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Chromosome 22q13.3 deletion (Phelan‐McDermid) syndrome (PMS, OMIM 606232) is a rare genetic condition that impacts neurodevelopment. PMS most commonly results from heterozygous contiguous gene deletions that include the SHANK3 gene or likely pathogenic variants of SHANK3 (PMS‐SHANK3 related). Rarely, chromosomal rearrangements that spare SHANK3 share the same general phenotype (PMS‐SHANK3 unrelated). Very recent human and model system studies of genes that likely contribute to the PMS phenotype point to overlap in gene functions associated with neurodevelopment, synaptic formation, stress/inflammation and regulation of gene expression. In this review of recent findings, we describe the functional overlaps between SHANK3 and six partner genes of 22q13.3 (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, and TCF20), which suggest a model that explains the commonality between PMS‐SHANK3 related and PMS‐SHANK3 unrelated classes of PMS. These genes are likely not the only contributors to neurodevelopmental impairments in the region, but they are the best documented to date. The review provides evidence for the overlapping and likely synergistic contributions of these genes to the PMS phenotype. [ABSTRACT FROM AUTHOR]

Phelan–McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS. [ABSTRACT FROM AUTHOR]

Lymphedema is a troubling condition present in many disorders including the rare genetic disorder known as Phelan–McDermid syndrome (PMS). The neurobehavioral features of PMS, also known as 22q13.3 deletion syndrome, have been investigated, but little research exists on lymphedema in PMS. In this investigation, clinical and genetic data from 404 people with PMS were reviewed from the PMS‐International Registry revealing a prevalence of 5% with lymphedema. Lymphedema was reported in 1 out of 47 people (2.1%) with PMS due to a SHANK3 variant and 19 out of 357 people (5.3%) with PMS due to 22q13.3 deletions. Lymphedema was more common among those in their teens or adulthood (p = 0.0011) and those with deletions >4 Mb. People with lymphedema had significantly larger deletions (mean 5.375 Mb) than those without lymphedema (mean 3.464 Mb, p = 0.00496). Association analysis identified a deletion of the CELSR1 gene to be the biggest risk factor (OR = 12.9 95% CI [2.9–56.2]). Detailed assessment of 5 subjects identified all had deletions of CELSR1, developed symptoms of lymphedema starting at age 8 or older, and typically responded well to standard therapy. In conclusion, this is the largest assessment of lymphedema in PMS to date and our results suggest that individuals with deletions >4 Mb or those with CELSR1 deletions should be assessed for lymphedema. [ABSTRACT FROM AUTHOR]

Phelan‐McDermid Syndrome (PMS) is caused by deletions at chromosome 22q13.3 or pathogenic/likely pathogenic SHANK3 variants. The clinical presentation is extremely variable and includes global developmental delay/intellectual disability (ID), seizures, neonatal hypotonia, and sleep disturbances, among others. This study investigated the prevalence of sleep disturbances, and the genetic and metabolic features associated with them, in a cohort of 56 individuals with PMS. Sleep data were collected via standardized observer/caregiver questionnaires, while genetic data from array‐CGH and sequencing of 9 candidate genes within the 22q13.3 region, and metabolic profiling utilized the Biolog Phenotype Mammalian MicroArray plates. Sleep disturbances were present in 64.3% of individuals with PMS, with the most common problem being waking during the night (39%). Sleep disturbances were more prevalent in individuals with a SHANK3 pathogenic variant (89%) compared to subjects with 22q13.3 deletions of any size (59.6%). Distinct metabolic profiles for individuals with PMS with and without sleep disturbances were also identified. These data are helpful information for recognizing and managing sleep disturbances in individuals with PMS, outlining the main candidate gene for this neurological manifestation, and highlighting potential biomarkers for early identification of at‐risk subjects and molecular targets for novel treatment approaches. [ABSTRACT FROM AUTHOR]

Phelan–McDermid syndrome (PMS) is a multisystem disorder that is associated with deletions of the 22q13 genomic region or pathogenic variants in the SHANK3 gene. Notable features include developmental issues, absent or delayed speech, neonatal hypotonia, seizures, autism or autistic traits, gastrointestinal problems, renal abnormalities, dolichocephaly, and both macro- and microcephaly. Assessment of the genetic factors that are responsible for abnormal head size in PMS has been hampered by small sample sizes as well as a lack of attention to these features. Therefore, this study was conducted to investigate the relationship between head size and genes on chromosome 22q13. A review of the literature was conducted to identify published cases of 22q13 deletions with information on head size to conduct a pooled association analysis. Across 56 studies, we identified 198 cases of PMS with defined deletion sizes and head size information. A total of 33 subjects (17%) had macrocephaly, 26 (13%) had microcephaly, and 139 (70%) were normocephalic. Individuals with macrocephaly had significantly larger genomic deletions than those with microcephaly or normocephaly (p < 0.0001). A genomic region on 22q13.31 was found to be significantly associated with macrocephaly with CELSR1, GRAMD4, and TBCD122 suggested as candidate genes. Investigation of these genes will aid the understanding of head and brain development. [ABSTRACT FROM AUTHOR]

Phelan–McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. We assessed the metabolic profiling of 48 individuals with PMS and 50 controls and determined subpopulations by taking the top and bottom 25% of responders to hGH and IGF-1. A distinct metabolic profile for individuals with PMS showed a reduced ability to metabolize major energy sources and a higher metabolism of alternative energy sources. The analysis of the metabolic response to hGH or IGF-1 highlighted a major overlap between both high and low responders, validating the model and suggesting that the two growth factors share many target pathways. When we investigated the effect of hGH and IGF-1 on the metabolism of glucose, the correlation between the high-responder subgroups showed less similarity, whereas the low-responders were still relatively similar. Classification of individuals with PMS into subgroups based on responses to a compound can allow an investigation into pathogenic mechanisms, the identification of molecular biomarkers, an exploration of in vitro responses to candidate drugs, and eventually the selection of better candidates for clinical trials. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Phelan–McDermid syndrome (PMS) is a multi-systemic disorder characterized by both genetic and phenotypic variability. Genetic abnormalities causing PMS span from pathogenic variants of the SHANK3 gene to chromosomal rearrangements affecting the 22q13 region and leading to the loss of up to over nine megabases. The clinical presentation of individuals with PMS includes intellectual disability, neonatal hypotonia, delayed or absent speech, developmental delay, and minor dysmorphic facial features. Several other features may present with differences in age of onset and/or severity: seizures, autism, regression, sleep disorders, gastrointestinal problems, renal disorders, dysplastic toenails, and disrupted thermoregulation. Among the causes of this phenotypic variability, the size of the 22q13 deletion has effects that may be influenced by environmental factors interacting with haploinsufficiency or hemizygous variants of certain genes. Another mechanism linking environmental factors and phenotypic variability in PMS involves the loss of one copy of genes like BRD1 or CYP2D6, located at 22q13 and involved in the regulation of genomic methylation or pharmacokinetics, which are also influenced by external agents, such as diet and drugs. Overall, several non-mutually exclusive genetic and epigenetic mechanisms interact with environmental factors and may contribute to the clinical variability observed in individuals with PMS. Characterization of such factors will help to better manage this disorder. [ABSTRACT FROM AUTHOR]

Phelan‐McDermid syndrome (PMS) (OMIM*606232) is a rare genetic disorder characterized by intellectual disability, autistic features, speech delay, minor dysmorphia, and seizures. This study was conducted to investigate the prevalence of seizures and the association with genetic and metabolic features since there has been little research related to seizures in PMS. For 57 individuals, seizure data was collected from caregiver interviews, genetic data from existing cytogenetic records and Sanger sequencing for nine 22q13 genes, and metabolic profiling from the Phenotype Mammalian MicroArray (PM‐M) developed by Biolog. Results showed that 46% of individuals had seizures with the most common type being absence and grand‐mal seizures. Seizures were most prevalent in individuals with pathogenic SHANK3 mutations (70%), those with deletion sizes >4 Mb (16%), and those with deletion sizes <4 Mb (71%) suggesting involvement of genes in addition to SHANK3. Additionally, a 3 Mb genomic region on 22q13.31 containing the gene TBC1D22A, was found to be significantly associated with seizure prevalence. A distinct metabolic profile was identified for individuals with PMS with seizures and suggested among other features a disrupted utilization of main energy sources using Biolog plates. The results of this study will be helpful for clinicians and families in anticipating seizures in these children and for researchers to identify candidate genes for the seizure phenotype. [ABSTRACT FROM AUTHOR]

Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder associated with a terminal deletion affecting chromosome 22 (22q13) that results in the loss of function of the SHANK3 gene. SHANK3 has also been identified in gene-linkage studies to be associated with autism spectrum disorder (ASD). Diagnosis of ASD in individuals with PMS is complicated by the presence of moderate to profound global developmental delay/intellectual disability as well as other co-morbid systemic and neurological symptoms. Methods: The current study aimed to characterize the symptoms of ASD in patients with PMS and to do a preliminary exploration of genotype-ASD phenotype correlations. We conducted a standardized interview with 40 parents/guardians of children with PMS. Further, we conducted analyses on the relationship between disruption of SHANK3 and adjacent genes on specific characteristic symptoms of ASD in PMS in small subset of the sample. Results: The majority of PMS participants in our sample displayed persistent deficits in Social communication, but only half met diagnostic criteria under the restricted, repetitive patterns of behavior, interests, or activities domain. Furthermore, logistic regressions indicated that general developmental delay significantly contributed to the ASD diagnosis. The analyses relating the PMS genotype to the behavioral phenotype revealed additional complex relationships with contributions of genes in both deleted and preserved SHANK3 regions to the ASD phenotype and other neurobehavioral impairments. Conclusions: There appears to be a unique behavioral phenotype associated with ASD in individuals with PMS. There also appears to be contributions of genes in both deleted and preserved SHANK3 regions to the ASD phenotype and other neurobehavioral impairments. Better characterization of the behavioral phenotype using additional standardized assessments and further analyses exploring the relationship between the PMS genotype and behavioral phenotype in a larger sample are warranted. [ABSTRACT FROM AUTHOR]

Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from <50 kb to >9 Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8 Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS. [ABSTRACT FROM AUTHOR]

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by rearrangements on chromosome 22q13.3 or sequence variants in SHANK3. Individuals with PMS caused by a 22 q terminal deletion and a ring chromosome are at increased risk for Neurofibromatosis type 2 (NF2). However, the prevalence of NF2 in individuals with PMS and a r (22) is unknown. Individuals with PMS and a r (22) chromosome evaluated at the Greenwood Genetic Center (GGC) or by international collaborators, or identified through the PMS International Registry (PMSIR) were contacted and participated in a clinical questionnaire. Forty-four families completed the questionnaire and consented for the study. Of the individuals with a r (22), 7 (16%) carried a diagnosis of NF2. The average age of diagnosis of r (22) was 18 years old in individuals with NF2 and three years old in individuals without NF2 (p -value <0.001). Clinical findings were similar among all individuals in our sample with the exception of hearing loss, present in 57% of individuals with NF2 and 8% of individuals without NF2 (p -value <0.01). This is the largest clinical report of individuals with PMS and a r (22) chromosome. We show a diagnosis of NF2 in individuals with r (22) is not uncommon and may be under ascertained. Moreover, the presentation of NF2 in this cohort is variable and lifelong routine screening for features of NF2 in this population should be considered. • This report describes the largest cohort of individuals with PMS (PMS), r(22) chromosome and NF2. • In our cohort 16% (7 of 44 individuals) with r(22) developed an NF2-associated tumor. • The age of NF2-associated tumor diagnosis was variable and ranged from the second decade of life to the fifth. • This report supports conservative and lifelong MRI screening for NF2-related tumors in the PMS population with r(22). [ABSTRACT FROM AUTHOR]