Chromosome Analysis and Postnatal Follow-Up of Fetuses With Abnormal Ultrasound Findings

Objective—To analyze the correlation between copy number variations (CNVs) and prenatal ultrasound abnormalities, characterize the CNVs in diverse prenatal phenotypes, and provide detailed follow-up results for prenatal diagnosis. Method—The results obtained in 1152 fetuses referred for chromosome testing due to different ultrasound anomalies were analyzed. CNV detection was performed by chromosomal microarray analysis (CMA) and copy number variation sequencing (CNV-seq). The postnatal outcomes of the fetuses were followed up.Result—Chromosomal abnormalities were detected in 149 of 1152 pregnancies (12.9%), including 84 (7.3%) macroscopic and 65 (5.6%) submicroscopic anomalies. The highest proportion of chromosomal defects was found in fetuses with hydrops (38.5%), followed by fetuses with multiple abnormalities (32.1%). The most common CNV number variation was 22q11 deletion (0.7%), followed by 17q12 deletion (0.4%) and 15q11.2 deletion (0.4%). Bilateral hyperechogenic kidneys were identified in all fetuses with the 17q12 deletion, and all cases of 15q11.2 deletion were positive only for soft markers. On postnatal follow-up of 362 live births, 2 cases of esophageal atresia and 2 cases of craniosynostosis were found that were not accurately diagnosed by prenatal ultrasound.Conclusion—we identified chromosomal abnormalities in approximately one eight of the pregnancies with abnormal ultrasound findings. More emphasis should be placed on the improvement of prenatal detection of esophageal atresia and craniosynostosis.

15q11.2 deletion is enriched in patients with total anomalous pulmonary venous connection

IntroductionCNV is a vital pathogenic factor of congenital heart disease (CHD). However, few CNVs have been reported for total anomalous pulmonary venous connection (TAPVC), which is a rare form of CHD. Using case-control study, we identified 15q11.2 deletion associated with TAPVC. We then used a TAPVC trio as model to reveal possible molecular basis of 15q11.2 microdeletion.MethodsCNVplex and Chromosomal Microarray were used to identify and validate CNVs in samples from 231 TAPVC cases and 200 healthy controls from Shanghai Children’s Medical Center. In vitro cardiomyocyte differentiation of induced pluripotent stem cells from peripheral blood mononuclear cells for a TAPVC trio with paternal inherited 15q11.2 deletion was performed to characterise the effect of the deletion on cardiomyocyte differentiation and gene expression.ResultsThe 15q11.2 microdeletion was significantly enriched in patients with TAPVC compared with healthy control (13/231 in patients vs 0/200 in controls, p=5.872×10−2, Bonferroni adjusted) using Fisher’s exact test. Induced pluripotent stem cells from the proband could not differentiate into normal cardiomyocyte. Transcriptomic analysis identified a number of differentially expressed genes in the 15q11.2 deletion carriers of the family. TAPVC disease-causing genes such as PITX2, NKX2-5 and ANKRD1 showed significantly higher expression in the proband compared with her healthy mother. Knockdown of TUBGCP5 could lead to abnormal cardiomyocyte differentiation.ConclusionWe discovered that the 15q11.2 deletion is significantly associated with TAPVC. Gene expression profile that might arise from 15q11.2 deletion for a TAPVC family was characterised using cell experiments.

Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice

BackgroundThe 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case–control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders.MethodsWe performed meta-analyses on new and previously published case–control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant.ResultsThe deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias.ConclusionsWe recommend that the deletion should be classified as ‘pathogenic of mild effect size’. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

A Rare Case of Concomitant Deletions in 15q11.2 and 19p13.3

A female individual with concomitant deletions in 15q11.2 and 19p13.3 is reported. She presents facial dysmorphisms, motor delay, learning difficulties, and mild behavioral impairment. After chromosomal microarray analysis, the final karyotype was established as 46,XX.arr[GRCh37] 15q11.2 (22770421_23282798)×1,19p13.3(3793904_4816330)×1. The deletion in 15q11.2 is 507 kb in size involving 7 non-imprinted genes, 4 of which are registered in the OMIM database and are implicated in neuropsychiatric or neurodevelopmental disorders. The deletion in 19p13.3 is 1,022 kb in size and encompasses 47 genes, most of which do not have a well-known function. The genotype-phenotype correlation is discussed, and most of the features could be related to the 19p13.3 deletion, except for velopharyngeal insufficiency. Other genes encompassed in the deleted region, as well as unrecognized epistatic factors could also be involved. Nevertheless, the two-hit model related to the 15q11.2 deletion would be an important hypothesis to be considered.