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. Family and clinical data of 31 fetuses with 22q11.2 microduplications confirmed by chromosomal microarray between June 2017 and June 2023 were considered. 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. 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.

Objective  A significant number of genetic variations have been identified in chromosome 22, using molecular genetic techniques. Various genomic disorders on chromosome 22, including cat's eye syndrome caused by extra copies of the proximal region of the 22q chromosome, are now well-defined. Our aim in the study was to show phenotypic variability associated with rearrangements of the 22q chromosomal region. Methods  We focused our study on clinical aspects of these disorders, including genetic testing, genotype-phenotype correlation, and potential treatments. A total of 998 patients were referred for genetic analysis (Karyotyping, MLPA, array-CGH) during January 2015 to February 2020 because of intellectual deficiency, behavior issues, and/or multiple congenital abnormalities in several genetics departments. Informed consent was obtained from all the patients and/or their parents. Results  22q11.21 or 22q13.33 microdeletions and 22q11.22-q11.23 microduplication were identified in 31 patients out of referrals. The 22q aberrations were detected in 31/998 patients, giving a prevalence of 3.1%. In this study, 18 patients with 22q11.2 (LCR22A-H) deletion, three patients with 22q13.31 deletion, 9 patients with 22q11.2 duplication and one patient with 22q13.31 duplication were identified. We report on the clinical and molecular characterization of 31 individuals with distal deletions and duplications of chromosome 22q. Conclusions  The current study demonstrated in the largest postnatal case series reporting the whole spectrum of atypical phenotypic and genotypic variations at 22q. We believe that when all the phenotypic differences are taken into account, various anomalies including developmental delay and intellectual disability might be considered as an indication to search for aberrations of 22q along with congenital heart diseases.

"22q11 deletion syndrome" (22q11DS) is a rare genetic syndrome, in which most patients share the same deletion, but their clinical features may vary a great deal. The genetic mechanisms underlying the variable expressivity and reduced penetrance of 22q11DS still have to be fully elucidated. Epilepsy has been reported in about 15.2% of the patients; however, few studies have focused on this topic, and in most cases, a detailed epileptic profile is missing. Since only a minority of patients experience epileptic seizures, 22q11deletion can be considered a predisposing factor, which is not sufficient "per se" to cause epilepsy; to date, no candidate gene for epilepsy has been identified in the deleted region. We report on a 6-year-old girl with 22q11DS presenting a form of epilepsy that can be classified as "Panayiotopoulos syndrome." Array CGH revealed an additional microduplication of 172 kb in 2q37, harboring three genes. One of these, DGKD (diacylglycerol kinase delta), is interrupted by the distal breakpoint of the duplication. DGKD encodes a cytoplasmic enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. This is an important second messenger in a pathway of lipid signaling that has been implicated in epilepsy and other neurological diseases. Disruption of DGKD by a t(X;2) has been previously reported in a patient with epilepsy. The 2q37 microduplication was inherited from her mother, who never experienced epileptic seizures, thus this imbalance is not "per se" sufficient to cause epilepsy. It can be hypothesized that the epileptic phenotype is provoked by the simultaneous presence of 22q11.2 deletion and 2q37 duplication. It has been shown that rare additional copy-number variations (CNVs) outside the 22q11.2 region may modulate the risk of congenital heart defects. It is possible that also for the epileptic phenotype, the additional CNVs may represent an important modifying factor underlying the variable expressivity and incomplete penetrance in the 22q11DS.

Misalignments of low-copy repeats (LCRs) located in chromosome 22, particularly band 22q11.2, predispose to rearrangements. A variety of phenotypic features are associated with 22q11.2 microduplication syndrome which makes it challenging for the genetic counselors to recommend appropriate genetic assessment and counseling for the patients. In this study, multiplex ligation probe dependent amplification (MLPA) analysis was performed on 378 patients with cleft lip and/or palate to characterize rearrangements in patients suspected of 22q11.2 microduplication and microdeletion syndromes. Of 378 cases, 15 were diagnosed with a microdeletion with various sizes and 3 with duplications. For the first time in this study an atypical 0.6 Mb duplication is reported. Illustration of the phenotypes associated with the microduplications increases the knowledge of phenotypes reported in the literature.