Search Results (34)

Objectives: To characterize the clinical and genetic features of Phelan–McDermid syndrome (PMS) in a Chinese prenatal and postnatal cohort, explore genotype–phenotype correlations, and provide evidence to support prenatal genetic counseling. Methods: G-banded karyotyping, single-nucleotide polymorphism arrays (SNP arrays), copy number variation sequencing, and trio whole-exome sequencing were used for genetic diagnosis. Fifteen patients with PMS (11 prenatal and 4 postnatal) were retrospectively enrolled. Genomic visualization, protein structural prediction, and phenotypic heatmap analyses were conducted to analyze genotype–phenotype associations. Results: The prenatal and postnatal detection rates of PMS were 0.061% and 0.49%, respectively. Only 13.3% of cases were detected by karyotyping, whereas 14 cases were confirmed by SNP array analysis. All 22q13 deletions (69.4 kb–8.5 Mb) involved SHANK3, and all copy number variants were de novo. A novel SHANK3 frameshift variant, c.3513_3514delCC, was identified and predicted to result in protein truncation leading to intellectual disability. Prenatal cases mainly presented non-specific ultrasound anomalies (63.6%, 7/11), with fetal growth restriction, renal malformations, and cardiovascular defects being the most frequent findings. A notable 36.4% (4/11) of prenatal cases were complicated by missed abortion, whereas postnatal patients showed predominant neurodevelopmental impairments. In our cohort, larger deletions were observed in cases presenting with more extensive multisystem involvement, a pattern that mirrors findings from recent large-cohort studies. central nervous system abnormalities were predominantly linked to SHANK3 haploinsufficiency, while multi-system malformations seemed to correlate with the cumulative loss of multiple genes across the 22q13 region, in keeping with current hypotheses on contiguous gene effects. Conclusions: PMS presents obvious prenatal–postnatal phenotypic heterogeneity. SHANK3 is the core pathogenic gene, and deletion may influence the extent of multisystem involvement. Combined genetic testing can improve the accuracy of prenatal diagnosis and counseling for PMS. Full article

Objectives and Background: Individuals with Phelan–McDermid Syndrome (PMS) present with a variety of symptoms, including a breadth of behavioral issues. Clinically assessing behavior in PMS remains challenging due to the overabundance of behavioral assessments and the lack of tools validated explicitly for use in individuals with intellectual disability (ID) and neurodevelopmental disorders. This review sought to suggest which assessment tools would best clinically assess behavior in individuals with PMS. Methods: Validated behavioral assessment tools were identified using a systematic search of the literature, and relevant data for each assessment were extracted. The consensus guidelines for PMS were reviewed. Results: This review identified 131 validated assessment tools that were categorized by the intended age group and into specific behavioral domains: Autism spectrum disorder (ASD) screening, adaptive behavior, restricted and repetitive behaviors, challenging/disruptive behaviors, mental health screening, and other miscellaneous behaviors such as avoidance and impulsivity. Discussion: Based on the 2023 consensus guidelines, suggestions were given on which tools would be best for assessing various symptoms and behaviors in PMS. Choosing the best assessment tools to appraise behavior and related symptoms in individuals with PMS will aid clinicians in decision-making and lead to more personalized treatment plans. Full article

Background/Objectives: Phelan–McDermid syndrome (PMS), caused by either chromosome 22q13.3 deletions or pathogenic/likely pathogenic variants in the SHANK3 gene, is a rare neurodevelopmental disorder. Behavioral issues greatly impair the quality of life for affected individuals and their families. This genotype–phenotype study intended to further characterize key behavioral features and their genetic and metabolic correlates in PMS. Methods: We conducted a cross-sectional analysis of data on 56 individuals with PMS. Autistic and related behaviors were assessed with the Autism Diagnosis Interview—Revised (ADI-R) and adaptive behavior skills were assessed with the Vineland Adaptive Behavior Scales-Third Edition (Vineland-3), both covering multiple aspects of communication, socialization and abnormal behaviors. Genetic diagnostic information on deletions or pathogenic variants was supplemented with the sequencing data of nine candidate genes on 22q13.3. Metabolic data were obtained using the Biolog Phenotype Mammalian MicroArray plates (PM-M). Results. Every subject in the cohort presented either prominent autistic behavior or adaptive behavior impairment, 55.4% of them meeting the ASD cutoff in every ADI-R domain and 92.9% scoring in the lowest level of adaptive behavior (range of 20–70). Individuals with SHANK3 variants had lower adaptive behavioral skills than those with 22q13 deletions regardless of deletion size, while genomic parameters were largely unrelated to ADI-R scores. Metabolic profiling identified unique profiles of individuals with PMS compared with controls, while distinct profiles distinguished those who met or did not meet the ADI-R ASD cutoff. Cluster analyses revealed groups of individuals with ASD and other clinical features. Conclusion. This study highlighted the importance of SHANK3 in adaptive behavioral skills and uncovered potential metabolic biomarkers of therapeutic relevance. Full article

We present a family case study of Phelan–McDermid syndrome (PMS), a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene, in which two of three siblings were clinically diagnosed with PMS. Sanger sequencing identified a novel heterozygous deletion in exon 20 of SHANK3 (c.3679del, p.Ala1227Profs*168), predicted to introduce a premature stop codon and truncate the protein; this variant was absent in the unaffected sibling. Auditory steady-state responses (ASSRs) were recorded at 16, 27, and 40 Hz. The 40 Hz ASSR was markedly reduced in both affected siblings, reaching statistical significance in the younger child and remaining non-significant in the older sibling, while it was preserved in the unaffected sibling. These findings suggest that the 40 Hz ASSR is particularly sensitive to SHANK3-related cortical inhibitory dysfunction during childhood and adolescence, with reduced sensitivity in early adulthood. The results highlight the potential of the 40 Hz ASSR as an electrophysiological biomarker in PMS and underscore the need for age-stratified normative control datasets to enable robust individual-level interpretation and support its use in biomarker development, clinical trial stratification, and monitoring of treatment response. Full article

Background: Phelan–McDermid syndrome (PMS), caused by SHANK3 variants or 22q13.3 deletions, often includes systemic features such as gastrointestinal and hepatic abnormalities. This study highlights the overlap between PMS and metabolic-associated steatotic liver disease (MASLD), focusing on PNPLA3 variants and underscoring the need for structured metabolic monitoring. Methods: We describe a 25-year-old male with PMS due to a 22q13.33 microdeletion involving SHANK3. He exhibited developmental delay, seizures, and hypotonia. Genetic testing revealed homozygosity for the PNPLA3 p.I148M variant. Clinical, anthropometric, biochemical, imaging, and metabolic investigations were performed, including liver ultrasound and metabolic profiling of lymphoblastoid cell lines. Results: Ultrasound revealed moderate hepatic steatosis consistent with MASLD. After ursodeoxycholic acid treatment and a Mediterranean-style diet, steatosis improved to mild. Metabolic profiling demonstrated increased nicotinamide adenine dinucleotide generation under metabolic stimuli, suggesting altered energy homeostasis. Conclusions: We highlight the contribution of PNPLA3 to MASLD in PMS and support systematic hepatic monitoring. Genotype–phenotype associations in PMS may provide insights relevant to MASLD research and clinical management. Full article

Background: The coexistence of sickle cell disease (SCD), vascular Ehlers–Danlos syndrome (vEDS), primary ciliary dyskinesia (PCD), and Phelan–McDermid syndrome (PMS) in a single pediatric patient is extremely rare and poses substantial diagnostic and management challenges. Case presentation: We report an 8-year-old male from Jazan, Saudi Arabia, born to consanguineous parents, with early-onset SCD, followed by the identification of vEDS, PCD, and PMS through clinical presentation and whole exome sequencing. His disease course has been exceptionally severe, marked by monthly hospitalizations, multiple PICU admissions, and a wide spectrum of systemic complications. Conclusions: The coexistence of SCD, vEDS, PCD, and PMS may lead to synergistic vascular, pulmonary, and neurodevelopmental compromise, demanding multidisciplinary long-term management. This case underscores the need for a comprehensive targeted genetic assessment in patients with unusually aggressive or syndromic SCD phenotypes, particularly in regions with high levels of consanguineous marriages. Full article

Phelan–McDermid syndrome (PMS; #MIM: 606232) is a rare neurodevelopmental disorder primarily caused by the haploinsufficiency of the SHANK3 gene, most often due to deletions encompassing the gene or single nucleotide variants within it. Individuals with PMS display a wide range of clinical abnormalities and considerable genetic heterogeneity. This study aims to investigate genotype–phenotype correlations in a cohort of 213 individuals with PMS and to identify novel candidate genes, beyond SHANK3, that may contribute to the syndrome’s diverse clinical manifestations. Unsupervised clustering based on deletion size and Global Functional Assessment of the Patient (GFAP, previously described and developed by our group), along with additional analytical approaches, were employed to explore genotype–phenotype relationships. Deletion size within the 22q13.3 region emerged as a major determinant of phenotype, with larger deletions associated with more severe global functional impairment. Furthermore, CERK, TBC1D22A, CELSR1, and GRAMD4 were identified as candidate genes within 22q13.3, potentially contributing to core PMS phenotypes, and their putative interactions were explored. Our findings support the central role of SHANK3 in PMS, while also indicating that it does not account for the full phenotypic spectrum. This study underscores the variable impact of distinct genetic alterations in PMS and proposes additional loci implicated in its pathogenesis. These insights may inform future therapeutic strategies, emphasizing the importance of patient stratification and precision medicine. Full article

Phelan–McDermid syndrome (PMS) is a rare genetic disorder primarily caused by deletions or structural alterations of chromosome 22q13, often involving the SHANK3 gene. However, mutations in other genes, such as CELSR1, or deletions in the interstitial regions of 22q13 contribute to the phenotypic variability of PMS. The syndrome is characterized by developmental delay, cognitive impairment, absent or significant impairment speech, autism spectrum disorder (ASD), and distinctive craniofacial features. Lymphedema, present in 10–25% of cases, typically affects peripheral regions, while facial involvement has not been documented to date. Orofacial manifestations frequently include dolichocephaly, widely spaced eyes, prominent ears, and dysmorphic features, such as a bulbous nose and arched palate. This scoping review analyzed seven studies on orofacial features associated with PMS, highlighting a higher phenotypic variability, with frequent findings of intellectual disability, hypotonia, and craniofacial dysmorphisms. Genomic analyses identified consistent deletions in 22q13.31–q13.33 and complex genomic rearrangements. This review, through the report of the first documented case of hemifacial lymphedema in the literature, analyzes the facial features of patients with PMS and their genetic origins. It also highlights the importance of interdisciplinary collaboration and inclusive genetic testing to better define the phenotypic spectrum of this syndrome. A deeper understanding of the genetic and clinical characteristics of PMS can facilitate early diagnosis and personalized management for these patients. Full article

Phelan–McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by a developmental delay and autism spectrum disorder (ASD)-like behaviors. Emerging research suggests a link between gut microbiota and neuropsychiatric conditions, including PMS. This study aimed to investigate the fecal microbiota and immune profiles of children with PMS compared to healthy controls. Fecal samples were collected from children diagnosed with PMS and age-matched healthy controls. The bacterial composition was analyzed using 16S rRNA gene sequencing, while short-chain fatty acids (SCFAs) were quantified through gas chromatography. Immunological profiling was conducted using a multiplex cytokine assay. Significant differences were observed in the gut microbiota composition between PMS patients and controls, including a lower abundance of key bacterial genera such as Faecalibacterium and Agathobacter in PMS patients. SCFA levels were also reduced in PMS patients. Immunological analysis revealed higher levels of several pro-inflammatory cytokines in the PMS group, although these differences were not statistically significant. The findings indicate that children with PMS have distinct gut microbiota and SCFA profiles, which may contribute to the gastrointestinal and neurodevelopmental symptoms observed in this syndrome. These results suggest potential avenues for microbiota-targeted therapies in PMS. Full article

Cytosolic sulfotransferases (SULTs) are Phase 2 drug-metabolizing enzymes that catalyze the conjugation of sulfonate to endogenous and xenobiotic compounds, increasing their hydrophilicity and excretion from cells. To date, 13 human SULTs have been identified and classified into five families. SULT4A1 mRNA encodes two variants: (1) the wild type, encoding a 284 amino acid, ~33 kDa protein, and (2) an alternative spliced variant resulting from a 126 bp insert between exon 6 and 7, which introduces a premature stop codon that enhances nonsense-mediated decay. SULT4A1 is classified as an SULT based on sequence and structural similarities, including PAPS-domains, active-site His, and the dimerization domain; however, the catalytic pocket lid ‘Loop 3’ size is not conserved. SULT4A1 is uniquely expressed in the brain and localized in the cytosol and mitochondria. SULT4A1 is highly conserved, with rare intronic polymorphisms that have no outward manifestations. However, the SULT4A1 haplotype is correlated with Phelan–McDermid syndrome and schizophrenia. SULT4A1 knockdown revealed potential SULT4A1 functions in photoreceptor signaling and knockout mice display hampered neuronal development and behavior. Mouse and yeast models revealed that SULT4A1 protects the mitochondria from endogenously and exogenously induced oxidative stress and stimulates cell division, promoting dendritic spines’ formation and synaptic transmission. To date, no physiological enzymatic activity has been associated with SULT4A1. Full article

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. Full article

Background: Phelan–McDermid syndrome (PMS) is caused by the loss (deletion) of a small portion of chromosome 22 in a region designated q13.3 (22q13.3 deletion). PMS is one of the most common genetic forms of autism spectrum disorder (ASD) in which sensory reactivity difficulties have been described on limited occasions. Methods: The objective of this study is to identify whether changes in sensory reactivity skills occur after one year of follow-up in a group of 44 participants diagnosed with PMS. All participants completed the Short Sensory Profile (SSP). Two-factor ANOVA tests were performed with repeated measures for the study of the evolution of the scores. Results: Participants with PMS showed significant changes after one year of follow-up in sensory reactivity skills associated with tactile hyperreactivity (p = 0.003). The rest of the study variables did not show significant differences compared to the baseline assessment, showing definite differences associated with patterns of hypo-responsiveness and sensory seeking, low/weak energy, and difficulties in auditory filtering. Conclusions: Understanding the evolution of sensory reactivity skills can facilitate the adjustment to behavioral changes in people with PMS and design-targeted interventions to address sensory reactivity challenges. Full article

Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene–protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed. Full article

Phelan-McDermid syndrome is an inherited global developmental disorder commonly associated with autism spectrum disorder. Due to a significantly increased radiosensitivity, measured before the start of radiotherapy of a rhabdoid tumor in a child with Phelan-McDermid syndrome, the question arose whether other patients with this syndrome also have increased radiosensitivity. For this purpose, the radiation sensitivity of blood lymphocytes after irradiation with 2Gray was examined using the G0 three-color fluorescence in situ hybridization assay in a cohort of 20 patients with Phelan-McDermid syndrome from blood samples. The results were compared to healthy volunteers, breast cancer patients and rectal cancer patients. Independent of age and gender, all but two patients with Phelan-McDermid syndrome showed significantly increased radiosensitivity, with an average of 0.653 breaks per metaphase. These results correlated neither with the individual genetic findings nor with the individual clinical course, nor with the respective clinical severity of the disease. In our pilot study, we saw a significantly increased radiosensitivity in lymphocytes from patients with Phelan-McDermid syndrome, so pronounced that a dose reduction would be recommended if radiotherapy had to be performed. Ultimately, the question arises as to the interpretation of these data. There does not appear to be an increased risk of tumors in these patients, since tumors are rare overall. The question, therefore, arose as to whether our results could possibly be the basis for processes, such as aging/preaging, or, in this context, neurodegeneration. There are no data on this so far, but this issue should be pursued in further fundamentally based studies in order to better understand the pathophysiology of the syndrome. Full article

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. Full article