Terminal deletion of chromosome 4 (4q deletion syndrome) is a rare genetic condition that is characterized by a broad clinical spectrum and phenotypic variability. Diagnosis of the distinct condition can be identified by conventional chromosome analysis and small deletions by novel molecular cytogenetic methods such as microarray comparative genome hybridization (aCGH). Prenatal diagnosis is challenging; to date 10 cases have been described. We report a prenatally diagnosed case of de novo 4q deletion syndrome confirmed by conventional karyotyping and FISH due to an elevated combined risk for Down syndrome and prenatal ultrasound findings. aCGH validated the diagnosis and offered exact characterization of the disorder. Cytogenetic and microarray results described a 4q32.1qter terminal deletion of the fetus. Prenatal ultrasound detected multiple nonstructural findings (micrognathia, choroid plexus cysts, echogenic fetal bowel, short femur, and cardiac axis deviation). Pregnancy was terminated at 20 weeks. In addition to the index patient, we reviewed the 10 prenatally published cases of 4q deletion syndrome in the literature and compared these with our results. We summarize the patients' characteristics and prenatal clinical findings. Alterations of maternal serum biochemical factors, an elevated combined risk for trisomies, and distinct ultrasonographic findings can often be observed in cases of prenatal 4q deletion syndrome and may facilitate the otherwise difficult prenatal diagnosis.
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Összefoglaló. Bevezetés és célkitűzés: A gyakori autoszomális trisomiák és a nemi kromoszómaeltérések a mikroszkóppal észlelhető kromoszóma-rendellenességek kb. 80–85%-át képviselik. A ritka kromoszóma-rendellenességek klinikai következménye jelentős, kimutatásukat a jelenlegi szűrővizsgálatok ugyan nem célozzák, de a teljes kromoszómaszerelvényt vizsgáló, nem invazív praenatalis tesztelés új lehetőséget nyitott a korai felismerésükre. Módszer: Retrospektív analízis (2014–2019) a mikroszkóppal kimutatható kromoszóma-rendellenességek eloszlására, a fetoplacentaris mozaikosság előfordulására, klinikai összefüggéseire a praenatalis vizsgálatok tükrében egy hazai tercier centrumban. Eredmények: 2504 invazív beavatkozást végeztünk és 200 kromoszómaeltérést mutattunk ki (8%), melyek közül újonnan kialakult, ritka rendellenesség 27 volt (13,5%). Ritka autoszomális trisomia 14, poliploidia 6, de novo szerkezeti kromoszómaeltérés 5, marker kromoszóma 2 esetben igazolódott. A fetoplacentaris mozaikosság aránya a gyakori/ritka kromoszómaeltérésekben 12,4%/77,8% volt (p = 0,001), 17/40 esetben lepényre korlátozódott. A gyakori trisomiákkal kóros tarkóredő-vastagság 58%-ban, major ultrahangeltérés 35%-ban társult, melyek jelentősen különböztek a ritka kromoszómaeltérésekben (11%, p = 0,006; 67%, p = 0,047). A ritka kromoszómaeltérések jellemző praenatalis major ultrahangeltérése a facialis dysmorphismus volt. A teljes kromoszómaszerelvényt vizsgáló praenatalis tesztelés a ritka kromoszómaeltérések 12 lepényi mozaikos esetében (44%) feltételezhetően álpozitív, 1 esetben (3,7%) álnegatív eredményt generált volna, miközben a ritka autoszomális trisomiák 2 esetében ultrahangeltérés nélkül is korán detektálta volna a ritka magzati kromoszómaeltérést (7,4%). Következtetés: A normális tarkóredő-vastagság esetén észlelt major ultrahangeltérések felhívhatják a figyelmet a döntően mozaikos ritka kromoszóma-rendellenességekre. A teljes kromoszómaszerelvényt vizsgáló, nem invazív szűrőteszt a korai diagnosztika alternatívája lehet, a mozaikosságból adódó álpozitív eredményekre azonban számítani kell. A fetoplacentaris mozaikosság ismerete fontos klinikai információt biztosít, mely befolyásolhatja a terhesség kimenetelét, a terhesség követésének módját. A pontos citogenetikai karakterizálás elengedhetetlen. Orv Hetil. 2021; 162(29): 1156–1165. Summary. Introduction and objective: To determine the prevalence of microscopically visible de novo atypical chromosomal aberrations and fetoplacental mosaicism in a prenatal tertial referral center, and to investigate the maternal and fetal characteristics in connection with genomewide non-invasive prenatal screening. Method: Retrospective cohort study from 2014 to 2019 of pregnancies with invasive genetic analysis. Results: In the cohort of 2504 cases, the proportion of CVS was 53.3%. We diagnosed 200 chromosomal aberrations (8%), including 13.5% of de novo rare chromosomal aberrations (14 rare autosomal trisomies, 6 polyploidies, 5 structural aberrations and 2 small supernumerary marker chromosomes). The rate of fetoplacental mosaicism was 12.4%/77.8% in common/atypical chromosomal aberrations (p = 0.001) and confined to placenta in 17/40 cases. Associated ultrasound abnormalities were abnormal nuchal translucency and major malformations in 58% and 35% with common trisomies and 11% (p = 0.006) and 67% (p = 0.047) with true mosaic cases of rare abnormalities, respectively. Major ultrasound malformation was facial dysmorphism with rare aberrations. Potential application of genomewide non-invasive prenatal test in atypical chromosomal aberrations presumably would have been false-positive in 12 cases (44%), false-negative in 1 case (3.7%), and would have early detected 2 cases of rare autosomal trisomies (7.4%) without ultrasound anomalies. Conclusion: Structural ultrasound malformations with normal nuchal translucency thickness may be indicative of rare chromosomal aberrations. Application of genomewide non-invasive prenatal test is an alternative of early diagnostic methods with a potential of discordant results due to mosaicism. Knowledge about the presence of fetoplacental mosaicism influences risk estimation and genetic counseling, detailed cytogenetic characterization is of utmost importance. Orv Hetil. 2021; 162(29): 1156–1165.
Background. Small supernumerary marker chromosome (sSMC) is a challenge in prenatal diagnosis. Its’ presence is associated with advanced maternal age and distinct ultrasound findings, prediction of postnatal clinical consequences and prenatal counselling is difficult. Exact characterization of an sSMC is augmented by the application of novel molecular methods such as fluorescent in situ hybridization (FISH) and array comparative genome hybridization (aCGH). Case presentation. Chorion villous sampling of a fetus of a 42-year old secundipara was carried out due to advanced maternal age and the conventional banding cytogenetic examination revealed a mosaic sSMC. Detailed prenatal ultrasound scan showed no fetal malformations. The karyotype from confirmatory amniocentesis was 47,XY,+mar[45]/46,XY. The level of mosaicism was 70% from chorionic villus and amnion cells as well. By using FISH and SNP based aCGH the exact origin of the marker was described and the final prenatal karyotype was determined as 47,XY,+mar[70].arr[GRCh38]16p11.2p11.1(31699804_35989873)x3dn/46,XY[30]. The increase in DNA dosage was 4,29 Mb affecting 20 genes with two OMIM ones (ZNF267 and TP53TG3), the SNP analysis excluded the possibility of uniparental disomy (UPD) of the chromosome. The application of the molecular cytogenetic methods allowed us the differentiate the mosaic marker chromosome from the known 16p11.2 duplication syndrome in close neighboring that is connected to developmental delay and autism spectrum disorder. The present case was identified as a harmless de novo euchromatic variant (EV) of the short arm of chromosome 16. Postnatal karyotyping from neonatal peripheral blood confirmed the presence of the marker. FISH analysis with probe D16Z2 on cultured lymphocyte and buccal smear samples revealed a 64% and 45% mosaic state of the sSMC, respectively. The precise karyotype was finally defined as 47,XY,+min(16)(:16p11.2->p11.1:)dn[64]/46,XY. Conclusions. Novel microarray methods combined with molecular cytogenetic analysis is particularly effective in the rapid and accurate diagnosis of sSMCs, especially in a prenatal situation when the exact characterization of a genomic imbalance is of utmost importance. Precise diagnosis facilitates proper genetic counseling, allows informed decision making and helps avoiding unnecessary pregnancy termination.
Összefoglaló. A 3p25-deletiós szindróma nagyon ritka genetikai rendellenesség, a nemzetközi szakirodalom jelenleg kevesebb mint 60 esetet ír le. A kórképre általánosan jellemző a növekedési és pszichomotoros visszamaradottság, a microcephalia, a hypotonia, a veleszületett szívfejlődési rendellenesség, a ptosis és micrognathia, de nagyon ritkán előfordul klinikai tünetek nélküli megjelenése is. Általában újonnan kialakult rendellenesség, bár egyes esetekben előfordulhat familiáris formája. A kromoszomális töréspont változó helyen fordul elő. Közleményünkben egy 3p25-deletiós szindrómával született gyermek esetét mutatjuk be: a deletiót kariotipizálással és fluoreszcens in situ hibridizációval igazoltuk, majd microarray-komparatív genomhibridizálással meghatároztuk a pontos töréspontot és a hiányzó géneket. Az érintett régióban 43 OMIM-gént találtunk, melyek szerepet játszanak a megkésett pszichomotoros és növekedési elmaradásban, valamint az intellektuális zavarban. A genetikai háttér pontos karakterizálása hozzásegít a várható tünetek és a prognózis meghatározásához, egyben támpontot biztosíthat a jövőbeli terápia tervezéséhez és a személyre szabott fejlesztés kivitelezéséhez. Orv Hetil. 2022; 163(12): 478–483. Summary. The 3p25 deletion syndrome is a very rare genetic abnormality, characterized by growth and psychomotor retardation, microcephaly, hypotonia, congenital heart defects, ptosis and micrognathia. Less than 60 cases have been published in the literature so far. However, a few patients with normal or mild phenotype have also been described. The majority of the cases are de novo mutations, with variable chromosomal breakpoints. We present the case of a newborn infant with 3p25 deletion syndrome, whose genetic analysis was done by karyotyping, fluorescent in situ hybridization and array comparative genomic hybridization. The latter method enabled us to define the precise breakpoint and the genes involved in the deletion, thus we could provide information for further clinical management. We identified 43 OMIM genes in the deleted region, which may have a causative effect on the pscychomotor and developmental delay and also on the intellectual disability. Exact cytogenomic characterisation of a rare genetic syndrome may allow to employ personalised treatment. Orv Hetil. 2022; 163(12): 478–483.
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