Position effects of 22q13 rearrangements on candidate genes in Phelan-McDermid syndrome.
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ABSTRACT:
SUBMITTER: Srikanth S
PROVIDER: S-EPMC8259982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chromosome 22q13.3 deletion (Phelan McDermid) syndrome (PMS) is a rare genetic neurodevelopmental disorder resulting from deletions or other genetic variants on distal 22q. Pathological variants of the SHANK3 gene have been identified, but terminal chromosomal deletions including SHANK3 are most common. Terminal deletions disrupt up to 108 protein-coding genes. The impact of these losses is highly variable and includes both significantly impairing neurodevelopmental and somatic manifestations. The current review combines two metrics, prevalence of gene loss and predicted loss pathogenicity, to identify likely contributors to phenotypic expression. These genes are grouped according to function as follows: molecular signaling at glutamate synapses, phenotypes involving neuropsychiatric disorders, involvement in multicellular organization, cerebellar development and functioning, and mitochondrial. The likely most impactful genes are reviewed to provide information for future clinical and translational investigations.
| S-EPMC5838980 | biostudies-literature
Project description: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.
| S-EPMC10048319 | biostudies-literature
Project description:Phelan-McDermid syndrome (PMS, OMIM #606232), also known as chromosome 22q13 deletion syndrome, is a rare genetic disorder characterized by intellectual disability, hypotonia, delayed or absent speech, motor impairment, autism spectrum disorder, behavioral anomalies, and minor aspecific dysmorphic features. Haploinsufficiency of SHANK3, due to intragenic deletions or point mutations, is sufficient to cause many neurobehavioral features of PMS. However, several additional genes located within larger 22q13 deletions can contribute to the great interindividual variability observed in the PMS phenotype. This review summarizes the phenotypic contributions predicted for 213 genes distributed along the largest 22q13.2-q13.33 terminal deletion detected in our sample of 63 PMS patients by array-CGH analysis, spanning 9.08 Mb. Genes have been grouped into four categories: (1) genes causing human diseases with an autosomal dominant mechanism, or (2) with an autosomal recessive mechanism; (3) morphogenetically relevant genes, either involved in human diseases with additive co-dominant, polygenic, and/or multifactorial mechanisms, or implicated in animal models but not yet documented in human pathology; (4) protein coding genes either functionally nonrelevant, with unknown function, or pathogenic through mechanisms other than haploinsufficiency; piRNAs, noncoding RNAs, miRNAs, novel transcripts and pseudogenes. Our aim is to understand genotype-phenotype correlations in PMS patients and to provide clinicians with a conceptual framework to promote evidence-based genetic work-ups, clinical assessments, and therapeutic interventions.
| S-EPMC8251815 | biostudies-literature
Project description:Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS. However, it is still unclear to what extent SHANK3 deletions contribute to the PMS phenotype, and what other genes nearby are causal to the neurologic disease. In an effort to better understand the functional landscape of the PMS region during normal neurodevelopment, we assessed RNA-sequencing (RNA-seq) expression data collected from post-mortem brain tissue from developmentally normal subjects over the course of prenatal to adolescent age and analyzed expression changes of 65 genes on 22q13. We found that the majority of genes within this region were expressed in the brain, with ATNX10, MLC1, MAPK8IP2, and SULT4A1 having the highest overall expression. Analysis of the temporal profiles of the highest expressed genes revealed a trend towards peak expression during the early post-natal period, followed by a drop in expression later in development. Spatial analysis revealed significant region specific differences in the expression of SHANK3, MAPK8IP2, and SULT4A1. Region specific expression over time revealed a consistently unique gene expression profile within the cerebellum, providing evidence for a distinct developmental program within this region. Exon-specific expression of SHANK3 showed higher expression within exons contributing to known brain specific functional isoforms. Overall, we provide an updated roadmap of the PMS region, implicating several genes and time periods as important during neurodevelopment, with the hope that this information can help us better understand the phenotypic heterogeneity of PMS.
| S-EPMC6420160 | biostudies-literature
Project description:In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.
| S-EPMC3136441 | biostudies-other
Project description:INTRODUCTION:Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS. METHODS:Following the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with SHANK3 deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism. RESULTS:WGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microhomology-mediated insertion of partial Alu-elements at one breakpoint junction disrupted the topological associating domain joining NFAM1 to the transcriptional coregulator TCF20. WES failed to detect BPP-associated variants. CONCLUSIONS:Although we were unable to highlight the molecular basis of BPP, our data suggest that SHANK3 haploinsufficiency and TCF20 misregulation, both associated with intellectual disability, contributed to the patient's NDD, while NFAM1 interruption likely caused her skin rashes, as previously reported. We provide the first example of chromoanasynthesis in a constitutional ring chromosome and reinforce the growing evidence that chromosomal rearrangements may be more complex than estimated by conventional diagnostic approaches and affect the phenotype by global alteration of the topological chromatin organisation rather than simply by deletion or duplication of dosage-sensitive genes.
| S-EPMC5869459 | biostudies-literature
Project description:ObjectiveThe aim of the study was to evaluate gastrointestinal symptoms and continence in the context of Phelan-McDermid Syndrome (PMS).MethodsA prospective evaluation of children with PMS (n = 17) at the National Institutes of Health.ResultsParent-reported history of symptoms were common: constipation (65%), reflux (59%), choking/gagging (41%), and more than half received gastrointestinal specialty care. No aspiration was noted in 11/11 participants who completed modified barium swallows. Four participants met criteria for functional constipation, 2 of whom had abnormal colonic transit studies. Stool incontinence was highly prevalent (13/17) with nonretentive features present in 12/17. Participants who were continent had significantly smaller genetic deletions (P = 0.01) and higher nonverbal mental age (P = 0.03) compared with incontinent participants.ConclusionsIncontinence is common in PMS and associated with intellectual functioning and gene deletion size. Management strategies may differ based on the presence of nonretentive fecal incontinence, functional constipation, and degree of intellectual disability for children with PMS.
| S-EPMC6658348 | biostudies-literature
Project description:The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a contiguous gene disorder resulting from deletion of the distal long arm of chromosome 22. In addition to normal growth and a constellation of minor dysmorphic features, this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia. In addition, more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD). The differential diagnosis includes Angelman syndrome, velocardiofacial syndrome, fragile X syndrome, and FG syndrome. Over 600 cases of 22q13.3 deletion syndrome have been documented. Most are terminal deletions of ∼100 kb to >9 Mb, resulting from simple deletions, ring chromosomes, and unbalanced translocations. Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton. Two mouse knockout models and cell culture experiments show that SHANK3 is involved in the structure and function of synapses and support the hypothesis that the majority of 22q13.3 deletion syndrome neurological defects are due to haploinsufficiency of SHANK3, although other genes in the region may also play a role in the syndrome. The molecular connection to ASD suggests that potential future treatments may involve modulation of metabotropic glutamate receptors.
| S-EPMC3366702 | biostudies-literature
Project description:Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
| S-EPMC5677962 | biostudies-literature
Project description:Phelan-McDermid syndrome (PMS), also called 22q13.3 deletion syndrome, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, severe speech delays, poor motor tone and function, and autism spectrum disorder (ASD). Although the overall prevalence of PMS is unknown, there have been at least 1200 cases reported worldwide, according to the Phelan-McDermid Syndrome Foundation. PMS is now considered to be a relatively common cause of ASD and intellectual disability, accounting for between 0.5% and 2.0% of cases. The cause of PMS has been isolated to loss of function of one copy of SHANK3, which codes for a master scaffolding protein found in the postsynaptic density of excitatory synapses. Reduced expression of SH3 and multiple ankyrin repeat domains 3 (SHANK3) leads to reduced numbers of dendrites, and impaired synaptic transmission and plasticity. Recent mouse and human neuronal models of PMS have led to important opportunities to develop novel therapeutics, and at least 2 clinical trials are underway, one in the USA, and one in the Netherlands. The SHANK3 pathway may also be relevant to other forms of ASD, and many of the single-gene causes of ASD identified to date appear to converge on several common molecular pathways that underlie synaptic neurotransmission. As a result, treatments developed for PMS may also affect other forms of ASD.
| S-EPMC4489957 | biostudies-literature