Molecular Delineation of De Novo Small Supernumerary Marker Chromosomes in Prenatal Diagnosis, A Retrospective Study

Background To define the genotype-phenotype correlation of small supernumerary marker chromosomes (sSMCs) and conduct precise genetic counseling, we retrospectively searched and reviewed de novo sSMC cases detected during prenatal diagnosis at The First Affiliated Hospital of Zhengzhou University. Chromosome karyotypes of 20,314 cases of amniotic fluid from pregnant women were performed. For 16 samples with de novo sSMCs, 10 were subjected to single-nucleotide polymorphism (SNP) array or low-coverage massively parallel copy number variation sequencing (CNV-seq) analysis. Results Among the 10 sSMC cases, two sSMCs derived from chromosome 9, and three sSMCs derived from chromosomes 12, 18 and 22. The remaining 5 cases were not identified by SNP array or CNV-seq because they lacked euchromatin or had a low proportion of mosaicism. Four of them with a karyotype of 47,XN,+mar presented normal molecular cytogenetic results (seq[hg19] 46,XN), and the remaining patient with a karyotype of 46,XN,+mar presented with Turner syndrome (seq[hg19] 45,X). Five sSMC samples were mosaics of all 16 cases. Conclusion Considering the variable origins of sSMCs, further genetic testing of sSMCs should be performed by SNP array or CNV-seq. Detailed molecular characterization would allow precise genetic counseling for prenatal diagnosis.

Molecular delineation of de novo Small Supernumerary Marker Chromosomes in prenatal diagnosis, a retrospective study

Objective To define the genotype-phenotype correlation of small supernumerary marker chromosomes (sSMC) and conduct precise genetic counseling.Methods We retrospectively searched and reviewed the de novo sSMC cases detected during prenatal diagnosis in The First Affiliated Hospital of Zhengzhou University. Chromosome karyotypes of 20314 cases of amniotic fluid from pregnant women were performed. For 17 samples with de novo sSMC, 11 of them were subjected to single nucleotide polymorphism (SNP) array or low-coverage massively parallel copy number variation sequencing (CNV-seq) analysis. Results Among the 11 sSMC cases, two sSMC were derived from chromosome 9, four sSMC were derived from chromosome 12, 18, 22 and X , separately. For the remaining 5 cases, they were not identified by SNP array or CNV-seq because they lacked euchromatin or had low proportion mosaicism. Four of them with the karyotype of 47,XN,+mar presented normal molecular cytogenetic results (seq[hg19] 46,XN ) , the left one with the karyotype of 46,XN,+mar was Turner syndrome (seq[hg19] 45,XO). Five sSMC samples were mosaics of all these 17 cases. Conclusion Considering the variable origins of sSMC, further genetics testing of sSMC should be performed by SNP array or CNV-seq. The detailed molecular characterization would allow precise genetic counseling for prenatal diagnosis.

Prevalence of rare chromosomal abnormalities according to epidemiological register of congenital malformations in the Moscow region

Популяционная частота редких хромосомных аномалий (ХА) до сих пор достоверно не определена. Выполнить эту задачу можно путем регистрации случаев редких ХА среди плодов, живорожденных и мертворожденных в популяционных регистрах врожденных пороков развития, которые существуют в большинстве стран мира. По данным эпидемиологического регистра Московской области за период с 2011 по 2019 годы частота редких ХА составила 0,49 случаев на 1000 рождений, их доля в структуре всех ХА составляет 11,3%. В процентном соотношении структура редких ХА выглядит следующим образом: триплоидии - 41,2%, делеции - 23,9%, несбалансированные транслокации - 10,6%, редкие трисомии - 6%, дупликации - 5,6%, маркерные хромосомы - 3,7%, другие редкие ХА - 9%. Учитывая международные данные можно предполагать, что полученная популяционная частота редких ХА является заниженной за счет их недоучета и недостаточной диагностики в исследуемом регионе, что требует дальнейших исследований. The prevalence of rare chromosomal abnormalities (CAs) has not yet been reliably determined. This task can be accomplished by registering cases of rare CAs among fetuses, live births and stillborn in population-based registries of congenital malformations that exist in most countries of the world. According to the epidemiological register of the Moscow region for the period from 2011 to 2019, the prevalence rate of rare CA was 0,49 cases per 1000 births, their share in the structure of all CA is 11,3%. In percentage terms, the structure of rare CAs is presented as follows: triploidy - 41.2%, deletions - 23.9%, unbalanced translocations - 10.6%, rare trisomies - 6%, duplications - 5.6%, marker chromosomes - 3.7%, other rare CAs - 9%. Taking into account the international data, we can assume that the obtained prevalence rate of rare CAs is underestimated due to their underreporting and insufficient diagnosis in the studied region, which requires further research.

Small supernumerary marker chromosomes derived from chromosome 14 and/or 22

Small supernumerary marker chromosomes (sSMCs) are additional derivative chromosomes present in an otherwise numerically and structurally normal karyotype. They may derive from each of the 24 human chromosomes, and most contain a normal centromeric region with an alphoid sequence from a single chromosome. The majority of human chromosomes have a unique centromeric DNA-sequence enabling their indubitable characterization. However, chromosomes 14 and 22 share a common centromeric sequence D14/22Z1, and sSMCs with this DNA-stretch can derive from either chromosome. Euchromatin-carrying sSMCs(14 or 22) may be further characterized by molecular cytogenetics. However, in most diagnostic laboratories, heterochromatic sSMCs cannot be differentiated between chromosomes 14 or 22 derivation and are often reported as der(14 or 22). Still, heterochromatic sSMC(14 or 22) can be distinguished from each other using the D22Z4 probe (non-commercial) localized to 22p11.2. Herein, 355 sSMC(14 or 22) analyzed in the authors’ laboratory during the last ~ 20 years are summarized to address the questions: (1) What are the true frequencies of chromosome 14- and chromosome 22- derived sSMCs within D14/22Z1-positive cases? (2) Does sub-characterization of sSMC(14) and sSMC(22) make a difference in routine diagnostics? These questions could be answered as follows: (ad 1) within the studied group of sSMCs ~ 40% are derived from chromosome 14 and ~ 60% from chromosome 22; (ad 2) the knowledge on exact sSMC origin can help to save costs in routine diagnostics; i.e. in a clinically abnormal person with sSMC(14) a test for uniparental disomy is indicated, which is not necessary if a chromosome 22 origin for the sSMC was determined.

Complex sSMC Involving X and Y Chromosomes in two Patients with 45,X/46,X,+mar Karyotype

Complex small supernumerary marker chromosomes (sSMCs) consist of chromosomal material derived from two or more different chromosomal regions and constitute one of the smallest subsets of sSMC. Most of complex sSMCs are represented by a der(22)t(11;22) in Emanuel syndrome. As far as we know, only one recent report has described sSMCs involving simultaneously X and Y chromosomes in Turner Syndrome. We report two patients, a female and a male, both with a complex sSMC derived from X and Y chromosomes in mosaic with a 45,X cell line. In both patients, the marker chromosomes were early replicating and the XIST gene was absent. FISH and PCR confirmed the presence of Yp loci (TSPY, AMGY, SRY, DYZ3), and negative for DYZ1. The DAZ4 sequence was present only in patient 1.Our findings suggested that complex sSMC involving X and Y chromosome could be a kind of sSMC of the gonosomes.