement protocol was simplified, and subject’s own upper body weight is used to induce muscle fatigue in low back muscles. Surface EMG signals were recorded during static contractions above m. erector spinae. The adaptive time-frequency method, Hilbert-Huang transform, was utilized to estimate power spectrum of the recorded surface EMG signals. As a descriptor of surface EMG spectral changes, the regression line of slope of the median frequency of the power spectrum was calculated and used as classification feature for the decision tree classification. Proposed measurement protocol, defined classification feature and classification model enable electromyographic differentiation of low back pain patients with radiculopathy and chronic nonspecific low back pain patients, where achieved overall accuracy of classification is up to 86.8 %. Križobolja je jedan od vodećih razloga izostajanja s posla. Zato je dijagnosticiranje križobolje u pacijenata ili već i samo njihovo razlikovanje od zdravih osoba zanimljiv problem za proučavanje. Jedan od načina dijagnosticiranja proizlazi iz svojstva površinskih EMG signala da odražavaju složene promjene u skeletnim mišićima što nastaju tijekom umarajućih statičkih kontrakcija. Ovaj doktorski rad uvodi diferencijaciju pacijenata s križoboljom s radikulopatijom od pacijenata s kroničnom nespecifičnom križoboljom, te od zdravih ispitanika, temeljem samo četiri površinska EMG signala. Mjerni protokol je pojednostavljen te se težina gornjeg dijela tijela ispitanika koristi za izazivanje mišićnog umora u mišićima donjeg dijela leđa. Površinski EMG signali snimani su tijekom statičkih kontrakcija iznad m. erector spinae. Adaptivna vremensko-frekvencijska metoda, Hilbert-Huang transformacija, korištena je za procjenu spektra snage snimljenih površinskih EMG signala. Kao deskriptor promjene spektra površinskih EMG signala, izračunat je nagib regresijskog pravca frekvencije medijana spektra snage i korišten kao klasifikacijska značajka za klasifikaciju stablom odlučivanja. Predloženi mjerni protokol, definirana klasifikacijska značajka i klasifikacijski model omogućavaju elektromiografsku diferencijaciju pacijenata s križoboljom s radikulopatijom i pacijenata s kroničnom nespecifičnom križoboljom, pri čemu je ostvarena ukupna točnost klasifikacije do 86,8 %.

Aim: Recurrent pregnancy loss (RPL) is a reproductive disorder defined as the loss of two or more pregnancies from the time of conception until 24 weeks of gestation. Despite the fact that several mechanisms have been previously described for the pathogenesis of RPL, the causes of approximately 50% remain unknown. However, recent studies indicate association of vitamin D with adverse pregnancy outcome, including RPL. The vitamin D receptor (VDR) is a crucial mediator of the pleiotropic cellular effects of vitamin D. It's function is influenced by several single nucleotide polymorphisms (SNPs). The main objective of the present study was to assess whether three different maternal VDR SNPs are associated with the risk of RPL in Slovenian and Croatian women. Methods: A case – control study including 320 women was designed to examine the potential association of VDR polymorphisms (FokI rs222857, Cdx2 rs115688 and Taq1 rs731236) with RPL. Genotyping was performed using PCR-RFLP methods. Results: We found a statistically significant higher frequency of the FokI rs222857 CC genotype (X2=6.61, P=0.036) and C allele (X2=5.93, P=0.015) in women with RPL compared to controls. Additionally, the odds for RPL were increased under the recessive (CCvsCT+TT: OR=1.78 ; 95% CI=1.12-2.82 ; P=0.015) and codominant genetic models (CCvsTT: OR=2.21 ; 95% CI=1.08-4.53 ; P=0.029 ; CCvsCT: OR=1.68 ; 95% CI=1.04-2.72 ; P=0.036). Furthermore, Taq1 rs731236 C allele showed a statistically significant higher frequency in women with RPL compared to controls (X2=4.13, P=0.042). Conclusion: Our results suggest that the CC genotype of the FokI rs222857 polymorphism in women might be a genetic marker for RPL.