Genotype–phenotype correlation in <scp>Phelan‐McDermid</scp> syndrome: A comprehensive review of chromosome 22q13 deleted genes

Ricciardello, Arianna; Tomaiuolo, Pasquale; Persico, Antonio M.

doi:10.1002/ajmg.a.62222

Cited by 35 publications

(51 citation statements)

References 103 publications

(276 reference statements)

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“…Renal abnormalities were one of the most striking differences in our cohort (0% in Class I and sequence variants vs. 24% in Class II deletions), indicating that the renal abnormalities seen in PMS are not due to haploinsufficiency of SHANK3 . Recent literature has suggested CELSR1 as a candidate for the renal abnormalities seen in PMS ( 24 , 39 ). Among the individuals with renal abnormalities in our cohort ( n = 20), 16 had CELSR1 deleted.…”

Section: Discussionmentioning

confidence: 99%

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

Levy

Foss‐Feig

Betancur

et al. 2021

Human Molecular Genetics

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Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive, and behavioral abnormalities. Previous literature has begun to elucidate genotype–phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype–phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (include SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions), or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype–phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories, and comorbidities as a function of specific genetic alteration.

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Section: Discussionmentioning

confidence: 99%

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

Levy

Foss‐Feig

Betancur

et al. 2021

Human Molecular Genetics

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“…[3][4][5] Although SHANK3 haploinsufficiency resulting from pathogenic mutations 6 or deletions [7][8][9] have been associated with PMS characteristics, there have also been numerous studies where genes other than SHANK3 have been demonstrated to play contributory roles toward PMS symptoms. [8][9][10][11][12][13] The literature illustrates inconsistencies and gaps of knowledge about seizures in PMS, despite their relatively high frequency and significant clinical burden. Treatment guidelines for PMS include supportive care and management of comorbidities such as seizures.…”

mentioning

confidence: 99%

Genetic and metabolic profiling of individuals with Phelan‐McDermid syndrome presenting with seizures

et al. 2021

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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.

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“…He was a carrier of a 25 kB duplication of the 9q34.3 chromosomal region that included NOTCH1 . Subjects with Phelan–McDermid syndrome usually appear to develop puberty at normal times [ 66 ]. NOTCH1 duplication may have caused the early onset of puberty in this patient.…”

Section: Clinical Evidence Demonstrates That Pubertal Onset May Be As...mentioning

confidence: 99%

Aberrant Notch Signaling Pathway as a Potential Mechanism of Central Precocious Puberty

Shim

Lee

Hwang

2022

IJMS

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The Notch signaling pathway is highly conserved during evolution. It has been well documented that Notch signaling regulates cell proliferation, migration, and death in the nervous, cardiac, and endocrine systems. The Notch pathway is relatively simple, but its activity is regulated by numerous complex mechanisms. Ligands bind to Notch receptors, inducing their activation and cleavage. Various post-translational processes regulate Notch signaling by affecting the synthesis, secretion, activation, and degradation of Notch pathway-related proteins. Through such post-translational regulatory processes, Notch signaling has versatile effects in many tissues, including the hypothalamus. Recently, several studies have reported that mutations in genes related to the Notch signaling pathway were found in patients with central precocious puberty (CPP). CPP is characterized by the early activation of the hypothalamus–pituitary–gonadal (HPG) axis. Although genetic factors play an important role in CPP development, few associated genetic variants have been identified. Aberrant Notch signaling may be associated with abnormal pubertal development. In this review, we discuss the current knowledge about the role of the Notch signaling pathway in puberty and consider the potential mechanisms underlying CPP.

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Genotype–phenotype correlation in Phelan‐McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes

Cited by 35 publications

References 103 publications

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

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

Genetic and metabolic profiling of individuals with Phelan‐McDermid syndrome presenting with seizures

Aberrant Notch Signaling Pathway as a Potential Mechanism of Central Precocious Puberty

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