Rare Chromosome 15 Duplication Syndrome Often Evades Prenatal Detection, Case Analysis Reveals

A rare neurodevelopmental disorder caused by extra copies of a critical region on chromosome 15 often slips through prenatal screening unnoticed, according to a new case report and pooled analysis published in Frontiers in Medicine. The study, led by researchers at West China Second University Hospital of Sichuan University, followed a young girl diagnosed with 15q duplication syndrome after birth and combined her case with a systematic review of 34 previously reported prenatal cases, producing one of the most detailed pictures yet of how this condition presents before and after delivery.

15q duplication syndrome, first described in 1993, arises when one or more extra copies of the Prader-Willi/Angelman critical region (PWACR) within chromosome 15q11.2-q13.1 appear in a person’s genome. The estimated incidence is roughly one in 30,000 births worldwide, although the true figure is likely higher because variable expressivity, limited clinical recognition, and disparities in healthcare access mean many cases go undiagnosed. The duplicated interval contains genes central to brain development and synaptogenesis, including UBE3A, SNRPN, and three gamma-aminobutyric acid type-A receptor genes, GABRA5, GABRB3, and GABRG3. The resulting clinical picture typically includes early-onset hypotonia, developmental delay, intellectual disability, autism spectrum disorder-related symptoms, epilepsy, and mild dysmorphic features, with severity varying widely between individuals.

The patient in the new report was the second child of healthy, non-consanguineous parents, delivered vaginally at 39 weeks and 6 days with a birth weight of 3.31 kilograms. During the second trimester, prenatal ultrasound had revealed three abnormalities: a fetal abdominal circumference below the 10th percentile, suggestive of fetal growth restriction; polyhydramnios, an excess of amniotic fluid; and mild tricuspid regurgitation. Serum prenatal screening returned a low-risk result, and the family declined further prenatal genetic testing, including non-invasive prenatal screening and amniocentesis. That decision meant the diagnosis was missed before birth, a scenario the researchers argue is far too common for this condition.

After delivery, the girl was hospitalized for neonatal pneumonia, a left temporoparieto-occipital subdural hemorrhage, and neonatal jaundice. During infancy she experienced recurrent respiratory infections, one febrile seizure, poor sleep, increased fussiness, frequent choking with feeding, abdominal distension, and lactose intolerance. At one year of age, her growth measurements fell within normal ranges, with a length of 72.3 centimeters, weight of 7.8 kilograms, and head circumference of 46.6 centimeters, but physical examination revealed frontal bossing, mild scaphocephalic features, and generalized hypotonia. Echocardiography showed a patent foramen ovale, and brain MRI at 1 and 8 months showed no definite abnormalities.

Developmental assessments painted a more concerning picture. She achieved rolling over at 5 months and grasping at 7 months, but at 9 months she still could not maintain a stable sitting position even with support, crawl, or pull to stand. The Bayley Scales of Infant Development yielded Mental and Psychomotor Development Index scores both below 50, indicating significant delay. Rehabilitation therapy began at approximately 9 months and continued for four months with minimal motor improvement. Independent sitting was achieved only at 12 months, and by 13 months she could produce nonspecific babbling sounds but remained unable to crawl or pull to stand. She also showed poor eye contact and absent social interaction, features consistent with the autism-related profile of the syndrome.

The definitive diagnosis came from trio-based whole-exome sequencing, which identified a copy number gain of four copies, a tetrasomy, involving 15q11.1-q13.1, spanning 8.75 megabases on the GRCh38 reference genome. The duplication was absent from both parents, confirming it arose de novo, and SNP-based analysis suggested the duplicated region was maternal in origin. This pattern is compatible with an isodicentric supernumerary chromosome, the mechanism behind roughly 60 to 80 percent of cases, in which a small extra chromosome carries two additional copies of the region. Interstitial duplications within chromosome 15 itself, typically adding one extra copy, account for the remaining 20 to 40 percent. Copy numbers ranging from three to six copies have been documented, with rare octasomy cases also reported.

To place the case in context, the team searched PubMed, Web of Science, and Embase through September 8, 2026, ultimately including 12 publications plus one additional study identified through reference review. Across the 35 prenatal cases analyzed, including the new patient, 48.6 percent involved advanced maternal age and 22.2 percent had an adverse pregnancy history or abnormal family history. Among the 29 cases with available ultrasound records, 62.1 percent showed normal prenatal ultrasonography, while 37.9 percent showed abnormalities including fetal growth restriction, polyhydramnios, cardiac defects such as ventricular septal defect, dysmorphic features like facial anomalies and polydactyly, and soft markers including increased nuchal translucency, absent nasal bone, cerebral ventriculomegaly, echogenic intracardiac focus, renal pelvis separation, and bilateral choroidal cysts.

Notably, all 20 cases that underwent non-invasive prenatal screening were classified as high risk, and the researchers suggest NIPS may facilitate prenatal identification of the syndrome. All abnormal karyotypes with available inheritance information were de novo. Most families, 63.6 percent, opted for termination of pregnancy. Among the 21 cases with parental origin information, termination rates were markedly higher for maternal-origin duplications, 70.6 percent, than paternal-origin ones, 25.0 percent, a difference the authors attribute to the perceived severity of postnatal outcomes. The two live-born patients with reported clinical abnormalities both carried maternal four-copy gains and exhibited overlapping neurodevelopmental features, while no abnormalities were reported in paternal-origin cases or those with lower copy numbers, consistent with prior evidence that parental origin and copy number influence phenotypic severity.

The genetics underlying this variability are complex. The proximal 15q region contains multiple low copy repeats with five breakpoints, making it prone to rearrangements. The PWACR is imprinted, meaning expression depends on parental origin: paternal deletions cause Prader-Willi syndrome, maternal deletions cause Angelman syndrome, and duplications produce Dup15q syndrome. Penetrance estimates suggest maternally inherited 15q11.2-q13.1 duplications show a 50.5 percent penetrance for developmental delay, autism, or multiple congenital anomalies, roughly 2.5 times that of paternally inherited duplications at 20.7 percent. In one three-generation pedigree, two first-generation females with paternally inherited duplications were phenotypically normal, while all ten affected descendants carried maternally inherited duplications with outcomes ranging from mild delay to severe disability.

Therapeutic prospects are slowly emerging from the laboratory. Researchers have shown that antisense oligonucleotide-mediated reduction of UBE3A expression in patient-derived Dup15q neurons can prevent or ameliorate abnormal cellular phenotypes, and a negative allosteric modulator of alpha5-containing GABA-A receptors improved abnormal social behaviors and cognitive inflexibility in a mouse model while partially normalizing aberrant electroencephalographic patterns. Basmisanil, a related GABA-A-alpha5 modulator, has entered human clinical trials. For now, however, management remains largely symptomatic, which is why the authors emphasize that infants with early-onset hypotonia, global developmental delay, autistic-like behaviors, and poor response to rehabilitation should undergo genetic testing, and that unexplained fetal growth restriction or polyhydramnios, particularly when accompanied by additional ultrasound abnormalities, positive screening results, or family history, should prompt etiological evaluation including chromosomal microarray analysis.

Subject of Research: Prenatal and postnatal clinical manifestations of 15q duplication syndrome based on a longitudinal case report and pooled analysis of 35 prenatal cases

Article Title: Case Report: Prenatal and postnatal clinical manifestations of 15q duplication syndrome: a single longitudinal case combined with pooled analysis of 35 prenatal cases

Article References: Xu, Z., Ufei, M., Chen, H., Yang, S., Zou, P., Lu, Y., Xiong, F., & Li, J. (2026). Case Report: Prenatal and postnatal clinical manifestations of 15q duplication syndrome: a single longitudinal case combined with pooled analysis of 35 prenatal cases. Frontiers in Medicine, 13, Article 1928018. https://doi.org/10.3389/fmed.2026.1928018

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1928018

Keywords: 15q duplication syndrome, Dup15q syndrome, prenatal diagnosis, non-invasive prenatal screening, copy number variation, fetal growth restriction, polyhydramnios, genetic counseling, neurodevelopmental disorder, whole-exome sequencing, UBE3A, chromosome 15q11.2-q13.1