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De Novo SHANK3 Mutation Causes Rett Syndrome-Like Phenotype in a Female Patient

Published on Jul 1, 2015in American Journal of Medical Genetics Part A
· DOI :10.1002/AJMG.A.36775
Munetsugu Hara9
Estimated H-index: 9
,
Chihiro Ohba17
Estimated H-index: 17
(YCU: Yokohama City University)
+ 3 AuthorsToyojiro Matsuishi41
Estimated H-index: 41
(Kurume University)
Sources
Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability. © 2015 Wiley Periodicals, Inc.
  • References (17)
  • Citations (16)
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References17
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#1Chikako WagaH-Index: 6
#2Hirotsugu AsanoH-Index: 1
Last. Shigeo Uchino (Teikyo University)H-Index: 21
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SHANK3 is a synaptic scaffolding protein enriched in the post-synaptic density of excitatory synapses. Since several SHANK3 mutations have been identified in a particular phenotypic group of patients with autism spectrum disorder (ASD), SHANK3 is strongly suspected of being involved in the pathogenesis and neuropathology of ASD. Several SHANK3 isoforms are known to be produced in the developing brain, but they have not been fully investigated. Here, we identified two different amino-terminus tru...
15 CitationsSource
#1Catalina Betancur (French Institute of Health and Medical Research)H-Index: 49
#2Joseph D. Buxbaum (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 104
Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with Phelan-McDermid syndrome, caused by either deletion of 22q13.33 or SHANK3 mutations, using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. Th...
85 CitationsSource
#1Hirotomo Saitsu (YCU: Yokohama City University)H-Index: 43
#2Taki Nishimura (UTokyo: University of Tokyo)H-Index: 12
Last. Naomichi MatsumotoH-Index: 61
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Hirotomo Saitsu, Noboru Mizushima, Naomichi Matsumoto and colleagues report the identification of de novo mutations in WDR45 that cause static encephalopathy of childhood with neurodegeneration in adulthood. WDR45 encodes a homolog of the yeast autophagy protein Atg18.
273 CitationsSource
#1Luigi BoccutoH-Index: 16
#2Maria Lauri (UCSC: Catholic University of the Sacred Heart)H-Index: 1
Last. Charles E. SchwartzH-Index: 72
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Autism spectrum disorders (ASDs) include three main conditions: autistic disorder (AD), pervasive developmental disorder, not otherwise specified (PDD-NOS), and Asperger syndrome. It has been shown that many genes associated with ASDs are involved in the neuroligin–neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3. We screened this last gene in two cohorts of ASD patients (133 patients from US and 88 from Italy). We found 5/221 (2.3%) cases with pathogenic a...
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SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses, and plays important roles in the formation, maturation, and maintenance of synapses. Haploinsufficiency of the SHANK3 gene causes a developmental disorder, 22q13.3 deletion syndrome (known as Phelan–McDermid syndrome), that is characterized by severe expressive language and speech delay, hypotonia, global developmental delay, and autistic behavior. Since several SHANK3 mutations have been identi...
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Variants of SHANK3, a gene encoding a structural component of the postsynaptic density, have been associated with autism. Mice engineered to carry mutant genes showed autism-like behavioral features that included repetitive grooming and disinclination to socialize.
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#1João Peça (UC: University of Coimbra)H-Index: 9
#2Catia Feliciano (Duke University)H-Index: 5
Last. Guoping Feng (Broad Institute)H-Index: 65
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Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 d...
810 CitationsSource
#1Eric SmeetsH-Index: 1
#2Karine PelcH-Index: 8
Last. Bernard DanH-Index: 42
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#1Jeffrey L. Neul (BCM: Baylor College of Medicine)H-Index: 34
#2Walter E. Kaufmann (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 64
Last. Alan K. Percy (UAB: University of Alabama at Birmingham)H-Index: 51
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Objective Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatme...
631 CitationsSource
#1Alan K. Percy (UAB: University of Alabama at Birmingham)H-Index: 51
#2Jeffrey L. Neul (UAB: University of Alabama at Birmingham)H-Index: 34
Last. Katherine Barnes (UAB: University of Alabama at Birmingham)H-Index: 9
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The diagnosis of Rett syndrome, described by Andreas Rett in 19651 as a neurodevelopmental disorder predominantly affecting females, is based on clearly defined clinical criteria, modified periodically with improved understanding of its core features. In 1985, Hagberg and colleagues developed consensus criteria exclusively for females2, modified in 1988 to include males3. Following identification of mutations in the gene, Methyl-CpG-binding-protein 2 (MECP2), in individuals with RTT4, an interna...
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#1Mari Wold Henriksen (University of Oslo)H-Index: 2
#1Mari Wold Henriksen (Vestre Viken Hospital Trust)
Last. Ola H. Skjeldal (University of Gothenburg)H-Index: 19
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Abstract Background and purpose Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in MECP2. The diagnostic criteria of RTT are clinical; mutations in MECP2 are neither diagnostic nor necessary, and a mutation in another gene does not exclude RTT. We attempted to correlate genotype and phenotype to see if there are significant clinical associations. Methods All available females diagnosed with RTT in Norway were invited to the study. Parents were interviewed, the gir...
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#1Gali Heimer (TAU: Tel Aviv University)H-Index: 16
#2Geeske M. van Woerden (Erasmus University Medical Center)H-Index: 15
Last. Bruria Ben Zeev (TAU: Tel Aviv University)H-Index: 14
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We describe the underlying genetic cause of a novel Rett-like phenotype accompanied by areflexia in three methyl-CpG-binding protein 2-negative individuals from two unrelated families. Discovery analysis was performed using whole-exome sequencing followed by Sanger sequencing for validation and segregation. Functional studies using short-hairpin RNA for targeted gene knockdown were implemented by the transfection of mouse cultured primary hippocampal neurons and in vivo by in utero electroporati...
Source
#1E. S. Frankel (TGen: Translational Genomics Research Institute)
#2J. Dodson (TGen: Translational Genomics Research Institute)
Last. Sampath Rangasamy (TGen: Translational Genomics Research Institute)H-Index: 3
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Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms of Rett syndrome (RTT) in girls. Patients with features of classical Rett syndrome, but do not fulfill all the diagnostic criteria (e.g. absence of a MECP2 mutation), are defined as atypical Rett syndrome. Genes encoding for cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are more commonly found in patients with atypical Rett syndrome. Nevertheless, a subset of patients who are r...
Source
ABSTRACTCaring for a disabled child as a lone parent is complex and dynamic and can affect well-being significantly. Five single mothers caring for a daughter with Rett syndrome took photographs to...
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Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the MECP2 gene, the research community’s effort is focused on obtaining a better understanding of the genetics and the complex biology of...
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#1Kazuhiro Iwama (YCU: Yokohama City University)H-Index: 7
#2Takeshi Mizuguchi (YCU: Yokohama City University)H-Index: 22
Last. Naomichi Matsumoto (YCU: Yokohama City University)H-Index: 61
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Background Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 ( MECP2 ). Our objective to investigate the genetic landscape of MECP2 -negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). Methods We performed WES on 77 MECP2 -negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like p...
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#1Bitten Schönewolf-Greulich (Copenhagen University Hospital)H-Index: 4
#2A-M. Bisgaard (Copenhagen University Hospital)H-Index: 1
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The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing-based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett-like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett-like disorders wi...
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#1Ying Li (CSU: Central South University)H-Index: 7
#1Ying Li (CSU: Central South University)H-Index: 8
Last. Hui Guo (CSU: Central South University)H-Index: 4
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: SHANK3 has been identified as the causative gene of 22q13.3 microdeletion syndrome phenotype. De novo mutations (DNMs) of SHANK3 were subsequently identified in patients with several neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia (SCZ), a Rett syndrome-like phenotype, and intellectual disability (ID). Although broad developmental phenotypes of these patients have been described in single studies, few studies have reviewed the genotype and phenotype rela...
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#1Wendy A. Gold (Children's Hospital at Westmead)H-Index: 9
#2Rahul Krishnarajy (Children's Hospital at Westmead)H-Index: 1
Last. John Christodoulou (Children's Hospital at Westmead)H-Index: 52
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Rett syndrome (RTT) is a unique neurodevelopmental disorder that primarily affects females resulting in severe cognitive and physical disabilities. Despite the commendable collective efforts of the research community to better understand the genetics and underlying biology of RTT, there is still no cure. However, in the past 50 years, since the first report of RTT, steady progress has been made in the accumulation of clinical and molecular information resulting in the identification of a number ...
16 CitationsSource
#1Dejian Zhao (Albert Einstein College of Medicine)H-Index: 12
#2Ryan Mokhtari (Albert Einstein College of Medicine)H-Index: 4
Last. Herbert M. Lachman (Albert Einstein College of Medicine)H-Index: 16
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Background Rett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Although the behavioral phenotype appears to be primarily due to neuronal Mecp2 deficiency in mi...
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