Mosaicism for a 15q11.2 microduplication with a normal euploid cell line at amniocentesis in a pregnancy with a favorable fetal outcome and postnatal decrease of the aneuploid cell line with the microduplication.

OBJECTIVE: We present mosaicism for a 15q11.2 microduplication with a normal euploid cell line at amniocentesis in a pregnancy with a favorable fetal outcome and postnatal decrease of the aneuploid cell line with the microduplication. CASE REPORT: A 35-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed 33.76% mosaicism for a 15q11.2 microduplication. She was referred for genetic counseling. Repeat amniocentesis was performed at 23 weeks of gestation, and the karyotype was 46,XY. Simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes revealed the result of arr [GRCh37 (hg19)] 15q11.2 (23, 889, 686-25,514,125) × 2.45, consistent with a mosaic 1.624-Mb microduplication with the mosaic level of 40%-45% (log2 ratio = 0.28) encompassing nine OMIM genes of MAGEL2, NDN, PWRN2, PWRN1, NPAP1, SNRPN, SNHG14, SNORD116-1 and SNORD115-1. Interphase fluorescence in situ hybridization (FISH) analysis on 100 uncultured amniocytes detected a 15q11.2 duplication in 19 cells, consistent with 19% (19/100 cells) mosaic15q11.2 duplication. Polymorphic DNA marker analysis excluded uniparental disomy (UPD) 15. Prenatal ultrasound findings were unremarkable. She was advised to continue the pregnancy, and a 3865-g phenotypically normal male baby was delivered. aCGH analysis on the DNA extracted from cord blood at birth and buccal mucosal cells at age four months revealed arr (1-22) × 2, X × 1, Y × 1 and detected no genomic imbalance in all samples. Interphase FISH analysis on 104 buccal mucosal cells at age four months detected four cells (4/104 = 4%) with a 15q11.2 duplication, compared with 0% (0/102 cells) in the normal control. The neonate was normal in the development. CONCLUSION: Mosaicism for a 15q11.2 microduplication at amniocentesis with a normal euploid cell line can be a benign condition and associated with a favorable fetal outcome and postnatal decrease of the aneuploid cell line with the microduplication.

The Prenatal Diagnosis and Clinical Outcomes of Fetuses With 15q11.2 Copy Number Variants: A Case Series of 36 Patients.

Prenatal genetic counseling of fetuses diagnosed with 15q11.2 copy number variants (CNVs) involving the BP1-BP2 region is difficult due to limited information and controversial opinion on prognosis. In total, we collected the data of 36 pregnant women who underwent prenatal microarray analysis from 2010 to 2017 and were assessed at National Taiwan University Hospital. Comparison of the maternal characteristics, prenatal ultrasound findings, and postnatal outcomes among the different cases involving the 15q11.2 BP1-BP2 region were presented. Out of the 36 fetuses diagnosed with CNVs involving the BP1-BP2 region, five were diagnosed with microduplications and 31 with microdeletions. Among the participants, 10 pregnant women received termination of pregnancy and 26 gave birth to healthy individuals (27 babies in total). The prognoses of 15q11.2 CNVs were controversial and recent studies have revealed its low pathogenicity. In our study, the prenatal abnormal ultrasound findings were recorded in 12 participants and were associated with 15q11.2 deletions. No obvious developmental delay or neurological disorders were detected in early childhood.

Difficulties of Prenatal Genetic Counseling for a Subsequent Child in a Family With Multiple Genetic Variations.

Many parents with a disabled child caused by a genetic condition appreciate the option of prenatal genetic diagnosis to understand the chance of recurrence in a future pregnancy. Genome-wide tests, such as chromosomal microarray analysis and whole-exome sequencing, have been increasingly used for prenatal diagnosis, but prenatal counseling can be challenging due to the complexity of genomic data. This situation is further complicated by incidental findings of additional genetic variations in subsequent pregnancies. Here, we report the prenatal identification of a baby with a MECP2 missense variant and 15q11.2 microduplication in a family that has had a child with developmental and epileptic encephalopathy caused by a de novo KCNQ2 variant. An extended segregation analysis including extended relatives, in addition to the parents, was carried out to provide further information for genetic counseling. This case illustrates the challenges of prenatal counseling and highlights the need to understand the clinical and ethical implications of genome-wide tests.

Adverse Perinatal and Early Life Outcomes following 15q11.2 CNV Diagnosis.

The copy number variation (CNV) of 15q11.2, an emerging and common condition observed during prenatal counseling, is encompassed by four highly conserved and non-imprinted genes-TUBGCP5, CYFIP1, NIPA1, and NIPA2-which are reportedly related to developmental delays or general behavioral problems. We retrospectively analyzed 1337 samples from genetic amniocentesis for fetal CNV using microarray-based comparative genomic hybridization analysis between January 2014 and December 2019. 15q11.2 CNV showed a prevalence of 1.5% (21/1337). Separately, 0.7% was noted for 15q11.2 BP1-BP2 microdeletion and 0.8% for 15q11.2 microduplication. Compared to the normal array group, the 15q11.2 BP1-BP2 microdeletion group had more cases of neonatal intensive care unit transfer, an Apgar score of <7 at 1 min, and neonatal death. Additionally, the group was symptomatic with developmental delays and had more infantile deaths related to congenital heart disease (CHD). Our study makes a novel contribution to the literature by exploring the differences in the adverse perinatal outcomes and early life conditions between the 15q11.2 CNV and normal array groups. Parent-origin gender-based differences may help in the prognosis of the fetal phenotype; development levels should be followed up in the long term and echocardiography should be offered prenatally and postnatally for the prevention of a delayed diagnosis of CHD.

Clinical and genetic study of a child with 15q11.2 microduplication / 中华医学遗传学杂志

Objective@#To explore the genetic basis of a child with developmental delay and intellectual disability.@*Methods@#Peripheral blood samples of the child and his parents were collected for routine G-band karyotyping analysis and single nucleotide polymorphism array (SNP array) assay. Amniotic fluid sample was collected during the next pregnancy for prenatal diagnosis.@*Results@#No karyotypic abnormality was found in the child and his parents. SNP array showed that the child has carried a 855.3 kb microduplication in 15q11.2. His mother carried the same duplication but had no phenotypic anomaly. No microdeletion/microduplication was found in his father. Upon prenatal diagnosis, no abnormalities was found with the chromosomal karyotype and SNP array result of the fetus.@*Conclusion@#15q11.2 microduplication may result in developmental delay and intellectual disability, for which CYFIP1 may be a candidate gene. However, the duplication may increase the risk but with a low penetrance. This should attract attention during clinical consultation.