Genetska testiranja kod pacijenata s neurorazvojnim poremećajima vrlo su važna za postavljanje konačne dijagnoze. Prema trenutnim smjernicama prve metode izbora uključuju komparativnu genomsku ...hibridizaciju na mikropostroju te genetsko testiranje fragilnog X sindroma. Cjeloeksomsko sekvenciranje koje omogućuje detekciju jednonukleotidnih varijanti u kodirajućim regijama gena predstavlja sljedeći dijagnostički korak. Dijagnostički prinos komparativne genomske hibridizacije na mikropostroju raste do 15%, a cjeloeksomskog
sekvenciranja čak do 40%. Međutim, kod velikog broja pacijenata (čak do 50%) etiologija neurorazvojnih poremećaja ostaje nerazjašnjena. Danas su poznati mnogi genetski mehanizmi koje nije moguće ustanoviti rutinskim dijagnostičkim metodama, a uključuju varijante broja kopija u nekodirajućim regulacijskim DNA regijama, varijante broja kopija koje utječu na strukturu i funkciju topoloških domena, duboke intronske varijante u kodirajućim genima kao i metilacijske obrasce u genomu. Navedene genske promjene moguće je detektirati novijim tehnologijama kao što je cjelogenomsko sekvenciranje i mapiranje topoloških domena (Hi-C sekvenciranje). Cjelogenomskim sekvenciranjem moguće je odrediti i precizne točke loma u naoko balansiranim kromosomskim razmještanjima.
Uvođenje cjelogenomskog sekvenciranja u rutinsku dijagnostiku genetskih bolesti svakako bi povećalo dijagnostički prinos i omogućilo postavljanje dijagnoze za velik broj pacijenata s neurorazvojnim poremećajima. S napredovanjem tehnologije i sve većom dostupnošću cjelogenomskog sekvenciranja, u skoroj budućnosti se očekuje i povećanje genomskih baza koje bi omogućile interpretaciju velike količine podataka koju ova metoda generira, čime bi se ubrzalo uvođenje ove moćne metode u rutinsku medicinsku skrb kod pacijenata s genetskim poremećajima.
Parasomnija je poremećaj spavanja s visokom prevalencijom u općoj populaciji. Bez obzira na to što je parasomnija većinom benigne naravi, najčešće predstavlja vrlo neugodan i nepoželjan fenomen u ...spavanju u djece i odraslih, snižava kvalitetu života, a može biti krivo protumačena i liječena kao epilepsija. Diferencijalna dijagnostika je posebice izazovna u osoba s napadajima s predominantnim kompleksnim motoričkim ponašanjem koji nastaju tijekom hipermotorne epilepsije s noćnim napadajima, kada može dovesti do nepotrebnih i skupih pretraga te neuspješnog liječenja. Koegzistencija parasomnije i epilepsije u istoj obitelji i/ili u iste osobe upućuje na zajedničke neurofiziološke temelje. U ovom preglednom radu opisane su kliničke i neurofiziološke osobitosti najčešćih parasomnija, genetske osnove te pouzdani elementi u diferencijalnoj dijagnostici parasomnija i noćnih epileptičkih napadaja. Prikazana je dijagnostička vrijednost anamnestičkih podataka, video EEG polisomnografije i dijagnostičkih skala. U djece s epilepsijom i parasomnijama, pogotovo u djece koja imaju noćne napadaje, ne smije se zanemariti postojanje dnevne pospanosti i poteškoća spavanja. Svaku osobu s epilepsijom
i s dnevnom pospanošću ili sumnjom i na neepileptogene noćne događaje treba poslati na cjelonoćnu polisomnografiju. Liječenje komorbiditeta koji pogoršavanju spavanje u osoba s epilepsijom i kronofarmakologija epilepsije osiguravaju bolji uspjeh liječenja epilepsije. Pravovremeno prepoznavanje postojanja parasomnije omogućava pravilnu procjenu njezinoga zdravstvenog značenja za osobu i utjecaja na kvalitetu života. Uvođenje medicine spavanja u kurikulume diplomskog i poslijediplomskog obrazovanja omogućava adekvatno obrazovanje zdravstvenih radnika i stjecanje potrebnih vještina za rad u specijaliziranim laboratorijima i odjelima za
poremećaje spavanja.
Although the risk of pregnancy with Down syndrome (DS) increases with age, conceptions with trisomy 21 can occur in mothers aged 35 or less. The micronucleus test on peripheral blood lymphocytes is a ...well-recognized method for studying chromosomal instability. The aim of this study was to evaluate the application of the micronucleus assay and fluorescence in situ hybridization (FISH) for estimation of chromosome instability and occurrence of trisomy 21 in young parents having pregnancy or a child with the regular form of Down syndrome. The study included 54 parents (27 couples) who had previous pregnancy with trisomy 21 at age 35 or less. The control group consisted of 30 couples with two healthy children and no previous spontaneous abortions. Parents with trisomy 21 pregnancy had significantly higher frequencies of micronuclei in binucleated cells. There was no statistically significant difference between the study and control groups in the frequencies of micronuclei in mononuclear cells, nuclear buds, or nucleoplasmic bridges. FISH analysis showed higher percentages of micronuclei containing whole chromosomes as well as statistically significant higher numbers of micronuclei containing chromosome 21 in the peripheral blood of DS parents. There was no statistically significant difference between the two groups in the responses of peripheral blood lymphocytes to treatment with the mutagen mitomycin C. Our results suggest that young parents with a history of the regular form of Down syndrome have a higher susceptibility to chromosome nondisjunction in peripheral blood lymphocytes. The micronucleus assay showed high specificity, but moderate sensitivity, for risk assessment of trisomy 21 pregnancy.
•Young parents of Down syndrome have higher susceptibility to nondisjunction.•The micronucleus assay have high specificity for risk assessment of T21.•No significant difference was found in the response to mitomycin C treatment.
The purpose of this study was to determine the prevalence of allele and genotype variants of the follicle-stimulating hormone receptor (FSHR) gene polymorphic region at position Asn680Ser in the ...Albanian male population and associate them with the clinical parameters of infertility. The study included 114 infertile men (mean age 35.04±5.85 years) stratified according to the level of spermatogenetic impairment (oligoasthenozoospermia, asthenozoospermia and normospermia) and 112 fertile men (mean age 36.44±7.05 years) with normal semen parameters. Genotyping of the FSHR gene at position 680 was performed by TaqMan genotyping assay. All the participants underwent semen analysis, and serum reproductive hormones (FSH, luteinizing hormone, prolactin and testosterone) were also measured. The FSHR Asn680Ser genotype frequencies were as follows: Asn/Ser 42%, Ser/Ser 33.9% and Asn/Asn 24.1% in the control group, and Asn/Ser 56.1%, Ser/Ser 22.8% and Asn/Asn 21.1% in the whole group of infertile men (χ2-test: P=0.08). There was no statistically significant correlation between serum hormone levels and semen characteristics or between fertility status and FSHR Asn680Ser gene variants in the control group and the group of infertile men. However, adjusted logistic regression analysis (age, body mass index, smoking and alcohol as covariates) revealed increased odds ratio for male infertility among heterozygous Asn/Ser genotype carriers associated with lower values of semen parameters (normal morphology, concentration, total sperm count and motility). In conclusion, our case-control study further confirmed previous reports on no significant association between the FSHR Asn680Ser polymorphisms and male infertility. Nevertheless, the data presented herein indicate that the Asn/Ser genotype may increase the risk of male infertility in Albanian population.
The aim of this study is to summarize the experience on prenatal diagnosis of Down syndrome.
The study includes a retrospective data analysis of 157 prenatally detected cases of Down syndrome, ...routinely diagnosed among 6448 prenatal investigations performed during a 13-year period (2002–2014) in a single tertiary center.
The prevalence of diagnosed Down syndrome cases was 2.4%. Maternal age alone was indication for prenatal diagnosis in 47 cases (45.2%), increased first-/second-trimester biochemical screening test in 34 cases (21.7%), abnormal ultrasound examination in 69 cases (43.9%), positive familial history for chromosomal abnormalities in four cases, and high risk for trisomy 21 revealed by cell-free DNA testing in three cases. Ultrasound anomalies were present in total of 94 fetuses (59.8%). The most common abnormality was cystic hygroma found in 46 cases (29.3%). A regular form of Down syndrome (trisomy 21) was found in 147 cases (93.6%), Robertsonian translocation in six cases (3.8%), and mosaic form in four cases (2.6%).
In prenatal diagnosis of Down syndrome noninvasive screening methods are important for estimation of individual risks, in both, young population of woman and older mothers, while conventional and molecular cytogenetic methods are essential for definite diagnosis and proper genetic counseling.
Analysis of prenatally diagnosed sex chromosome aneuploidies and disorders of sex development (DSDs).
This study includes a retrospective data analysis of 46 prenatally detected sex chromosome ...aneuploidies and one case of 46,XY DSD diagnosed during an 11-year period (2002–2012) at our department.
Of the 46 sex chromosome aneuploidies, 29 cases (63.0%) were in the group of a selected population of women according to abnormal first-/second-trimester ultrasound and 17 (37.0%) cases in an unselected population of women who underwent fetal karyotyping because of advanced maternal age. The most common aneuploidy was Turner syndrome in full and mosaic form (50%). Complete androgen insensitivity syndrome was diagnosed in the case of 46,XY DSD.
Sex chromosome aneuploidies must be taken into consideration if, in the first or second trimester, abnormalities are revealed on ultrasound, mainly Turner syndrome in full or mosaic form and 47,XYY.
Introduction
Noninvasive prenatal testing (NIPT) using cell‐free fetal DNA has increasingly been adopted as a screening tool for fetal aneuploidies. Several studies have discussed benefits and ...limitations of NIPT compared with both ultrasound and invasive procedures, but in spite of some shortcomings NIPT has become extensively used within the last 5 years. This study aims to describe the current use of NIPT in Europe, Australia and the USA.
Material and methods
We conducted a survey to describe the current use of NIPT. Colleagues filled in a simple email‐based questionnaire on NIPT in their own country, providing information on (a) access to NIPT, (b) NIPT’s chromosomal coverage, (c) financial coverage of NIPT for the patient and (d) the proportion of women using NIPT in pregnancy. Some data are best clinical estimates, due to a lack of national data.
Results
In Europe, 14 countries have adopted NIPT into a national policy/program. Two countries (Belgium and the Netherlands) offer NIPT for all pregnant women, whereas most other European countries have implemented NIPT as an offer for higher risk women after first trimester screening. In Australia, either combined first trimester screening (cFTS) or NIPT is used as a primary prenatal screening test. In the USA, there are no national consensus policies on the use of NIPT; however, NIPT is widely implemented. In most European countries offering NIPT, the proportion of women using NIPT is well below 25%. In the Netherlands, Austria, Italy, Spain and most Australian and American States, 25%‐50% of women have NIPT performed and in Belgium testing is above 75%. In most countries, NIPT reports on trisomy 13, 18 and 21, and often also on sex chromosome aneuploidies. Only in Belgium, the Netherlands, Lithuania, Greece, Cyprus and Italy is NIPT offered predominantly as a genome‐wide test (including some microdeletions or a whole genome coverage).
Conclusions
Noninvasive prenatal testing has been widely adopted throughout Europe, Australia and the USA, but only a few countries/states have a national policy on the use of NIPT. The variation in NIPT utilization is considerable.
Approximately 90% of "XX males" are positive for
. However, there are isolated cases of sex reversal associated to other genes in male-determining pathway.
We describe a 1.3-old patient with 46,XX ...karyotype, male phenotypic gender and cryptorchidism. Microarray analysis revealed a
273 kb duplication in the Xq27.1 region that contains
. FISH with probe specific to
confirmed a unique genomic location of this duplication, dislocated proximal to the centromere of the X chromosome.
This rare genetic condition was described in few other isolated cases that have associated
genetic rearrangements and DSD. Microarray and genome-wide-sequencing presents important part in routine diagnostics, and in delineation of other sex-determination-pathway genes in sex reversal disorders.
Primary cilia are a component of almost all vertebrate cells with a crucial role in sensing and transducing environmental signals during tissue development. Their dysfunction is known as ciliopathies ...and can manifest with a wide spectrum of clinical disorders. Overlapping features and molecular heterogeneity of ciliopathies make diagnoses distinctly challenging. In this group of diseases, tectonic genes, and their mutations play an important role. We present a first-trimester fetus with occipital encephalocele and OFD type IV caused by TCTN3 compound heterozygous pathogenic variants: c.1423_1429del (p.Arg475Serfs*10) and c.3G>A (initiator codon). A severe arm anomaly was described in our case, with two fingers along the atrophic forearm and polydactyly on other limbs. This could be a new phenotypic characteristic contributing to further understanding of TCTN3-related disorders as well as other tectonic proteins in ciliopathy spectrum diseases.
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