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BackgroundThe clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype–phenotype correlations to improve genetic counselling and patients’ medical care.MethodsWe retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents.ResultsClinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype–phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype.ConclusionOur study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

Objective To analyze the ultrasound findings, single nucleotide polymorphism microarray (SNP array) results, pregnancy outcomes, and follow‐up information of fetuses with 16p13.11 deletion or duplication. Methods This retrospective study collected data from 14 fetuses diagnosed with 16p13.11 deletion and 12 fetuses with 16p13.11 duplication. The study involved a review and analysis of maternal demographics, ultrasound findings, SNP‐array results, pregnancy outcomes, and follow‐up information. Results The copy number variations (CNVs) observed ranged in size from 0.92 to 2.85 Mb for 16p13.11 deletions and from 0.89 to 2.84 Mb for duplications. These CNVs included seven OMIM genes: NDE1, MYH11, ABCC1, XYLT1, MARF1, CEP20, and ABCC6. Among the 14 fetuses with 16p13.11 deletions, seven (50.0%, 7/14) revealed abnormalities in ultrasound findings. Cardiovascular anomalies were present in five cases (35.7%, 5/14); two cases (14.3%, 2/14) showed lateral ventricular widening. Cases 2 and 14 were particularly noteworthy, as both presented complex malformations affecting multiple organs. Among the 12 fetuses with duplications, five cases (41.7%, 5/12) exhibited ultrasound abnormalities. Of these, three cases (25.0%, 3/12) presented with cardiovascular abnormalities; two cases (16.7%, 2/12) displayed widened lateral ventricles. Case 25 was particularly distinct, featuring complex multiorgan malformations that included widened lateral ventricles, tricuspid regurgitation, and a right ear malformation. Of the eight fetuses with 16p13.11 deletions whose pregnancies were continued, three exhibited neurodevelopmental abnormalities. Ten fetuses with 16p13.11 duplications that were followed up, two cases showed neurodevelopmental abnormalities. Conclusion Our study expanded the clinical phenotype spectrum of fetuses with 16p13.11 deletion and duplication and conducted a preliminary evaluation of prenatal ultrasound findings in conjunction with postnatal clinical phenotypes. The primary manifestations observed in fetuses with 16p13.11 deletion and duplication are likely to be cardiovascular malformations and widened lateral ventricles. What do the results of this study add? We expanded the clinical phenotype spectrum of fetuses with 16p13.11 deletion and duplication and conducted a preliminary evaluation of prenatal ultrasound findings in conjunction with postnatal clinical phenotypes. The primary manifestations observed in fetuses with 16p13.11 deletion and duplication are likely to be cardiovascular malformations and widened lateral ventricles. The deletion and duplication of 16p13.11 are closely linked to neural development, necessitating careful monitoring of the fetus after birth.

Background Chromosome 16p13.11 duplication is a well‐known genetic risk factor for schizophrenia (SCZ) (odds ratio = 1.84). However, no case reports focusing on patients with SCZ and 16p13.11 duplication have been published. Therefore, here, we report the detailed clinical cases of four patients with SCZ and 16p13.11 duplication who were identified in our previous whole‐genome copy number variant (CNV) study. Case Presentation In the four patients with SCZ and 16p13.11 duplication detected by array comparative genomic hybridization, one patient was found to have treatment‐resistant SCZ and an additional pathogenic rare CNV. Two of the four patients in this study had environmental risk factors that may have been involved in the development of SCZ. Conclusions The results of this case series suggest that a genetic cohort study would be useful for evaluating which genetic and environmental risk factors could better explain the variable expressivity of 16p13.11 duplication. Furthermore, this work could be useful for elucidating the pathophysiology of SCZ. Chromosome 16p13.11 duplication is a well‐known genetic risk factor for schizophrenia (SCZ) (odds ratio = 1.84). Therefore, here, we report the detailed clinical cases of four patients with SCZ and 16p13.11 duplication who were identified in our previous whole‐genome copy number variant (CNV) study.

Objectives To expand the clinical phenotype spectrum and improve the understanding of prenatal ultrasound manifestations and fetal prognosis of 16p13.11 deletion/duplication syndrome in the East Asian population. Methods We conducted a comprehensive ultrasound phenotypic analysis, pedigree analysis and long-term postnatal outcome follow-up on 201 fetuses with 16p13.11 deletion/duplication, as well as on the phenotypic manifestations of 14 patients who underwent chromosomal microarray analysis between April 2013 and July 2024. Descriptive statistical analysis was used. Results The detection rates were 0.08% and 0.18%, the frequencies of de novo occurrence were 26.9% and 14.5%, and the rates of abnormal postnatal phenotypes were 25% and 17.5% in our prenatal cohort of deletion and duplication, respectively. Overall, 28.6% of deletions and 15.9% of duplications exhibited abnormal postnatal phenotypes even if they were inherited from a phenotypically normal parent. Developmental delay was the most common clinical abnormality. Immune disorders, torticollis, concealed penis and cryptorchidism were closely related phenotypes that had previously gone unnoticed. Copy number variations extending to intervals I + II or II + III appeared to be associated with a broader range of phenotypes. Isolated choroid plexus cysts may be the most relevant ultrasound soft marker for deletion, whereas isolated thickened nuchal translucency appears to be more closely associated with duplication. Cardiovascular and urinary malformations were the most frequently detected ultrasound structural abnormalities. Conclusion The large East Asian prenatal cohort is conducive to enhancing genetic counseling for 16p13.11 deletion/duplication syndrome by facilitating a more accurate prediction of fetal prognosis and developmental potential.

Background We and others have previously reported that familial cytogenetic studies in apparently de novo genomic imbalances may reveal complex or uncommon inheritance mechanisms. Methods A familial, combined genomic and cytogenetic approach was systematically applied to the parents of all patients with unbalanced genome copy number changes. Results Discordant array-CGH and FISH results in the mother of a child with a prenatally detected 16p13.11 interstitial microduplication disclosed a balanced uncommon rearrangement in this chromosomal region. Further dosage and haplotype familial studies revealed that both the maternal grandfather and uncle had also the same 16p duplication as the proband. Genomic compensation observed in the mother probably occurred as a consequence of interchromosomal postzygotic nonallelic homologous recombination. Conclusions We emphasize that such a dualistic strategy is essential for the full characterization of genomic rearrangements as well as for appropriate genetic counseling.

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.

The chromosome 16p13.11 heterozygous deletion is associated with a diverse array of neuropsychiatric disorders including intellectual disabilities, autism, schizophrenia, epilepsy and attention-deficit hyperactivity disorder. However the clinical significance of its reciprocal duplication is not clearly defined yet. We evaluated 1645 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and identified four deletions and eight duplications within the 16p13.11 region, representing ∼0.73% (12/1645) of the patients analyzed. Recurrent clinical features in these patients include mental retardation/intellectual disability, autism, seizure, dysmorphic feature or multiple congenital anomalies. Our data expand the spectrum of the clinical findings in patients with these genomic abnormalities and provide further support for the pathogenic involvement of this duplication in patients who carry them.

Background The MACF1 gene, found on chromosome 1p34.3, is vital for controlling cytoskeleton dynamics, cell movement, growth, and differentiation. It consists of 101 exons, spanning over 270 kb. The 16p13.11 microduplication syndrome results from the duplication of 16p13.11 chromosome copies and is associated with various neurodevelopmental and physiological abnormalities. Both MACF1 and 16p13.11 microduplication have significant impacts on neural development, potentially leading to nerve damage or neurological diseases. This study presents a unique case of a patient simultaneously experiencing a de novo MACF1 mutation and a hereditary 16p13.11 microduplication, which has not been reported previously. Case presentation In this report, we describe a Chinese preterm newborn girl exhibiting the typical characteristics of 16.13.11 microduplication syndrome. These features include developmental delay, respiratory issues, feeding problems, muscle weakness, excessive joint movement, and multiple congenital abnormalities. Through whole-exome sequencing, we identified a disease-causing mutation in the MACF1 gene (c.15266T > C / p. Met5089Thr). Additionally, after microarray analysis, we confirmed the presence of a 16p13.11 microduplication (chr16:14,916,289 − 16,315,688), which was inherited from the mother. Conclusions The patient’s clinical presentation, marked by muscle weakness and multiple birth defects, may be attributed to both the de novo MACF1 mutation and the 16p13.11 duplication, which could have further amplified her severe symptoms. Genetic testing for individuals with complex clinical manifestations can offer valuable insights for diagnosis and serve as a reference for genetic counseling for both patients and their families.

The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.