Self-injurious behavior (SIB) is among the most serious conditions affecting individuals with intellectual disability (ID). It is characterized by production of physical injury to the individual's own body, resulting in tissue damage [1]. The most common topographies of SIB include head banging, self-biting, eye poking, selfscratching, hair pulling, and self-hitting. While definitive epidemiological studies have not yet been performed [2], the prevalence of SIB is estimated at 5 to 32% of persons with ID or autism spectrum disorder (ASD) [3-7]. Chronic SIB is associated with medical complications, restricted educational, vocational, and social opportunities, residential or institutional placement and poor long-term outcome [8]. In severe cases, SIB may produce permanent tissue damage or in extreme cases, death. Thus, SIB often has devastating adverse impacts on child health, family functioning, and quality of life. With the recent emergence of both single nucleotide polymorphism (SNP) arrays and next-generation sequencing, it has become possible to determine the genetic basis of a series of clinical disorders. Recent studies suggest a substantial contribution to ID risk from de novo copy number variants (CNVs) such as those measured using SNP arrays;from de novo single nucleotide variants (SNVs) such as those identified from whole exome sequencing of father/mother/child trios;and from rare complete (homozygous) knockouts. We propose to determine genetic contributions to SIB when it occurs in individuals with unknown etiology, hypothesizing that we will see significant genetic contribution to their clinical phenotypes, given the extreme severity of their disability and clinical profile. Because the vast majority of these cases are simplex (i.e. there is only one affected individual per pedigree), we hypothesize that dominant, de novo variants (CNVs and/or SNVs) will be found to be associated with SIB. Several genetic syndromes that are associated with self-injury, such as Lesch-Nyhan Syndrome and Cornelia de Lange Syndrome, implicate underlying genetic mechanisms as a possible cause of SIB. The patients we propose to study have very dramatic clinical phenotypes, and while their behaviors are studied intensively as part of a treatment regimen, there have been few studies to characterize the genetic bases of the disorders. There is expected to be some genetic heterogeneity underlying self-injury, and yet the clinical heterogeneity is consistent with the hypothesis that the disruption of common pathways may be important. We propose to identify candidate genes associated with SIB that may potentially lead to evidence-based pharmacological treatment or other therapeutic approaches.
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