Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations

Mg, Butler; Dasouki, MJ; Xp, Zhou; Talebizadeh, Zohreh; Brown, Michael D.; Tn, Takahashi; Jh, Miles; Ch, Wang; Stratton, Robert F.; Pilarski, Robert; Eng, Charis

doi:10.1136/jmg.2004.024646

Cited by 700 publications

(608 citation statements)

References 26 publications

(19 reference statements)

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“…Consistent with this view, the genes differentially expressed in cell lines of 16p11.2 600 kb BP4-BP5 carriers were enriched not only in pathways relevant to neurodevelopmental defects and ciliopathy but also in genes involved in phosphoinositide signaling. 22 Of note, germline variants in PTEN present the ASD, obesity, and macrocephaly triad of phenotypes, [66][67][68][69][70] whereas those in the Ras/MAPK signaling pathway are associated with social impairment. 71 The interactions observed at this cluster of genes, both at the chromatin and genetic level, suggest that the CNVprone non-overlapping loci at 16p11.2 should be approached and studied as ''connected regions'' rather than completely independent entities.…”

Section: Discussionmentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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Section: Discussionmentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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“…Autism with macrocephaly (also known as Cole-Hughes syndrome) is a monogenic form of autism with progressive postnatal macrocephaly [30][31][32]. Affected individuals can present with ID and language/social delays, as well as obesity, retarded bone growth, and facial anomalies [30,32].…”

Section: Autism With Macrocephalymentioning

confidence: 99%

“…The data in the pie chart are hypothetical to reflect a large number of individually rare loci identified in cases; the largest piece of the pie represents a majority of cases in whom a genetic mutation is still not identified phosphatase and tensin homologue protein on chromosome 10 (PTEN) [31,34,35]. Although reports of the exact incidence vary, it is estimated that between 5% and 17% of individuals with autism and macrocephaly carry a PTEN mutation [31,34]. PTEN is a tumor suppressor gene, and the PTEN protein functions as a dual-specificity phosphatase, capable of acting on both tyrosine and threonine/serine residues.…”

Section: Autism With Macrocephalymentioning

confidence: 99%

“…PTEN is a tumor suppressor gene, and the PTEN protein functions as a dual-specificity phosphatase, capable of acting on both tyrosine and threonine/serine residues. Although it is active within several pathways involving cell growth, cell cycle arrest, and apoptosis, one key function is inhibition of phosphoinositide 3-kinase/protein kinase B signaling [31,34,36].…”

Section: Autism With Macrocephalymentioning

confidence: 99%

“…In Cowden syndrome, these hamartomas frequently become malignant, and affected individuals present with macrocephaly, ID, and autistic traits [40]. Characteristic features of Bannayan-Riley-Ruvalcaba syndrome also include macrocephaly, ID, and autistic traits, as well as thyroiditis, vascular malformations, and delayed motor development [31,41].…”

Section: Autism With Macrocephalymentioning

confidence: 99%

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Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

et al. 2015

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Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

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Early Generalized Overgrowth in Boys With Autism

Chawarska

Campbell²,

Chen³

et al. 2011

Arch Gen Psychiatry

107

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Context Multiple studies have reported an overgrowth in head circumference (HC) in the first year of life in autism. However, it is unclear whether this phenomenon is independent of overall body growth and whether it is associated with specific social or cognitive features. Objectives To examine the trajectory of early HC growth in autism compared with control groups; to assess whether HC growth in autism is independent of height and weight growth during infancy; and to examine HC growth from birth to 24 months in relationship to social, verbal, cognitive, and adaptive functioning levels. Design Retrospective study. Setting A specialized university-based clinic. Participants Boys diagnosed as having autistic disorder (n=64), pervasive developmental disorder–not otherwise specified (n=34), global developmental delay (n=13), and other developmental problems (n=18) and typically developing boys (n=55). Main Outcome Measures Age-related changes in HC, height, and weight between birth and age 24 months; measures of social, verbal, and cognitive functioning at age 2 years. Results Compared with typically developing controls, boys with autism were significantly longer by age 4.8 months, had a larger HC by age 9.5 months, and weighed more by age 11.4 months (P=.05 for all). None of the other clinical groups showed a similar overgrowth pattern. Boys with autism who were in the top 10% of overall physical size in infancy exhibited greater severity of social deficits (P=.009) and lower adaptive functioning (P=.03). Conclusions Boys with autism experienced accelerated HC growth in the first year of life. However, this phenomenon reflected a generalized process affecting other morphologic features, including height and weight. The study highlights the importance of studying factors that influence not only neuronal development but also skeletal growth in autism.

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Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations

Cited by 700 publications

References 26 publications

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

Early Generalized Overgrowth in Boys With Autism

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