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Possible Phenotypic Consequences of Structural Differences in Idic(15)

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Possible Phenotypic Consequences of Structural Differences in Idic(15) International Journal of Molecular Sciences Article Possible Phenotypic Consequences of Structural Differences in Idic(15) in a Small Cohort of Patients Márta Czakó 1,2,* , Ágnes Till 1, András Szabó 1,2,Réka Ripszám 1,Béla Melegh 1,2 and Kinga Hadzsiev 1,2 1 Department of Medical Genetics, Medical School, University of Pécs, H-7624 Pécs, Hungary; [email protected] (Á.T.); [email protected] (A.S.); [email protected] (R.R.); [email protected] (B.M.); [email protected] (K.H.) 2 Szentágothai Research Centre, H-7624 Pécs, Hungary * Correspondence: [email protected]; Tel.: +36-72-535-978 Received: 30 August 2019; Accepted: 3 October 2019; Published: 5 October 2019 Abstract: Among human supernumerary marker chromosomes, the occurrence of isodicentric form of 15 origin is relatively well known due to its high frequency, both in terms of gene content and associated clinical symptoms. The associated epilepsy and autism are typically more severe than in cases with interstitial 15q duplication, despite copy number gain of approximately the same genomic region. Other mechanisms besides segmental aneuploidy and epigenetic changes may also cause this difference. Among the factors influencing the expression of members of the GABAA gene cluster, the imprinting effect and copy number differences has been debated. Limited numbers of studies investigate factors influencing the interaction of GABAA cluster homologues. Five isodicentric (15) patients are reported with heterogeneous symptoms, and structural differences of their isodicentric chromosomes based on array comparative genomic hybridization results. Relations between the structure and the heterogeneous clinical picture are discussed, raising the possibility that the structure of the isodicentric (15), which has an asymmetric breakpoint and consequently a lower copy number segment, would be the basis of the imbalance of the GABAA homologues. Studies of trans interaction and regulation of GABAA cluster homologues are needed to resolve this issue, considering copy number differences within the isodicentric chromosome 15. Keywords: idic(15) syndrome; array CGH; supernumerary marker chromosome; GABAA gene cluster; CHRNA7; epilepsy; autism spectrum disorder 1. Introduction A wide variety of constitutional supernumerary marker chromosomes (SMCs) have been described in the human genome, with birth prevalence of 2–7 per 10,000 [1]. The identification and characterization of them became more and more accurate as the investigation methods evolved over time, which allowed for a more precise phenotype association and had many benefits in genetic counselling and prenatal diagnosis [2]. About half of the SMCs in humans are of 15 origins due to instability of 15q11.2–q13 genomic region. In the background of frequent rearrangements, there are five clusters of low copy repeats which are the basis of recurrent breakpoints known as BP1–BP5 being detected in the derivative chromosomes arising through different recombination events (non-allelic homologous recombination). U-type exchange is one of the crossovers which can result in a supernumerary isodicentric chromosome 15 (idic(15)) showing remarkable structural heterogeneity [3]. The most often described breakpoints involved in large idic(15) are BP4 and BP5 with two extra copies of genomic regions between BP2-BP3 (partial tetrasomy) [4]. The appearance of idic(15) can be also bisatellited; one of the centromeres can be inactive (pseudo-isodicentric form). It is of maternal origin in 70% of the patients and occurs Int. J. Mol. Sci. 2019, 20, 4935; doi:10.3390/ijms20194935 www.mdpi.com/journal/ijms Int.Int. J. Mol. J. Mol. Sci. Sci.2019 2019, 20, 20, 4935, x FOR PEER REVIEW 2 of2 12 of 12 of idic(15) can be also bisatellited; one of the centromeres can be inactive (pseudo-isodicentric form). withIt is increasing of maternal frequency origin in with70% of advanced the patients maternal and occurs age [with5]. The increasing clinical frequency features characteristicwith advanced for idic(15)maternal are centralage [5]. hypotoniaThe clinical in features early age, characteristic developmental for idic(15) delay (DD),are central moderate hypotonia to severe in early intellectual age, disabilitydevelopmental (ID), seizures, delay autistic(DD), moderate behaviour, to and severe absent intellectual or very poor disability speech in(ID), the vastseizures, majority autistic of the patientsbehaviour, [6]. Major and malformationsabsent or very arepoor rarely speech reported. in the Incidence vast majority at birth of is estimatedthe patients to be[6]. 1 inMajor 30,000 withmalformations a sex ratio of are almost rarely 1, reported. however Incidence its incidence at birth is probably is estimated higher to be due 1 in to 30,000 under-ascertainment with a sex ratio of [ 7]. Karyotypingalmost 1, however is not indicated its incidence in some is probably patients higher due to due subtle to under-ascertainment dysmorphic signs and[7]. theKaryotyping lack of major is malformations,not indicated soin theysome can patients remain due undiagnosed. to subtle dysmorphic A high prevalence signs and the of idic(15) lack of chromosome,major malformations, out of the SMCs,so they is detected can remain byfluorescence undiagnosed. in A situ high hybridization prevalence (FISH)of idic(15) that chromoso targets theme, Prader–Willi out of the /SMCs,Angelman is regiondetected of idic(15) by fluorescence as the next in situ diagnostic hybridization procedure. (FISH) After that targets karyotyping, the Prader–Willi/Angelman array comparative genomicregion hybridizationof idic(15) (arrayas the CGH)next isdiagnostic a powerful procedure. method forAfter detailed karyotyping, characterization array comparative of the genomic genomic content involvedhybridization in idic(15), (array possibly CGH) providing is a powerful additional method data for for detailed genotype–phenotype characterization correlation, of the genomic especially incontent cases with involved atypical in idic(15), clinical possibly signs. Hereproviding we report additional five idic(15)data for genotype–phenotype cases diagnosed at di correlation,fferent ages, whereespecially the diagnosis in cases was with confirmed atypical clinical and completed signs. Here by array we report CGH infive each idic(15) case. cases diagnosed at different ages, where the diagnosis was confirmed and completed by array CGH in each case. 2. Results 2. Results 2.1. GTG Banding and FISH 2.1. GTG Banding and FISH GTG-banding of the five patients (P.1.–P.5.) was performed at a 550-band level resolution. The karyotype of eachGTG-banding patient contained of the a supernumerary five patients (P.1.–P.5.) acrocentric was marker performed chromosome at a 550-band of G-group level size.resolution. Based The on the karyotype of each patient contained a supernumerary acrocentric marker chromosome of G-group evaluation of 100 cells in each case, mosaicism could be excluded. Due to the clinical symptoms and the size. Based on the evaluation of 100 cells in each case, mosaicism could be excluded. Due to the presence of the SMC, metaphase FISH analysis of the UBE3A locus (Prader–Willi/Angelman Critical Region) clinical symptoms and the presence of the SMC, metaphase FISH analysis of the UBE3A locus was performed in each case that showed the presence of both, the D15Z1 and UBE3A regions on the SMCs (Prader–Willi/Angelman Critical Region) was performed in each case that showed the presence of (in addition to the normal chromosomes 15), thereby confirming that the extra chromosome is of 15 origin both, the D15Z1 and UBE3A regions on the SMCs (in addition to the normal chromosomes 15), (Figurethereby1). confirming that the extra chromosome is of 15 origin (Figure 1). FigureFigure 1. 1.A representativeA representative metaphase metaphase fluorescence fluorescence in in situ situ hybridization hybridization (FISH) (FISH) result result of of P.1. P.1. using using the Prader–Willithe Prader–Willi/Angelman/Angelman Critical Critical Region Region (UBE3A ()UBE3A probe) (Vysis, probe Abbott)(Vysis, (1000Abbott)magnification). (1000× magnification). The arrow × indicatesThe arrow the idic(15). indicates Signals: the Aquaidic(15)./blue— Signals:D15Z1 ,Aqua/blue— Orange/red—D15Z1UBE3A, Orange/red—locus, FITC/green—UBE3APML locus,locus (15q24). Because of the signal positions, these probes show no difference between the markers of the five patients. Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 3 of 12 FITC/green—PML locus (15q24). Because of the signal positions, these probes show no difference between the markers of the five patients. In details, the karyotypes of Patient 1.–Patient 5. can be described and summarized as 47, XN, +idic(15) (pter→q13::q13→pter) (100). Each abnormality resulted in tetrasomy of the 15q11q13 region. None of the patients was mosaic. Parental cytogenetic studies were normal. 2.2. Uniparental Disomy UniparentalInt. J. Mol. Sci. 2019disomy, 20, 4935 could be excluded only in Patient 2. and 3. The parents of Patients3 of 1., 12 4. and 5. did not consent to the study. In details, the karyotypes of Patient 1.–Patient 5. can be described and summarized as 47, XN, 2.3. Array+idic(15) CGH (pter q13::q13 pter) (100). Each abnormality resulted in tetrasomy of the 15q11q13 region. ! ! None of the patients was mosaic. Parental cytogenetic studies were normal. The copy numbers and breakpoints of the different genomic regions in the SMCs 15 are presented2.2. Uniparentalin Table Disomy1. (according to ISCN 2016) [8]. In addition, common benign variants were detected. TheUniparental base pair disomy positions could beof excluded the genomi onlyc in imbalances Patient 2. and were 3. The designated parents of Patientsaccording 1., 4.to the Februaryand 2009 5. did Assembly not consent (GRCh37/hg19). to the study. 2.3. ArrayTable CGH 1. Molecular subtype and array CGH results of the idic(15) chromosomes. The copy numbers and breakpoints of the different genomic regions in the SMCs 15 are presented Molecular Patientin Table 1. (according to ISCN 2016) [ 8]. InArray addition, CGH common Results benign variants were detected.Figures Subtype The base pair positions of the genomic imbalances were designated according to the February 2009 P.1.
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