BACKGROUND: Patients with 22q11.2 microduplication syndrome exhibit a high degree of phenotypic heterogeneity and incomplete penetrance, making prenatal diagnosis challenging due to phenotypic variability. This report aims to raise awareness among prenatal diagnostic practitioners regarding the variant\'s complexity, providing a basis for prenatal genetic counseling.
METHODS: Family and clinical data of 31 fetuses with 22q11.2 microduplications confirmed by chromosomal microarray between June 2017 and June 2023 were considered.
RESULTS: Primary prenatal ultrasound features of affected fetuses include variable cardiac and cardiovascular anomalies, increased nuchal translucency (≥3 mm), renal abnormalities, and polyhydramnios. More than half of fetuses considered showed no intrauterine manifestations; therefore, prenatal diagnostic indicators were primarily advanced maternal age or high-risk Down syndrome screening. Most fetuses had microduplications in proximal or central 22q11.2 regions, with only three cases with distal microduplications. Among parents of fetuses considered, 87% (27/31) continued the pregnancy. During follow-up, 19 cases remained clinically asymptomatic.
CONCLUSIONS: Nonspecific 22q11.2 microduplication features in fetuses and its mild postnatal disease presentation highlight the need to cautiously approach prenatal diagnosis and pregnancy decision-making. Increased clinical efforts should be made regarding providing parents with specialized genetic counseling, long-term follow-up, and fetal risk information.

BACKGROUND: Despite the established knowledge that recurrent copy number variants (CNVs) at the 16p11.2 locus BP4-BP5 confer risk for behavioural and language difficulties, limited research has been conducted on the association between behavioural and social-communicative profiles. The current study aims to further delineate the prevalence, nature and severity of, and the association between, behavioural and social-communicative features of school-aged children with 16p11.2 deletion syndrome (16p11.2DS) and 16p11.2 duplication (16p11.2Dup).
METHODS: A total of 68 individuals (n = 47 16p11.2DS and n = 21 16p11.2Dup) aged 6-17 years participated. Standardised intelligence tests were administered, and behavioural and social-communicative skills were assessed by standardised questionnaires. Scores of both groups were compared with population norms and across CNVs. The influence of confounding factors was investigated, and correlation analyses were performed.
RESULTS: Compared with the normative sample, children with 16p11.2DS showed high rates of social responsiveness (67%) and communicative problems (69%), while approximately half (52%) of the patients displayed behavioural problems. Children with 16p11.2Dup demonstrated even higher rates of social-communicative problems (80-90%) with statistically significantly more externalising and overall behavioural challenges (89%). In both CNV groups, there was a strong positive correlation between behavioural and social-communicative skills.
CONCLUSIONS: School-aged children with 16p11.2 CNVs show high rates of behavioural, social responsiveness and communicative problems compared with the normative sample. These findings point to the high prevalence of autistic traits and diagnoses in these CNV populations. Moreover, there is a high comorbidity between behavioural and social-communicative problems. Patients with difficulties in both domains are vulnerable and need closer clinical follow-up and care.

OBJECTIVE: To report three families with chromosome 15q11q13 duplications.
METHODS: We report the prenatal diagnosis and genetic counseling of three 15q11q13 duplications.
CONCLUSIONS: Chromosomal microdeletions and microduplications are difficult to be detected by conventional cytogenetics. With molecular genetic techniques including array-based methods, the number of reported cases has rapidly increased. An integration of prenatal ultrasound, NIPT, karyotype analysis, CMA and genetic counseling is helpful for the prenatal diagnosis of chromosomal microdeletions/microduplications.

Duplications on Chromosome 22q11.2 (22q11.2 dup) are associated with a wide spectrum of physical and neurodevelopmental features. In this chart review, physical, developmental, and behavioral features of 28 patients with 22q11.2 dup (median age = 17.11 years) are reported, and phenotypes of de novo and inherited duplications are compared. Common medical anomalies include nutritional problems (57%), failure to thrive (33%), transient hearing impairment (52%), and congenital heart defects (33%). Developmental, speech-language, and motor delay are common in infancy, while attention (64%), learning (60%), and motor problems (52%) are typically reported at primary school age. Attention-deficit/hyperactivity disorders are diagnosed in 44%. Median full-scale intelligence quotient is in the borderline range (IQ 76), with one-fifth of patients having mild intellectual disability. Longitudinal data in 11 patients, with the first assessment at a median age of 5.2 years and the second assessment at a median age of 8.8 years, indicate that almost two-third of patients have a relative stable cognitive trajectory, whereas one-third show a growing into deficit profile. In patients with de novo duplications, there is a trend of more failure to thrive, while more patients with inherited duplications follow special education.

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.
CONCLUSIONS: 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.

OBJECTIVE: To assess the association between azoospermia factor c microrearrangements and semen quality, and between Y-chromosome background with distinct azoospermia factor c microrearrangements and semen quality impairment.
METHODS: This retrospective study, carried out in the Research Center for Genetic Engineering and Biotechnology \"Georgi D. Efremov,\" involved 486 men from different ethnic backgrounds referred for couple infertility from 2002-2017: 338 were azoospermic/oligozoospermic and 148 were normozoospermic. The azoospermia factor c microrearrangements were analyzed with sequence tagged site and sequence family variant markers, quantitative fluorescent polymerase chain reaction, and multiplex ligation probe amplification analysis. The Y-haplogroups of all participants were determined with direct single nucleotide polymorphism typing and indirect prediction with short tandem repeat markers.
RESULTS: Our participants had two types of microdeletions: gr/gr and b2/b3; three microduplications: b2/b4, gr/gr, and b2/b3; and one complex rearrangement gr/gr deletion + b2/b4 duplication. Impaired semen quality was not associated with microrearrangements, but b2/b4 and gr/gr duplications were significantly associated with haplogroup R1a (P<0.001 and P=0.003, respectively) and b2/b3 deletions with haplogroup E (P=0.005). There were significantly more b2/b4 duplication carriers in Albanians than in Macedonians with haplogroup R1a (P=0.031).
CONCLUSIONS: Even though azoospermia factor c partial deletions/duplications and Y-haplogroups were not associated with impaired semen quality, specific deletions/duplications were significantly associated with distinct haplogroups, implying that the Y chromosome background may confer susceptibility to azoospermia factor c microrearrangements.

The prognosis of paediatric acute myeloid leukaemia (AML) with primary induction failure (PIF) is extremely poor, and effective treatment strategies have not been established. We investigated the clinical and biological features of paediatric AML patients with PIF registered to the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study. The 3-year overall survival rate of the 41 PIF patients was 19.0%. High leucocyte count, M7 morphology, and unfavourable genetic aberrations, such as FLT3-internal tandem duplication, NUP98-NSD1 and high MECOM or PRDM16 expression, were risk factors for PIF. More effective treatment strategies based on leukaemia biology need to be urgently explored.

The 15q11.2 BP1-BP2 cytogenetic region has been associated with learning and motor delays, autism, and schizophrenia. This region includes a gene that codes for the cytoplasmic FMR1 interacting protein 1 (CYFIP1). The CYFIP1 protein is involved in actin cytoskeletal dynamics and interacts with the fragile X mental retardation protein. Absence of fragile X mental retardation protein causes fragile X syndrome. Because abnormal white matter microstructure has been reported in both fragile X syndrome and psychiatric disorders, we looked at the impact of 15q11.2 BP1-BP2 dosage on white matter microstructure.
Combining a brain-wide voxel-based approach and a regional-based analysis, we analyzed diffusion tensor imaging data from healthy individuals with the deletion (n = 30), healthy individuals with the reciprocal duplication (n = 27), and IQ-matched control subjects with no large copy number variants (n = 19), recruited from a large genotyped population sample.
We found global mirror effects (deletion > control > duplication) on fractional anisotropy. The deletion group showed widespread increased fractional anisotropy when compared with duplication. Regional analyses revealed a greater effect size in the posterior limb of the internal capsule and a tendency for decreased fractional anisotropy in duplication.
These results show a reciprocal effect of 15q11.2 BP1-BP2 on white matter microstructure, suggesting that reciprocal chromosomal imbalances may lead to opposite changes in brain structure. Findings in the deletion overlap with previous white matter differences reported in fragile X syndrome patients, suggesting common pathogenic mechanisms derived from disruptions of cytoplasmic CYFIP1-fragile X mental retardation protein complexes. Our data begin to identify specific components of the 15q11.2 BP1-BP2 phenotype and neurobiological mechanisms of potential relevance to the increased risk for disorder.

The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.

Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort.
This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders.
Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012-0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040-0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy.
The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry.
Capital Region\'s Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.