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Microduplication of the LCR22-A to LCR22-D region on chromosome 22q11.2 is a recurrent copy number variant found in clinical populations undergoing chromosomal microarray, and at lower frequency in controls. Often inherited, there is limited data on intellectual (IQ) and psychological functioning, particularly in those individuals ascertained through a family member rather than because of neurodevelopmental disorders. To investigate the range of cognitive-behavioral phenotypes associated with 22q11.2 duplication, we studied both probands and their non-proband carrier relatives. Twenty-two individuals with 22q11.2 duplication (10 probands, 12 non-proband carriers) were prospectively assessed with a battery of neuropsychological tests, physical examination, and medical record review. Assessment measures with standardized norms included IQ, academic, adaptive, psychiatric, behavioral, and social functioning. IQ and academic skills were within the average range, with a trend toward lower scores in probands versus non-probands. Adaptive skills were within age expectations. Prevalence of attention deficits (probands only) and anxiety (both groups) was high compared with norms. The prevalence of autism spectrum disorder was relatively low (5% of total sample). Assessment of both probands and non-probands with 22q11.2 duplication suggests that the phenotypic spectrum with respect to neurodevelopment overlaps significantly with the general population. IQ and academic abilities are in the average range for most of the individuals with 22q11.2 duplication in our study, regardless of ascertainment as a proband or non-proband relative. Symptoms of attention deficit and anxiety were identified, which require further study. Results of this study further clarify the phenotype of individuals with 22q11.2 duplication, and provides important information for genetic counseling regarding this recurrent copy number variant.

Phelan-McDermid syndrome (PMS) is a genetic disorder caused by a mutation or deletion of the SHANK3 gene (chromosome 22q13.3), characterized by different sensory processing anomalies. The objective of this study is to expand and provide a detailed definition of the sensory profile of patients with PMS. The secondary objective was to examine the relationship between sensory patterns and adaptive behavior. A cross-sectional study was carried out among 51 Spanish patients with a confirmed genetic diagnosis of PMS. All the participants’ parents completed the Short Sensory Profile-Spanish (SSP-S) and the Adaptive Behavior Assessment System II (ABAS-II). Correlational, multiple regression and hierarchical cluster analyses were performed. An atypical sensory profile was identified in almost 75% of PMS patients. Definite differences were found among scores; nonetheless, sub-threshold values were observed in tactile sensitivity, underresponsive/seeks sensation, auditory filtering, and low energy/weak sensory categories. Conceptual, social, and practical domains, as well as the General Adaptive Composite (GAC) of the ABAS-II showed extremely low scores (i.e., pConclusions: Patients with PMS show an atypical sensory profile, which correlates with limitations in general adaptive behaviors. What is Known:• PMS sensory processing difficulties were associated with a pattern of underresponsive/seeks sensation, low energy/weak, and tactile hyporeactivity.• Sensory processing difficulties have been associated with limitations in the development of appropriate adaptive communication and interaction behaviors. What is New:• Sensory definite differences associated with tactile hyperreactivity, as well as significant effects of underresponsiveness/seeks sensation and auditory filtering categories on the adaptive abilities were found in SHANK3deletionpatients.• Cluster analysis suggests that smaller mutation sizes were related to better sensory processing and higher adaptive skills, while patients with larger deletion sizes have greater adaptive difficulties and worse sensory processing skills.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare pediatric brain tumor with abnormalities in SMARCB1 located in 22q11.2. We report a case of AT/RT associated with Phelan-McDermid syndrome (PMS) characterized by congenital developmental disorder, mental retardation, and ring chromosome 22 with 22q13.3-qter depletion, for which we performed whole-genome sequencing (WGS). A 4-year-old girl with a developmental disability was referred to our hospital due to dysphoria. Brain magnetic resonance imaging showed a 5-cm well-demarcated mass that extended bilaterally in the frontal lobes. G-banding was performed preoperatively due to a history of developmental retardation. Ring chromosome 22 and deletion of 22q13.3-qter were observed, and she was diagnosed with PMS. She underwent gross total resection of the tumor, and the pathological diagnosis was AT/RT. WGS showed somatic SMARCB1 mutation (p.R201X) and somatic loss of the entire chromosome 22 in the tumor, but not in the blood sample. WGS confirmed previously unreported BRCA2 mutations, 6q loss, and 14q acquisition during tumor progression, but no other significant findings associated with tumor progression. The present case is discussed with reference to a systematic review of previous reports of AT/RT associated with PMS. PMS patients with ring chromosome 22 should be carefully followed up for AT/RT occurrence.

Background Phelan–McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. Methods rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. Results rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. Limitations Results should be interpreted with caution given the small sample size and lack of a placebo control. Conclusions Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207.

People with Phelan-McDermid Syndrome, caused by mutations in the SHANK3 gene, commonly exhibit reduced responses to sensory stimuli; yet the changes in brain-wide activity that link these symptoms to mutations in the shank3 gene remain unknown. Here we quantify movement in response to sudden darkness in larvae of two shank3 zebrafish mutant models and show that both models exhibit dampened responses to this stimulus. Using brain-wide activity mapping, we find that shank3−/− light-sensing brain regions show normal levels of activity while sensorimotor integration and motor regions are less active. Specifically restoring Shank3 function in a sensorimotor nucleus of the rostral brainstem enables the shank3−/− model to respond like wild-type. In sum, we find that reduced sensory responsiveness in shank3−/− models is associated with reduced activity in sensory processing brain regions and can be rescued by restoring Shank3 function in the rostral brainstem. These studies highlight the importance of Shank3 function in the rostral brainstem for integrating sensory inputs to generate behavioral adaptations to changing sensory stimuli., Robert Kozol et al. developed two zebrafish Shank3 models to characterize the basis of sensorimotor deficits, which are a consistent feature in SHANK3-deficient human patients (Phelan-McDermid Syndrome). Their results suggest that hindbrain regions require Shank3 for normal responses to light, and provide further insight toward the biology of sensory deficits in Shank3 mutants.

22q11.2 duplication syndrome has a frequency of ~1/700 in the intellectual disability population. Despite this frequency, there is limited information on the variable clinical presentation. Although the phenotype and incidence of congenital anomalies are well described for 22q11.2 deletion syndrome, they are not as well understood for individuals with 22q11.2 duplication syndrome. This study is a single-center, retrospective review of patients diagnosed with 22q11.2 duplication syndrome designed to categorize the variable phenotype seen in these individuals. The data suggest that the incidence of congenital anomalies may be higher than previously reported for this syndrome. Affected individuals are at increased risk for a variety of problems including gastrointestinal complications, endocrine dysfunction, ophthalmologic abnormalities, palatal anomalies, congenital heart disease, musculoskeletal differences, and neurologic abnormalities. Individuals with 22q11.2 duplication syndrome would benefit from care coordinated by a multidisciplinary team and managed according to the 22q11.2 deletion syndrome guidelines.

Myeloid/lymphoid neoplasm with t(8;22)(p11.2;q11.2)/BCR-FGFR1 is an extremely rare diagnosis, with few reported cases to date. In contrast to other FGFR1-partner rearrangements that are associated with chronic eosinophilic leukemia, acute myeloid leukemia, and/or lymphoblastic lymphoma, patients with BCR-FGFR1 have a myeloproliferative disorder that closely resembles chronic myeloid leukemia (CML). The current report describes a rare case of a 61 year old man with an atypical CML phenotype associated with t(8;22)(p11.2;q11.2)/BCR-FGFR1. A literature review is presented to enhance the awareness of this rare diagnostic entity.

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.

Background Cat eye syndrome (CES) is a rare chromosomal disease, with estimated incidence of about 1 in 100,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients, and other congenital defects may also be observed. The typical associated cytogenetic anomaly relies on an extra chromosome, derived from an inverted duplication of short arm and proximal long arm of chromosome 22, resulting in partial trisomy or tetrasomy of such regions (inv dup 22pter-22q11.2). Case presentation We report on a full-term newborn, referred to us soon after birth. Physical examination showed facial dysmorphisms, including hypertelorism, down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified left chorioretinal and iris coloboma and ostium secundum type atrial septal defect, respectively. Based on the suspicion of cat eye syndrome, a standard karyotype analysis was performed, and detected an extra small marker chromosome confirming the CES diagnosis. The chromosomal abnormality was then defined by array comparative genome hybridization (a-CGH, performed also in the parents), which identified the size of the rearrangement (3 Mb), and its de novo occurrence. Postnatally, our newborn presented with persistent hypoglycemia and cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism, cortisol and growth hormone (GH) deficiencies, which were treated with replacement therapies (levotiroxine and hydrocortisone). Brain magnetic resonance imaging, later performed, showed aplasia of the anterior pituitary gland, agenesis of the stalk and ectopic neurohypophysis, confirming the congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and included in a multidisciplinary follow-up. She currently is 7 months old and shows a severe global growth failure, and developmental delay. She started GH replacement treatment, and continues oral hydrocortisone, along with ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic and thyroid profiles as well as of cholestasis. Conclusions CES phenotypic spectrum is wide and highly variable. Our report highlights how among the possible associated endocrine disorders, congenital hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis. These patients should be promptly assessed for complete hormonal evaluations, in addition to major malformations and midline anomalies. Early recognition of such defects is necessary to decrease fatal events, as well as short and long-term related adverse outcomes.

Background The non-invasive prenatal test (NIPT) is based on next generation sequencing (NGS) and is used for screening for fetal trisomy. However, it is time-consuming and technically difficult. Recently, peptide nucleic acid (PNA) probe-based real-time polymerase chain reaction (RT-PCR) was developed. This study aimed to examine the performance of the RT-PCR-based NIPT for screening of common fetal trisomies Methods From stored maternal plasma, RT-PCR was performed using Patio™ NIPT Detection Kit. In melting curve analysis, the height of melting peaks of target chromosome and reference chromosome was calculated as a peak ratio. The adjusted peak ratio of 8 markers with correction factors in each target chromosome was summated and calculated to z-score. The cut-off value for each target chromosome was established for classification (low risk vs. high risk for trisomy) whose performance was obtained in the validation phase. Results 330 plasma samples from pregnant women with normal fetus and 22 trisomy cell-line samples were used to establish the optimal cut-off values for z-score of each target chromosome. In the validation phase, 1023 samples from pregnant women including 22 cases with fetal trisomy and 1001 cases of normal control were used. The RT-PCR-based NIPT showed 95.45% sensitivity [95% confidence interval (CI) 77.16–99.88%], 98.60% specificity (95% CI 97.66–99.23%), and 98.53% accuracy (95% CI 97.59–99.18%) for the identification of trisomy 21, 18, or 13. Of 1023 samples, fifteen cases were mismatched for classification [one case as a false negative (false negative rate: 4.5%) and 14 cases as false positives (false positive rate: 1.4%)]. Conclusion The RT-PCR-based NIPT showed high sensitivity and specificity for the detection of common fetal trisomies and it could be a feasible alternative to NGS-based NIPT.

Background Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability. Methods We used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison. Results We found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size. Conclusions This study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.

The 22q11.2 Deletion Syndrome has significant impact on brain and behavior, with about 25% of individuals developing schizophrenia. The condition offers a model for prospective studies on the emergence of psychosis and advancing mechanistic hypotheses on gene-environment interactions, with magnified power for examining genome-phenome association. Here, we highlight findings that build on the International 22q11.2 Brain and Behavior Consortium and relate to several key domains in the study of psychosis-risk and schizophrenia. We examine neurocognition, olfaction and neuroimaging data that indicate similar impairment patterns in this rare syndrome and idiopathic presentation of schizophrenia. We conclude that the converging paradigms, studying psychosis dimensionally in rare and common variants samples, provide complementary approaches that will propel precision medicine in psychiatry.

(1) Background: Phelan-McDermid Syndrome (PMS) in children causes significant challenges affecting social and family relationships. The purpose of this study was to explore the experience of parents with children diagnosed with PMS regarding interactions with their social environment; (2) Methods: A qualitative descriptive study was conducted. Participants were recruited using non-probabilistic purposeful sampling. In total, 32 parents of children with PMS were included. In-depth interviews and researchers’ field notes were used to collect the data. An inductive thematic analysis was performed; (3) Results: Five themes were identified: (a) challenges in the relationship as a couple; (b) challenges within the family and close social relationships; (c) challenges in the educational-school environment; (d) challenges in the health environment and with health professionals, and (e) reconnection through the PMS association. It would be beneficial for parents to create training programs on PMS in the educational and healthcare settings, to promote the participation of professionals in the PMS association and to develop care programs focusing in their physical, psychological and social health.

Sleep is essential to maintaining a healthy life. Sleep disturbances among individuals with neurodevelopmental disorders are not well studied, affecting their early detection and treatment. Sleep disturbances in individuals with Phelan-McDermid Syndrome (PMS) are among the primary concerns reported by parents. However, little research has been aimed at addressing their concern.The purpose of this investigation was to identify and quantify specific sleep disturbances in people with PMS by analyzing data collected by the PMS Foundation International Registry.The registry shows that 284 out of 384 (73.4%) individuals with confirmed chromosome 22q13 deletions or SHANK3 pathogenic variants have a sleep disturbance. The prevalence of sleep disturbances increases with age with 56% reporting a sleep disturbance in the 0-3 year age group and 90% reporting these disturbances in those over age 18 years old. The primary sleep disturbances were circadian rhythm sleep disorders that included difficulty falling asleep, frequent nighttime awakenings, difficulty returning to sleep after a nighttime awakening event, and hypersomnia and parasomnias including enuresis, night terrors, sleepwalking, and sleep apnea. Sleep disturbances were similarly frequent among individuals with SHANK3 pathogenic variants (84.8%) and those with deletions (71.9%), supporting the role of haploinsufficiency of SHANK3 in sleep.Sleep disturbances are a common feature of PMS and should be considered in clinical evaluation and management because of the effect they have on the quality of life of the patients and their families.

Background Sleep disturbance is common, impairing, and may affect symptomatology in developmental neuropsychiatric disorders. Here, we take a genetics-first approach to study the complex role of sleep in psychopathology. Specifically, we examine severity of sleep disturbance in individuals with a reciprocal copy number variant (CNV) at the 22q11.2 locus and determine sleep’s effect on psychiatric symptoms. CNVs (deletion or duplication) at this locus confer some of the greatest known risks of neuropsychiatric disorders; recent studies suggest the 22q11.2 deletion negatively impacts sleep, but sleep disruption associated with 22q11.2 duplication has not been investigated. Methods We compared subjective sleep disturbance and its relationship to psychiatric symptoms cross-sectionally and longitudinally over 1 year in 107 22q11.2 deletion (22qDel) carriers (14.56±8.0 years; 50% male), 42 22q11.2 duplication (22qDup) carriers (16.26±13.1 years; 54.8% male), and 88 age- and sex-matched controls (14.65±7.4 years; 47.1% male). Linear mixed models were used to compare sleep disturbance, assessed via the Structured Interview for Psychosis-Risk Syndromes (SIPS), across groups. Next, CNV carriers were categorized as good or poor sleepers to investigate sleep effects on multiple neurobehavioral traits: psychosis-risk symptoms (SIPS), autism-related behaviors (Repetitive Behavior Scale (RBS) and Social Responsiveness Scale (SRS)), real-world executive function (Behavior Rating Inventory of Executive Function (BRIEF)), and emotional/behavioral problems (Child Behavior Checklist (CBCL)). Linear mixed models tested the effect of sleep category and a group-by-sleep interaction on each measure, cross-sectionally and longitudinally. Results 22qDel and 22qDup carriers both reported poorer sleep than controls, but did not differ from each other. Cross-sectionally and longitudinally, poor sleepers scored higher on positive symptoms, anxious/depressed, somatic complaints, thought problems, and aggressive behavior, as well as RBS and SRS total scores. There were significant group-by-sleep interactions for positive symptoms and the majority of CBCL subdomains, in which the difference between good and poor sleepers was larger in 22qDel compared to 22qDup. Conclusions Our findings indicate that CNVs at the 22q11.2 locus impact sleep which, in turn, influences psychopathology. Sleep disturbances can differentially impact psychopathology, depending on 22q11.2 gene dosage. Our findings serve as a starting point for exploring a genetic basis for sleep disturbance in developmental neuropsychiatric disorders.

To explore the clinical and genetic characteristics of three children with 22q13 deletion syndrome.Clinical data were collected and copy number variations in the patients and their parents were detected by using array-based comparative genomic hybridization (aCGH) and copy number variation sequencing (CNV-seq). The DECIPHER, ClinGen, OMIM, PubMed and Gene Review databases were retrieved for pathogenicity analysis.The common phenotypes of the three children have included variable global developmental delay, among which speech delay was the most obvious. Patient 1 had abnormalities of corpus callosum shown by magnetic resonance imaging. Patient 2 had dental crowding, pale skin, thick palms, hypotonia, and other facial features. Patient 3 had the mildest symptoms including language dysfunction, which has caught up with the development and improved significantly. All of the three children had harbored de novo deletions of 22q13.33q13.33 region, which spanned 0.84 Mb, 8.70 Mb and 0.90 Mb and involved 37, 126, and 34 genes, respectively.Above finding has enriched the clinical and genetic characteristics of 22q13 deletion syndrome and laid a foundation for genetic counseling and prenatal diagnosis.

SMARCB1 is mutated in most rhabdoid tumors (RTs) developing in the kidney (RTK) and various other organs. Focal deletions found in patients with 22q11.2 deletion syndrome show breakpoints within clusters of segmental duplications (SDs), and those in some RTs show breakpoints in the 22q11-q12 region. SDs are known to cause focal deletion mediated by non-allelic homologous recombination. The present study identified SMARCB1 alterations in all 30 RTKs, using SNP array CGH, MLPA, and sequence analyses. Twenty-eight tumors had a total of 51 breakpoints forming focal 22q deletion and/or uniparental disomy (22qUPD), and the other two had compound mutation with no breakpoints in 22q. Twenty-four (47.1%) of the 51 breakpoints were within SDs, and occurred in 16 (53.3%) of the 30 tumors. The association of breakpoints with SDs was found not only in focal deletion, but also in 22qUPD, indicating that SDs mediate the first and second hits (focal deletion) and the second hit (22qUPD) of SMARCB1 alteration. Of the 51 breakpoints, 14 were recurrent, and 10 of the 14 were within SDs, suggesting the presence of hotspots in the 22q11.2 region. One recurrent breakpoint outside SDs resided in SMARCB1, suggesting inactivation of the gene by out-of-frame fusion. The association between SDs and focal deletion has been reported in two other types of cancer. RTKs may be the third example of SD-associated tumors. Thus, the present study indicated that RTKs exploit genomic instability in the 22q11.1-11.2 SDs region, and 22qUPD caused by mitotic recombination may also be mediated by SDs. This article is protected by copyright. All rights reserved.

A newborn male with cat eye syndrome presented with progressively worsening bilateral upper eyelid imbrication, floppy eyelids, and ptosis. Despite conservative management, he remained unable to open his eyelids. Surgical correction was planned to prevent bilateral sensory deprivation amblyopia and was delayed until 5 months of age due to systemic health concerns. Bilateral full-thickness wedge excision and frontalis suspension with silicone rods in a double rhomboid fashion was performed. Postoperatively, the patient demonstrated spontaneous eyelid opening, resolution of spastic eversion of the upper eyelids, and adequate eyelid closure. The authors present the first case of concurrent floppy eyelid syndrome and upper eyelid imbrication reported in a cat eye syndrome patient.

The rDNA clusters and flanking sequences on human chromosomes 13, 14, 15, 21 and 22 represent large gaps in the current genomic assembly. The organization and the degree of divergence of the human rDNA units within an individual nucleolar organizer region (NOR) are only partially known. To address this lacuna, we previously applied transformation-associated recombination (TAR) cloning to isolate individual rDNA units from chromosome 21. That approach revealed an unexpectedly high level of heterogeneity in human rDNA, raising the possibility of corresponding variations in ribosome dynamics. We have now applied the same strategy to analyze an entire rDNA array end-to-end from a copy of chromosome 22. Sequencing of TAR isolates provided the entire NOR sequence, including proximal and distal junctions that may be involved in nucleolar function. Comparison of the newly sequenced rDNAs to reference sequence for chromosomes 22 and 21 revealed variants that are shared in human rDNA in individuals from different ethnic groups, many of them at high frequency. Analysis infers comparable intra- and inter-individual divergence of rDNA units on the same and different chromosomes, supporting the concerted evolution of rDNA units. The results provide a route to investigate further the role of rDNA variation in nucleolar formation and in the empirical associations of nucleoli with pathology.

Background: Studies have shown that the overall copy number variant (CNV) load is associated with schizophrenia. Schizophrenia is a mental disorder that is frequently associated with suicidal behavior. Methods: We recruited 263 patients with schizophrenia from the Centre for Addiction and Mental Health. The Columbia Suicide Severity Rating Scale was used to assess the presence of lifetime suicide attempt. Genotyping was completed using the Illumina Omni 2.5 chip. We tested the association between deletion events on chromosome 22 with suicide attempt in our schizophrenia sample. Results: There was no significant difference between suicide attempters and non-attempters considering the presence/absence of deletion events on chromosome 22. Conclusion: Although our results did not show a significant association between deletions on chromosome 22 and suicide attempt in schizophrenia, CNV studies may reveal important, novel insights and open further investigation for the treatment of neuropsychiatric diseases.

To clarify the morphologic spectrum and molecular profiles of hybrid schwannoma/perineurioma (HSP), we investigated 15 tumors clinicopathologically and cytogenetically. HSP was classified into 2 morphologic types: mixed cellular and combined tumor types. The former comprising of 14 tumors mostly arose in the subcutaneous tissue of the extremities and the trunk of middle-aged adults. They were well-circumscribed and composed of elongated spindle-shaped tumor cells arranged in storiform and whorl patterns. Immunostaining revealed a mixed cellular proliferation of S-100 protein-positive and SOX10-positive Schwann cells and epithelial membrane antigen-positive, claudin 1-positive, and GLUT1-positive perineurial cells. During follow-up, no tumors were found to have recurred in any cases. In contrast, in the combined tumor type arising in the mediastinum of a young male with neurofibromatosis type 2, the intraneural perineurioma-like areas, characterized by small whorl-like structures, were present in plexiform schwannoma-like areas. No recurrence was noted in the case. Molecular analyses (array comparative genomic hybridization and fluorescence in situ hybridization) revealed LOH 22q in 2 tumors of 5 studied: one each of the mixed cellular and combined tumor types. Although the same diagnostic term, HSP, has been applied to both mixed and combined types, they should be separated from each other.

Small supernumerary marker chromosomes cannot be accurately identified by G-banding, and the related phenotypes vary greatly. It is essential to specify the origin, size, and gene content of marker chromosomes using molecular cytogenetic techniques. Herein, three fetuses with de novo marker chromosomes were initially identified by G-banding. Single nucleotide polymorphism array and fluorescence in situ hybridization were performed to characterize the origins of the marker chromosomes. The karyotypes of the three fetuses were 47,XY,+mar, 46,X,+mar[32]/45,X[68], and 45,X[62]/46,X,+mar[9]. In case 1, the karyotype was confirmed as 47,XY,+ idic(22)(q11.2). Therefore, the sSMC originated from chromosome 22 and was associated with cat eye syndrome. In case 2, the marker chromosome derived from ring chromosome X, and the karyotype was interpreted as 45,X[68]/46,X,+r(X)(p11.1q21.31)[32]. Meanwhile, the karyotype of case 3 was defined as 45,X[62]/46,X,idic(Y)(q11.2) and the marker chromosome originated from chromosome Y. Case 1 continued the pregnancy, whereas the other two pregnancies underwent elective termination. The detailed characterization of marker chromosomes can facilitate informed decision making, prevent uncertainty, and provide proper prognostic assessments. Our findings emphasize the importance for combining cytogenetic and molecular genetic techniques in marker chromosome characterization.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by chromosomal rearrangements affecting the 22q13.3 region or by SHANK3 pathogenic variants. The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders. Therefore, we first conducted a systematic review of the literature to identify kidney disorders in PMS and then pooled the data to create a cohort of individuals to identify candidate genes for renal disorders in PMS. We found 7 types of renal disorders reported: renal cysts, renal hypoplasia or agenesis, hydronephrosis, vesicoureteral reflux, kidney dysplasia, horseshoe kidneys, and pyelectasis. Association analysis from the pooled data from 152 individuals with PMS across 22 articles identified three genomic regions spanning chromosomal bands 22q13.31, 22q13.32, and 22q13.33, significantly associated with kidney disorders. We propose UPK3A, FBLN1, WNT7B, and CELSR1, located from 4.5 Mb to 5.5 Mb from the telomere, as candidate genes. Our findings support the hypothesis that genes included in this region may play a role in the pathogenesis of kidney disorders in PMS.

Crossed pulmonary arteries (CPAs) represent an uncommon anatomic variant, usually associated with some specific syndromes and conotruncal defects. This finding has been described in 22q11.2 Deletion Syndrome (22q11.2DS). We evaluated the correlation between CPAs and genetic diseases, in order to better define the characteristics of this variant, considered a rare anatomic pattern. An in-depth analysis of CPAs genotype-phenotype correlations was performed via a literature review. We detected 74 CPAs patients through echocardiography. Of these 74 patients, 35.1% of patients showed additional intracardiac malformations, while 29.7% showed extracardiac vascular anomalies, of which 16.2% were associated with intracardiac defects and 13.5% were not. In all, 62.2% of patients were diagnosed with genetic diseases and 52.2% of them were 22q11.2DS patients. In conclusions, CPAs represent a cardiovascular variant, which is detectable in nonsyndromic individuals, but especially in various genetic syndromes and in particular in 22q11.2DS patients. Data on the real prevalence of this morphology is lacking in literature. Knowledge of this anatomic variant is useful to interpret the unusual course of the pulmonary branches and is helpful information before cardiovascular surgical correction. Moreover, due to the strong association of CPAs with some genetic syndromes, the identification of this anatomic pattern can indicate the utility of a genetic assessment of these patients.

Non-alcoholic fatty liver(NAFLD) is prevalent in Asians despite the low obesity rate. We hypothesized that the haplotype of genetic variants in the 22q13 loci has a strong association with non-alcoholic fatty liver disease (NAFLD) that can be identified by genome-wide association study and that lifestyles may interact with the haplotype. We tested the hypothesis in middle-aged and elderly adults in a large city hospital-based cohort from the KoGES study. Men and women diagnosed with fatty liver, but who respectively consumed over 40 and 30 g ethanol per day were excluded. The haplotype of the selected SNPs from the 22q13 loci that influences NAFLD risk was generated. Among the 27374 participants, 1486 (5.4%) were diagnosed with NAFLD. LARGE_rs240072, RBFOX2_rs11089778, TRIOBP_rs12628603, PNPLA3_rs738409, and PARVB_rs2073080 in the 22q13 loci were included in the haplotype. Participants with the minor haplotype had 1.8, 2.3, and 1.8 times higher in the risk for NAFLD and serum AST and ALT activities, respectively, than those with the major haplotype. BMI, waist circumferences, serum glucose concentrations, and blood pressure interacted with the haplotype for NAFLD risk. We also found that a high carbohydrate intake and a dietary pattern characterized by high noodle and meat consumption significantly interacted with the minor haplotype to increase the risk of NAFLD. We hypothesized that the high incidence of NAFLD among Koreans, despite a relatively low incidence of obesity, might be due to genetic factors and perhaps their interactions with dietary patterns. The hypothesis was accepted since this study confirmed that participants with the minor allele of the haplotype in the 22q13 loci had a higher NAFLD risk that was exacerbated by high intakes of carbohydrates and a dietary pattern characterized by high noodle and meat consumption.

Phelan-McDermid syndrome or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder characterized by neonatal hypotonia, severe speech delay, moderate to profound intellectual disability, and minor dysmorphic features. Regression of developmental milestones is often recognized as characteristic of this syndrome. We report a 6-year-old patient with Phelan-McDermid syndrome who presented with rapid neurologic deterioration secondary to metachromatic leukodystrophy due to a mutation of the arylsulfatase A gene ( ARSA) on the other allele of 22q13.3. Metachromatic leukodystrophy was diagnosed later after clinical deterioration. Currently, there are no guidelines for screening Phelan-McDermid syndrome patients for metachromatic leukodystrophy. We propose screening for urine sulfatides at the time of Phelan-McDermid syndrome diagnosis to identify patients with pre-symptomatic or early symptomatic metachromatic leukodystrophy as it is important to facilitate discussion of treatment options and prognosis and provide medical surveillance for associated complications.

The q11.2 region on chromosome 22 contains numerous low-copy repeats that lead to deleted or duplicated regions in the chromosome, thereby resulting in different syndromes characterized by intellectual disabilities or congenital anomalies. The association between patient phenotypes and 22q11.2 copy number abnormalities has been previously described in postnatal cases; however, these features have not been systematically evaluated in prenatal cases because of limitations in phenotypic identification in prenatal testing. In this study, we investigated the detection rate of 22q11.2 copy number abnormalities in 2500 fetuses using single nucleotide polymorphism (SNP) array and determined the common abnormal ultrasound findings in fetuses carrying the 22q11.2 copy number abnormalities. The 22q11.2 copy number abnormalities were identified in 13 fetuses with cardiovascular malformations (6/13), kidney malformations (3/13), isolated ultrasound markers (3/13), or high-risk Down syndrome based on maternal serum screening (1/13). Approximately 0.5% (13/2500) of the fetuses harbored 22q11.2 copy number abnormalities. The most frequent ultrasound findings in fetuses with these abnormalities were cardiovascular malformations, followed by kidney malformations and isolated ultrasound markers. Prenatal diagnosis of these genetic abnormalities allows for the delineation of differential diagnoses, characterization of a wide spectrum of associated malformations, and determination of associations that exist between prenatal diagnosis and obstetrical outcomes.

To describe a unique ocular presentation of Cat Eye Syndrome and review the ocular and systemic findings associated with the syndrome.Case report with multimodal imaging.A newborn female presented with a unilateral Peters anomaly with contralateral microphthalmia with cyst. The patient's other systemic findings included a hypoplastic right heart, persistent ductus arteriosus, intrauterine growth retardation, bilateral anotia, preauricular ear pits and skin tags, micrognathia, hypoplastic female genitalia, and unilateral cranial nerve VII palsy. Chromosomal microarray testing showed tetrasomy of chromosome 22 in the q11.1-q11.21 region consistent with Cat Eye Syndrome. The patient ultimately underwent a successful optical iridectomy on one side and orbitotomy with excision of the cystic mass on the other.The co-occurrence of unilateral Peters anomaly with contralateral microphthalmia with cyst in Cat Eye Syndrome is rare and demonstrative of the syndrome's phenotypic variability. The medical and surgical management of these patients may require a multidisciplinary approach and must be tailored to the individual findings and overall systemic health of the patient.