Strong evidence for genotype–phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium

Levy, Tess; Foss‐Feig, Jennifer H.; Betancur, Catalina; Siper, Paige M.; Trelles-Thorne, María del Pilar; Halpern, Danielle; Frank, Yitzchak; Lozano, Reymundo; Layton, Christina; Britvan, Bari; Bernstein, Jonathan A.; Buxbaum, Joseph D.; Berry‐Kravis, Elizabeth; Powell, Craig M.; Srivastava, Siddharth; Şahin, Mustafa; Soorya, Latha; Thurm, Audrey; Kolevzon, Alexander

doi:10.1093/hmg/ddab280

Cited by 41 publications

(70 citation statements)

References 51 publications

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“…We first detected a 3.7 Mb de novo interstitial microdeletion at chromosome 22q13.1–13.3 in the younger sister using CMA. Deletion at 22q13 is associated with Phelan–McDermid syndrome (PMS, OMIM#606232), a neurodevelopmental disorder characterized by moderate to profound intellectual disability, global developmental delay, delay or absence of speech development, ASD, and various behavioral problems [ 36 , 37 , 38 , 39 , 40 ]. Dysfunction of the SHANK3 gene is thought to be the primary cause of PMS [ 36 , 38 , 41 , 42 ], as patients with SHANK3 mutations manifest various neurodevelopmental and psychiatric conditions such as ID, ASD, and schizophrenia [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Huang

Fang

Kung

et al. 2022

JPM

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Intellectual disability (ID) and autism spectrum disorder (ASD) are complex neurodevelopmental disorders with high heritability. To search for the genetic deficits in two siblings affected with ID and ASD in a family, we first performed a genome-wide copy number variation (CNV) analysis using chromosomal microarray analysis (CMA). We found a 3.7 Mb microdeletion at 22q13.3 in the younger sister. This de novo microdeletion resulted in the haploinsufficiency of SHANK3 and several nearby genes involved in neurodevelopment disorders. Hence, she was diagnosed with Phelan–McDermid syndrome (PMS, OMIM#606232). We further performed whole-genome sequencing (WGS) analysis in this family. We did not detect pathogenic mutations with significant impacts on the phenotypes of the elder brother. Instead, we identified several rare, likely pathogenic variants in seven genes implicated in neurodevelopmental disorders: KLHL17, TDO2, TRRAP, EIF3F, ATP10A, DICER1, and CDH15. These variants were transmitted from his unaffected parents, indicating these variants have only moderate clinical effects. We propose that these variants worked together and led to the clinical phenotypes in the elder brother. We also suggest that the combination of multiple genes with moderate effects is part of the genetic mechanism of neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Huang

Fang

Kung

et al. 2022

JPM

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“…Per the categorization scheme outlined in a recent manuscript on associations between genotype and phenotype in PMS, we divided participants with deletions into two classes ( Levy et al, 2021 ). Class I was comprised of sequence variants as well as deletions including only SHANK3 , or the combination of SHANK3 with ARSA and/or ACR and RABL2B ( n = 11); these final three genes are not thought to contribute to the phenotype of PMS.…”

Section: Resultsmentioning

confidence: 99%

Neural Markers of Auditory Response and Habituation in Phelan-McDermid Syndrome

et al. 2022

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Phelan-McDermid Syndrome (PMS) is a rare genetic disorder caused by deletion or sequence variation in the SHANK3 gene at terminal chromosome 22 that confers high likelihood of comorbid autism spectrum disorder (ASD). Whereas individuals with idiopathic ASD (iASD) can demonstrate diverse patterns of sensory differences, PMS is mainly characterized by sensory hyporesponsiveness. This study used electrophysiology and a passive auditory habituation paradigm to test for neural markers of hyporesponsiveness. EEG was recorded from 15 individuals with PMS, 15 with iASD, and 16 with neurotypical development (NT) while a series of four consecutive 1,000 Hz tones was repeatedly presented. We found intact N1, P2, and N2 event-related potentials (ERPs) and habituation to simple auditory stimuli, both in individuals with iASD and in those with PMS. Both iASD and PMS groups showed robust responses to the initial tone and decaying responses to each subsequent tone, at levels comparable to the NT control group. However, in PMS greater initial N1 amplitude and habituation were associated with auditory hypersensitivity, and P2 habituation correlated with ASD symptomatology. Additionally, further classification of the PMS cohort into genetic groupings revealed dissociation of initial P2 amplitude and habituation of N1 based on whether the deletions included additional genes beyond solely SHANK3 and those not thought to contribute to phenotype. These results provide preliminary insight into early auditory processing in PMS and suggest that while neural response and habituation is generally preserved in PMS, genotypic and phenotypic characteristics may drive some variability. These initial findings provide early evidence that the robust pattern of behavioral hyporesponsiveness in PMS may be due, at least in audition, to higher order factors.

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“…An additional 30 participants were enrolled by partner sites through the Rare Disease Clinical Research Network Developmental Synaptopathies Consortium (DSC), as part of a PMS phenotyping and natural history study. For each participant, a comprehensive battery of standardized assessments, semi-structured interviews, and caregiver report questionnaires was used to examine medical comorbidities, intellectual and adaptive functioning, expressive and receptive language, ASD symptomatology, and behavioral comorbidities, as previously described 8 . Studies were approved by the Institutional Review Board (IRB) for the protection of human subjects at Mount Sinai (Study IDs: 98–0436, 10-0527, 12-1718) and Boston Children’s Hospital (Study ID: P00013300), which serves as the central IRB for the DSC.…”

Section: Methodsmentioning

confidence: 99%

“…The majority of reported cases of PMS are caused by large 22q13.3 deletions, which encompass additional genes and can extend up to 9.2 Mb [6][7][8][9] . Given the variable nature of the deletions, it is useful to classify PMS genotypes as either Class I mutations (including SHANK3 sequence variants or deletions in SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), or Class II mutations (all other deletions) 8 .…”

Section: Introductionmentioning

confidence: 99%

“…Given the variable nature of the deletions, it is useful to classify PMS genotypes as either Class I mutations (including SHANK3 sequence variants or deletions in SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B ), or Class II mutations (all other deletions) 8 . The largest genotype-phenotype association analysis indicates that PMS participants with Class II mutations display increased rates of early developmental delays, intellectual disability, minimally verbal status, and various medical features 8 . Notably, individuals with Class I mutations attained more advanced developmental milestones, which were reached at a younger age compared to those with Class II mutations, and were more likely to exhibit higher language and communication skills 8 .…”

Section: Introductionmentioning

confidence: 99%

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Large deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

Breen

Fan

Levy

et al. 2022

Preprint

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Background: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused at least in part by haploinsufficiency of the SHANK3 gene, due to sequence variants in SHANK3 or subtelomeric 22q13.3 deletions. Divergent phenotypic profiles have been reported between PMS participants with Class I mutations, defined as sequence variants or small deletions, including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B, and those with Class II mutations, defined as those with larger 22q13.3 deletions. The molecular perturbations that underlie these divergent phenotypes remain poorly understood. Methods: Peripheral blood transcriptomic profiling was performed across 68 PMS participants, including Class I mutations (n=33) and Class II mutations (n=35), as well as an age and sex matched control group (n=24). In parallel, global serum metabolomic profiling was carried out across a subset of 25 participants, comprised of Class I mutations (n=11), Class II mutations (n=14), and an age and sex matched control group (n=29). Results: Transcriptomic data revealed 52 blood expressed genes on 22q13.3 with expression profiles that scaled with the size of Class II mutations, including expression for genes ARSA, BRD1 and RPP7A. Further analyses uncovered 208 under-expressed genes and 42 over-expressed genes in participants with Class II mutations relative to unaffected controls, which were unchanged in PMS participants with Class I mutations. These genes were not linked to 22q13.3, and under-expressed genes were strongly enriched for glycosphingolipid metabolism, NCAM1 interactions and cytotoxic immune cell signatures. Reductions in proportions of CD56+ CD16- natural killer cells in Class II mutations were confirmed by mass cytometry time of flight. Global metabolomics profiling identified 24 metabolites that were significantly altered with PMS participants with Class II mutations, and featured a general reduction in sphingolipid metabolism. Conclusions: Our results provide evidence for transcriptomic and metabolomic perturbations in the peripheral circulation of PMS participants with Class II mutations that implicate reduced frequency and expression of natural killer cells and related signatures and lower sphingolipid metabolism. These findings are a valuable resource for future studies examining peripheral biomarkers and immuno-genetics of PMS and other rare disorders.

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Strong evidence for genotype–phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium

Cited by 41 publications

References 51 publications

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Neural Markers of Auditory Response and Habituation in Phelan-McDermid Syndrome

Large deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

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