To investigate the incidence and clinical significance of a positive result on genome-wide non-invasive prenatal screening (NIPS) for trisomy 15. We conducted a prospective cohort study of singleton pregnancies that underwent genome-wide NIPS at a single center in Hong Kong between January 2020 and April 2023. The incidence of a positive genome-wide NIPS result for trisomy 15, positive predictive value (PPV) for trisomy 15 and risk of uniparental disomy 15 (UPD15) were assessed based on cytogenetic and molecular analyses at amniocentesis. Adverse fetal outcomes were reviewed. Furthermore, a systematic review of cohort studies reporting positive trisomy 15 results from genome-wide NIPS was performed, including data from our prospective cohort. Random-effects meta-analysis was used to obtain pooled estimates of incidence and PPV. The risk of UPD15 and adverse pregnancy outcomes was also evaluated. Heterogeneity was evaluated using Higgins' I2 statistic. In our cohort of 36 466 singleton pregnancies that underwent genome-wide NIPS, 10 (0.027%) cases were screen-positive for trisomy 15 (2.7 per 10 000 singleton pregnancies). Results from invasive diagnostic testing were available for all screen-positive cases. The PPV of genome-wide NIPS for trisomy 15 was 40.0% (4/10), and 3/10 (30.0%) cases were confirmed to have maternal UPD15. Together with our study, a total of 30 cohorts from 29 studies were included in the systematic review and meta-analysis, comprising 175 pregnancies that were screen-positive for trisomy 15. In 26 cohorts in which the total number of cases screened using NIPS were specified, the pooled incidence of trisomy 15 was 145/1 009 301 (0.013% (95% CI, 0.009-0.019%; I2 = 78.4%)), or 1.3 per 10 000 singleton pregnancies. The pooled incidence was significantly higher among women screened in the first trimester compared with those tested in the second trimester. Among 102 cases with a diagnostic result from invasive testing, 22 were confirmed as having fetal trisomy 15, including eight with full trisomy 15 and 14 with true fetal mosaicism. The pooled PPV for fetal trisomy 15 was 17.4% (95% CI, 4.0-35.0%; I2 = 51.5%). Among 69 cases with a result from UPD15 testing, 14 (20.3%) had maternal UPD15. Assuming that all diploid cases that did not undergo UPD15 testing had normal biparental inheritance of chromosome 15, the pooled PPV for either fetal trisomy 15 or UPD15 was 32.6% (95% CI, 14.4-53.0%; I2 = 55.3%), and the residual risk of UPD15 after a fetal normal karyotype was at least 11.3%. Among patients with clinical follow-up, 68.4% experienced an adverse pregnancy outcome, including fetal loss (29.1%), termination of pregnancy (21.5%) and/or pregnancy complication (17.7%). Although the PPV of genome-wide NIPS for fetal trisomy 15 was relatively low, a significant proportion of cases with a positive NIPS result for trisomy 15 had maternal UPD15 or fetal mosaicism, underscoring the need for diagnostic confirmation via amniocentesis. Amniocentesis should be strongly recommended for any case with a positive NIPS result for trisomy 15 to investigate UPD15 and true fetal mosaicism and guide subsequent clinical management. © 2025 International Society of Ultrasound in Obstetrics and Gynecology.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition often associated with genetic syndromes. Structural variants on the long arm of chromosome 15 (15q) are recurrently implicated in syndromic ASD, yet their phenotypic spectrum remains insufficiently characterized in diverse populations. We retrospectively analyzed clinical and molecular data from three patients with ASD treated at a Brazilian public reference center who also presented neurological and systemic comorbidities. Genetic investigations included G-banded karyotyping, chromosomal microarray analysis (CMA), methylation assays, and multiplex ligation-dependent probe amplification (MLPA) when indicated. Variants were classified according to ACMG guidelines and correlated with individual phenotypes. Case 1 showed an 8.4 Mb triplication at 15q11.2-q13.1 encompassing SNRPN, UBE3A, and GABRB3, which are associated with epilepsy, delayed neuropsychomotor development, and dysmorphic traits. Case 2 presented a 418 kb duplication at 15q13.3 involving CHRNA7 and OTUD7A, a variant of uncertain significance correlated with intellectual disability, speech apraxia, and self-injurious behavior. Case 3 demonstrated extensive loss of heterozygosity at 15q11.2-q13.1 and 15q21.3-q26.2, which is compatible with maternal uniparental disomy and Prader-Willi syndrome, manifesting hypotonia, seizures, and global delay. These findings underscore the potential involvement of the 15q region in syndromic ASD and related neurological comorbidities, highlighting the diverse pathogenic mechanisms and the importance of comprehensive genomic profiling for diagnosis, counseling, and individualized care.

Prader-Willi syndrome (PWS) is an uncommon genetic disorder caused by the lack of expression of a cluster of genes located in the 15q11.2q13 region, which are normally expressed only from the paternally-inherited allele due to genomic imprinting. PWS can result from a deletion of the 15q11.2q13 region on the paternally-inherited chromosome 15, maternal uniparental disomy, or imprinting defects. We report a patient with an atypical deletion within 15q11.2q13 and a PWS phenotype, including hypotonia, feeding difficulties, short stature, developmental delay, and dysmorphisms. She has a deletion from TUBGCP5 to SNURF-SNRPN (including the imprinting center) but not the SNORD region. These types of reports are crucial for further supporting the established role of the imprinting center in the pathophysiology and critical region of PWS.

Prader-Willi syndrome (PWS) represents a paradigm of genomic imprinting disorders. Given the severe lifelong complications of PWS, prenatal diagnosis is crucial for early intervention and genetic counseling. Noninvasive prenatal testing (NIPT) indicated a high risk for fetal trisomy 15 (T15), prompting confirmatory invasive testing. Amniocentesis was performed, and amniotic fluid was analyzed by karyotyping, chromosomal microarray analysis (CMA), trio-based whole-exome sequencing (trio-WES), and short tandem repeat (STR) linkage analysis to investigate the genetic etiology. Post-termination, placental tissue was analyzed by copy number variant sequencing (CNVseq) to evaluate potential mosaicism. NIPT indicated a suspected T15 (Z-score: 16.4). Subsequent invasive testing confirmed the following: a 13.16 Mb region of homozygosity on chromosome 15q25.1q26.1 and a 273 kb Duchenne muscular dystrophy (DMD) gene deletion on chromosome Xp21.1, both identified by CMA. Trio-WES and STR linkage analysis revealed maternal segmental uniparental disomy of chromosome 15 (UPD15), confirming the genetic basis of PWS. Post-termination, CNVseq further demonstrated confined placental mosaicism (CPM) for T15. When NIPT suggests a high risk of T15, clinicians should maintain a high suspicion for the "trisomy rescue" mechanism, where an initially trisomic zygote undergoes mitotic correction, ultimately forming UPD15 with CPM. The potential discordance between NIPT and the actual fetal genetic status necessitates definitive prenatal diagnosis, which has critical implications for subsequent pregnancy management. Therefore, the concomitant findings of PWS and DMD carrier status require comprehensive prognostic evaluation and recurrence risk assessment.

Prader-Willi Syndrome (PWS) is a complicated genetic disorder demonstrating a variety of clinical phenotypes. Using molecular cytogenetics approaches to detect the deletions of the paternal 15q11-q13 region and maternal uniparental disomy of chromosome 15 plays an important role in the prenatal diagnosis of PWS. A pregnant woman with advanced maternal age underwent amniocentesis. The amniotic fluid was subjected to karyotyping and chromosomal microarray analysis. A marker without autosomal material and loss of heterozygosity (LOH) of 15q14-q23 were found in the fetus. The LOH was consistent with maternal uniparental isodisomy (UPD) and the marker was inherited from the father. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) found increased methylation in the fetal 15q11.2-q13 region and fluorescence in situ hybridization confirmed the marker was not originated from chromosome 15. We presented a rare PWS case showing maternal UPD of chromosome 15 with concurrent paternal marker chromosome in the prenatal setting.