Annual Research Review: Rare genotypes and childhood psychopathology – uncovering diverse developmental mechanisms of ADHD risk

Abstract

A common imperative emerging within psychopathology research is the need to investigate mechanistically how developmental trajectories converge or diverge between and within genotype-defined groups. Crucially, as genetic predispositions modify interaction dynamics from the outset, longitudinal research is required to understand the multi-level developmental processes that mediate symptom evolution.

The attentive brain: insights from developmental cognitive neuroscience

“…These can be informative, because mechanisms can be studied from the single gene to the symptom level 143 . For example, the fragile X mental retardation 1 ( FMR1 ) gene is silenced in FXS 144 , an inherited condition associated with inattention and hyperactivity (BOX 3).…”

“…High-penetrance mutations may have converging (or diverging) effects on attentional functions, depending on the specific ways in which they regulate neural development, neurophysiological properties and network emergence, as has been proposed in the context of similarities and differences between tuberous sclerosis and FXS 153 . The body of information about how these individually rare but cumulatively rather common mutations affect attentional control networks is growing 143 . A fruitful approach to use this information is to group rare genetic differences that affect common networks and test their effects on attentional control skills in comparison with relatively well-understood abnormalities like those measured in FXS 154 .…”

“…Studying individuals with rare but highly penetrant genetic variants associated with high risk of attention difficulties from early childhood can provide insight into the genetic, cellular and systems mechanisms of risk, because these individuals can be studied at multiple levels, from genetics to behaviour 143 . For example, fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder affecting 1 in 4,000 males and 1 in 6,000 females 187 and is associated with a very high risk for attention deficits.…”

Genetic Syndromes and Developmental Risk for Autism Spectrum and Attention Deficit Hyperactivity Disorders: Insights From Fragile X Syndrome

“…A parallel to the discussion of ASD emerges when considering the mechanisms responsible for high prevalence of hyperactivity and inattention in individuals with FXS . Similar to the argument made for ASD in individuals with FXS, the earlier age of diagnosis of FXS (compared to when ADHD is diagnosed) allows for prospective longitudinal analysis of early markers of ADHD.…”

“…The increased availability of genetic testing has resulted in a growing cumulative frequency of diagnoses associating gene markers and generalized developmental delay , as well as more specific behaviorally defined difficulties, such as autism spectrum disorder (ASD; ) and attention deficit hyperactivity disorder (ADHD; ). Because specific genes can be mapped onto molecular, cellular, and systems neuroscience pathways, genetically identified syndromes have long offered the opportunity to study relationships among the genetic, neural, cognitive, and behavioral levels .…”