Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder
CLINICAL GENETICS
Authors: Chaudhry, A.; Noor, A.; Degagne, B.; Baker, K.; Bok, L. A.; Brady, A. F.; Chitayat, D.; Chung, B. H.; Cytrynbaum, C.; Dyment, D.; Filges, I.; Helm, B.; Hutchison, H. T.; Jeng, L. J. B.; Laumonnier, F.; Marshall, C. R.; Menzel, M.; Parkash, S.; Parker, M. J.; Raymond, L. F.; Rideout, A. L.; Roberts, W.; Rupps, R.; Schanze, I.; Schrander-Stumpel, C. T. R. M.; Speevak, M. D.; Stavropoulos, D. J.; Stevens, S. J. C.; Thomas, E. R. A.; Toutain, A.; Vergano, S.; Weksberg, R.; Scherer, S. W.; Vincent, J. B.; Carter, M. T.
Abstract
Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.
The Emerging Role of SHANK Genes in Neuropsychiatric Disorders
DEVELOPMENTAL NEUROBIOLOGY
Authors: Guilmatre, Audrey; Huguet, Guillaume; Delorme, Richard; Bourgeron, Thomas
Abstract
The genetic heterogeneity of neuropsychiatric disorders is high, but some pathways emerged, notably synaptic functioning. A large number of mutations have been described in genes such as neuroligins, neurexins, and SHANK that play a role in the formation and the maintenance of synapses. This review focuses on the disorders associated with mutations in SHANK3 and the other members of its family, SHANK1 and SHANK2. SHANKs are scaffolding proteins of the postsynaptic density of glutamatergic synapses. SHANK3 has been described in the Phelan-McDermid syndrome (PMS), but also in autism spectrum disorders (ASD) and schizophrenia associated to moderate to severe intellectual disability (ID) and poor language. The evolution of patients with PMS includes symptoms of bipolar disorder and regression. SHANK2 has been identified in patients with ASD with mild to severe ID. SHANK1 has been associated with high-functioning autism in male patients, while carrier females only display anxiety and shyness. Finally, based on neuropathological findings in animal models and patients, a possible role of SHANK in Alzheimer's disease is discussed. Altogether, this review describes the clinical trajectories associated with different mutations of the SHANK genes and provides information to further investigate the role of the SHANK genes in neuropsychiatric disorders. (C) 2013 Wiley Periodicals, Inc.
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