Abstract
Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. Furthermore, the relative homogeneity of neurodevelopmental disorders of known genetic origin allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioral outcomes. The current study investigated white matter structural connectivity in a group of individuals with intellectual disability due to mutations in ZDHHC9. In addition to shared cause of cognitive impairment, these individuals have a shared cognitive profile, involving oromotor control difficulties and expressive language impairment. Analysis of structural network properties using graph theory measures showed global reductions in mean clustering coefficient and efficiency in the ZDHHC9 group, with maximal differences in frontal and parietal areas. Regional variation in clustering coefficient across cortical regions in ZDHHC9 mutation cases was significantly associated with known pattern of expression of ZDHHC9 in the normal adult human brain. The results demonstrate that a mutation in a single gene impacts upon white matter organization across the whole-brain, but also shows regionally specific effects, according to variation in gene expression. Furthermore, these regionally specific patterns may link to specific developmental mechanisms, and correspond to specific cognitive deficits.
Highlights
Many cognitive and psychiatric disorders are highly heritable (Haworth et al 2009; Lee et al 2015)
The following section describes the results of the structural connectome comparison between the ZDHHC9 group and controls
The current investigation aimed to elucidate the association between a neurodevelopmental disorder of known monogenic origin and white matter organization
Summary
Many cognitive and psychiatric disorders are highly heritable (Haworth et al 2009; Lee et al 2015). Genetic risk factors have been identified, but understanding the neural mechanisms linking altered gene transcripts to cognitive or behavioral outcomes remains challenging One reason for this is the heterogenous nature of the vast majority of these disorders, which presents a major challenge to establishing the neural endophenotypes that mediate any gene–cognition relationships; any group defined on the basis of a cognitive impairment or behavioral difficulty will likely contain individuals with different genetic and neural causes, making it difficult to identify mechanisms at the group level. Structural Connectivity in a Single-Gene Disorder Bathelt et al | 3807 groups, while necessarily small in size, have a homogenous etiology Studying these groups can provide a powerful means for identifying the neurobiological pathways that potentially mediate cognitive and behavioral phenotypes in the wider population. The study of a rare familial speech disorder (KE family, FOXP2 mutation) highlighted the importance of striatal networks for emergent higher-order language skills (Liegeois et al 2011; Watkins 2011)
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