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22q13 Deletion Syndrome

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Elena Parkhomenko – One of the best experts on this subject based on the ideXlab platform.

  • Prospective investigation of autism and genotype-phenotype correlations in 22q13 Deletion Syndrome and SHANK3 deficiency.
    Molecular Autism, 2013
    Co-Authors: Latha Soorya, Alexander Kolevzon, Yitzchak Frank, Jessica Zweifach, Teresa Lim, Yuriy Dobry, Lily Schwartz, Guiqing Cai, Ting Wang, Elena Parkhomenko

    Abstract:

    BACKGROUND: 22q13 Deletion Syndrome, also known as Phelan-McDermid Syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this Syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal to provide a comprehensive picture of the medical and behavioral profile of the Syndrome. METHODS: A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G. RESULTS: Thirty participants with 22q13.3 Deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger Deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small Deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features. CONCLUSIONS: This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the predominance of autism spectrum disorder in the Syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

  • Prospective investigation of autism and genotype-phenotype correlations in 22q13 Deletion Syndrome and SHANK3 deficiency.
    Molecular Autism, 2013
    Co-Authors: Latha Soorya, Alexander Kolevzon, Yitzchak Frank, Jessica Zweifach, Teresa Lim, Yuriy Dobry, Lily Schwartz, A. Ting Wang, Guiqing Cai, Elena Parkhomenko

    Abstract:

    Background
    22q13 Deletion Syndrome, also known as Phelan-McDermid Syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this Syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the Syndrome.

Sara M. Sarasua – One of the best experts on this subject based on the ideXlab platform.

  • Chapter 21 – Phelan–McDermid Syndrome: Clinical Aspects
    Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability, 2016
    Co-Authors: Katy Phelan, Luigi Boccuto, Sara M. Sarasua

    Abstract:

    Phelan–McDermid Syndrome (PMS), also known as the 22q13 Deletion Syndrome, is a genetic condition characterized by neonatal hypotonia, developmental delay, absent or impaired speech, and minor dysmorphic features. PMS typically results from a Deletion of the distal long arm of chromosome 22, with the size of the deleted segment ranging from less than 100 kb to greater than 9 MB. The loss of 22q13 may result from a terminal Deletion, an interstitial Deletion, an unbalanced translocation, formation of a ring chromosome, or other types of structural chromosome aberrations. In most cases, the Deletion results in haploinsufficiency for the SHANK3 gene which codes for a scaffolding protein in the postsynaptic density of excitatory neurons. Mutation or disruption of the SHANK3 gene may also result in PMS. The diagnosis of PMS relies on laboratory confirmation by molecular cytogenetic or molecular genetic methods.

  • Clinical and genomic evaluation of 201 patients with Phelan–McDermid Syndrome
    Human Genetics, 2014
    Co-Authors: Sara M. Sarasua, Katy Phelan, Luigi Boccuto, Julia L. Sharp, Alka Dwivedi, Chin-fu Chen, Jonathan D. Rollins, R. Curtis Rogers, Barbara R. Dupont

    Abstract:

    This study is the first to describe age-related changes in a large cohort of patients with Phelan–McDermid Syndrome (PMS), also known as 22q13 Deletion Syndrome. Over a follow-up period of up to 12 years, physical examinations and structured interviews were conducted for 201 individuals diagnosed with PMS, 120 patients had a focused, high-resolution 22q12q13 array CGH, and 92 patients’ Deletions were assessed for parent-of-origin. 22q13 genomic anomalies include terminal Deletions of 22q13 (89 %), terminal Deletions and interstitial duplications (9 %), and interstitial Deletions (2 %). Considering different age groups, in older patients, behavioral problems tended to subside, developmental abilities improved, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints were less frequent. However, the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age. Some neurologic and dysmorphic features such as speech and developmental delay and macrocephaly correlated with Deletion size. Deletion sizes in more recently diagnosed patients tend to be smaller than those diagnosed a decade earlier. Seventy-three percent of de novo Deletions were of paternal origin. Seizures were reported three times more often among patients with a de novo Deletion of the maternal rather than paternal chromosome 22. This analysis improves the understanding of the clinical presentation and natural history of PMS and can serve as a reference for the prevalence of clinical features in the Syndrome.

  • Clinical and genomic evaluation of 201 patients with Phelan-McDermid Syndrome.
    Human Genetics, 2014
    Co-Authors: Sara M. Sarasua, Katy Phelan, Luigi Boccuto, Julia L. Sharp, Alka Dwivedi, Chin-fu Chen, Jonathan D. Rollins, R. Curtis Rogers, Barbara R. Dupont

    Abstract:

    This study is the first to describe age-related changes in a large cohort of patients with Phelan–McDermid Syndrome (PMS), also known as 22q13 Deletion Syndrome. Over a follow-up period of up to 12 years, physical examinations and structured interviews were conducted for 201 individuals diagnosed with PMS, 120 patients had a focused, high-resolution 22q12q13 array CGH, and 92 patients’ Deletions were assessed for parent-of-origin. 22q13 genomic anomalies include terminal Deletions of 22q13 (89 %), terminal Deletions and interstitial duplications (9 %), and interstitial Deletions (2 %). Considering different age groups, in older patients, behavioral problems tended to subside, developmental abilities improved, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints were less frequent. However, the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age. Some neurologic and dysmorphic features such as speech and developmental delay and macrocephaly correlated with Deletion size. Deletion sizes in more recently diagnosed patients tend to be smaller than those diagnosed a decade earlier. Seventy-three percent of de novo Deletions were of paternal origin. Seizures were reported three times more often among patients with a de novo Deletion of the maternal rather than paternal chromosome 22. This analysis improves the understanding of the clinical presentation and natural history of PMS and can serve as a reference for the prevalence of clinical features in the Syndrome.

Alexander Kolevzon – One of the best experts on this subject based on the ideXlab platform.

  • Phelan-McDermid Syndrome: a review of the literature and practice parameters for medical assessment and monitoring.
    Journal of Neurodevelopmental Disorders, 2014
    Co-Authors: Alexander Kolevzon, Benjamin Angarita, Lauren Bush, A. T. Wang, Yitzchak Frank, Amy C. Yang, Robert Rapaport, Jeffrey M. Saland, Shubhika Srivastava, Cristina Farrell

    Abstract:

    Autism spectrum disorder (ASD) and intellectual disability (ID) can be caused by mutations in a large number of genes. One example is SHANK3 on the terminal end of chromosome 22q. Loss of one functional copy of SHANK3 results in 22q13 Deletion Syndrome or Phelan-McDermid Syndrome (PMS) and causes a monogenic form of ASD and/or ID with a frequency of 0.5% to 2% of cases. SHANK3 is the critical gene in this Syndrome, and its loss results in disruption of synaptic function. With chromosomal microarray analyses now a standard of care in the assessment of ASD and developmental delay, and with the emergence of whole exome and whole genome sequencing in this context, identification of PMS in routine clinical settings will increase significantly. However, PMS remains a rare disorder, and the majority of physicians have never seen a case. While there is agreement about core deficits of PMS, there have been no established parameters to guide evaluation and medical monitoring of the Syndrome. Evaluations must include a thorough history and physical and dysmorphology examination. Neurological deficits, including the presence of seizures and structural brain abnormalities should be assessed as well as motor deficits. Endocrine, renal, cardiac, and gastrointestinal problems all require assessment and monitoring in addition to the risk of recurring infections, dental and vision problems, and lymphedema. Finally, all patients should have cognitive, behavioral, and ASD evaluations. The objective of this paper is to address this gap in the literature and establish recommendations to assess the medical, genetic, and neurological features of PMS.

  • Prospective investigation of autism and genotype-phenotype correlations in 22q13 Deletion Syndrome and SHANK3 deficiency.
    Molecular Autism, 2013
    Co-Authors: Latha Soorya, Alexander Kolevzon, Yitzchak Frank, Jessica Zweifach, Teresa Lim, Yuriy Dobry, Lily Schwartz, Guiqing Cai, Ting Wang, Elena Parkhomenko

    Abstract:

    BACKGROUND: 22q13 Deletion Syndrome, also known as Phelan-McDermid Syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this Syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal to provide a comprehensive picture of the medical and behavioral profile of the Syndrome. METHODS: A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G. RESULTS: Thirty participants with 22q13.3 Deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger Deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small Deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features. CONCLUSIONS: This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the predominance of autism spectrum disorder in the Syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

  • Prospective investigation of autism and genotype-phenotype correlations in 22q13 Deletion Syndrome and SHANK3 deficiency.
    Molecular Autism, 2013
    Co-Authors: Latha Soorya, Alexander Kolevzon, Yitzchak Frank, Jessica Zweifach, Teresa Lim, Yuriy Dobry, Lily Schwartz, A. Ting Wang, Guiqing Cai, Elena Parkhomenko

    Abstract:

    Background
    22q13 Deletion Syndrome, also known as Phelan-McDermid Syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this Syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the Syndrome.