Prenatal diagnosis of a de novo tetrasomy 15q24.3‐25.3: Case report and literature review

Abstract Background Terminal duplication on chromosome 15q is a rare chromosomal variation. Affected individuals show similar features such as growth dysplasia or the development of frontal bossing, body deformities, facial abnormalities, and genitourinary or cardiovascular disorders. However, it is not yet clear whether such 15q repeats lead to identifiable patterns of clinical abnormalities. Therefore, the purpose of this study was to analyze the prenatal diagnostic results and clinical manifestations of a fetus with 15q duplication and to summarize the literature. Methods The case was a fetus at 28 weeks of gestation. The risk of Down syndrome from second‐trimester screening was 1/140. Prenatal ultrasound and amniocentesis were performed, and chromosomal microarray analysis (CMA) was used for genetic analysis. Results The fetus had abnormal clinical features, including intracardiac echogenic focus in the left ventricle, an aberrant right subclavian artery, and growth delay. The fetal chromosomal karyotype was 46,XX,15q?,12q?,21pstk+, and CMA revealed a 10.163 Mb duplication at 15q24.3‐q25.3. The couple chose to terminate the pregnancy after careful consideration. Conclusions The combination and rational application of cytogenetics technology and molecular genetics technology such as CMA will open up the field of clinical application and provide useful genetic counseling for parents of fetuses carrying such chromosomal duplications.

duplication. 2,3 However, there are few de novo duplications in the region of 15q24-qter. 3 Previous studies have described some cases of 15qter duplication characterized by postnatal or prenatal overgrowth, craniofacial and skeletal malformations, developmental delay, and genital abnormalities. The significant abnormalities in fetal growth and development, and the formation of congenital malformations are caused by the abnormal expression of genes located in the 15qter region such as LINGO-1, CSPG4, MTHFS, KIF7, CHD2, and IGF1R. [4][5][6] Moreover, the range and severity of symptoms, and physical findings are closely related to the length and location of the duplicated region of chromosome 15q, and these can vary from case to case. 7 For example, patients with 15q duplications exhibit some clinical phenotypes that are opposite to overgrowth, such as postnatal or prenatal growth restriction and developmental delay. [8][9][10][11][12] Here, we reported a fetus with a double de novo duplication of chromosome 15q24.3-q25.3, producing abnormal sonography findings. The duplication was detected by chromosomal microarray analysis (CMA), and we identified 19 potentially pathogenic genes including LINGO-1 and MTHFS using the DECIPHER genome browser (https://decip her.sanger.ac.uk). To the best of our knowledge, no case of partial tetrasomy of 15q24.3-q25.3 has been reported previously. A 28-year-old primigravid woman underwent amniocentesis for prenatal diagnosis at 28 weeks of gestation because second-trimester screening for Down syndrome indicated a high risk (1/140), calculated from abnormal maternal serum screening markers. Color Doppler echocardiography at 28 weeks of gestation revealed an intracardiac echogenic focus in the left ventricle ( Figure 1A) and an aberrant right subclavian artery ( Figure 1B). Table 1 shows the results of systemic ultrasonography at 28 weeks of gestation. Fetal abdominal circumference, head circumference, humerus length, and weight were all low for gestational age (<10th centile). [13][14][15] Hence, the fetus might have experienced intrauterine growth restriction.

| Case report
The fetus's parents were not consanguineous and were healthy. The mother denied being exposed to teratogenic agents or irradiation, or using nicotine, alcohol, or caffeine during the pregnancy. No family history of genetic disease, congenital malformations, or diabetes mellitus was recorded. The study protocol was approved by the Ethics Committee of the First Hospital of Jilin University, and written informed consent was obtained from the couple. Informed consent for publication of this case has also been provided by the couple.

| Cytogenetic examination
According to the standard operating manual of our center's cytogenetics laboratory, at least 20 G-banded metaphases were used for

| Chromosome microarray and data analysis
Ultrasound-guided amniocentesis was performed to extract about The potential copy number variations (CNVs) were detected using an Affymetrix CytoScan750K_Array (Affymetrix). DNA processing included digestion, joining, breaking, marking, hybridization, staining, and scanning. Software of the chromosome analysis suite (ChAS) was used to analyze the data. The array data and genotype-phenotype correlations were analyzed by using the databases of Genomic Variants (http://dgv.tcag.ca/dgv/app/home; GRCh37/hg19), OMIM (https://omim.org), and DECIPHER (see above). 17

| RE SULTS
Initially, the fetus was diagnosed with an abnormal karyotype of Conventional cytogenetics demonstrated that the mother had a chromosomal polymorphism of 21pstk+ ( Figure 2B)  According to the literature, 27 we inferred that the clinical features of 15q24-qter duplication are genetic disorders that may be caused by nonallelic homologous recombination between low-copy repeats in the region of chromosome 15q24-qter. The 15q24-q26 region is one of several hotspots reported, with a high density of chromosome-specific duplications. Rearrangements of this region have been implicated as a susceptibility factor for panic and phobic disorders with joint laxity. 28 However, according to case reports, it is not yet clear whether the 15q repeats lead to identifiable patterns of clinical abnormalities. 4  Mental retardation seems to be a common feature of patients with duplication of 15qter, 8 because several genes related to brain development and function are involved in the 15q24.3qter region. 29 Schluth et al, 22 Liehr et al, 23 Table 3.
LINGO-1 and MTHFS have been shown to be related to the clinical manifestations.
Traditional chromosome banding and karyotyping have always been the gold standard of cytogenetics and have irreplaceable advantages. 33 It is generally known that chromosome rearrangements of <10 Mb are hard to recognize using routine karyotyping. CMA can be used to describe the location, functional genes involved, and size of the rearranged region more precisely. 34 However, it has some limitations. 33 In the present case, the fetal karyotype was 46,XX,15q?,12q?,21pstk+. The mother was 46,XX,21pstk+, and the father was normal (46,XY). The fetal 21pstk+ chromosomal polymorphism was inherited from the mother, but this is considered to have no detrimental phenotypic effect. 35   The clinical manifestations presented here were linked to 15q a duplication in the fetus detected by CMA. As a molecular genetics detection technique, CMA can detect many chromosome structural abnormalities, but the technology has limitations. The combination and rational application of cytogenetics and molecular genetics technologies will undoubtedly open up the field of clinical application for such anomalies.

ACK N OWLED G M ENTS
We appreciate everyone in the Reproductive Medicine & Prenatal Diagnosis Center, First Hospital of Jilin University. We would like to thank individuals such as Yuting Jiang, Fagui Yue, Qingyang Shi, and Jili Jing for counseling and sharing data.

CO N FLI C T O F I NTE R E S T
The authors declare that there is no conflict of interest.