Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence

Abstract

Neurodevelopmental disorders can be caused by many different genetic abnormalities that are individually rare but collectively common. Specific genetic causes, including certain copy number variants and single-gene mutations, are shared among disorders that are thought to be clinically distinct. This evidence of variability in the clinical manifestations of individual genetic variants and sharing of genetic causes among clinically distinct brain disorders is consistent with the concept of developmental brain dysfunction, a term we use to describe the abnormal brain function underlying a group of neurodevelopmental and neuropsychiatric disorders and to encompass a subset of various clinical diagnoses. Although many pathogenic genetic variants are currently thought to be variably penetrant, we hypothesise that when disorders encompassed by developmental brain dysfunction are considered as a group, the penetrance will approach 100%. The penetrance is also predicted to approach 100% when the phenotype being considered is a specific trait, such as intelligence or autistic-like social impairment, and the trait could be assessed using a continuous, quantitative measure to compare probands with non-carrier family members rather than a qualitative, dichotomous trait and comparing probands with the healthy population.

Figure 1. Cognitive effects of copy number variant syndromes in full-scale intelligence quotient scores

(A) The intelligence quotient (IQ) distribution curve in individuals with deletion 22q11.2 (red line) is shifted 2 SD to the left of the IQ distribution in the general population (mean 100; SD: 15; light blue line). (B) Individuals with deletion 16p11.2 have a mean IQ of 76·1 (dark blue line), which is significantly lower than the mean IQ of their non-carrier first-degree relatives (108·3, green line). The higher IQ of first-degree relatives compared to the general population was previously discussed by Zufferey and colleagues as likely due to ascertainment bias. For both copy number variant syndromes, many deletion carriers have IQ scores within the normal range (>70); this is often referred to as incomplete penetrance when cognitive function is viewed as a qualitative, dichotomous trait (normal intelligence vs intellectual disability) based on a cutoff of 70 points of IQ (dotted line), but may be better interpreted as variable expressivity of a continuous, quantitative trait.

Figure 2. Model of developmental brain dysfunction

Adapted from Myers SM.

Figure 3. The effect, or deleterious impact, of genetic or other insults on an individual’s neurodevelopmental profile across cognitive, neurobehavioural, and motor streams of development

In these examples, the actual observed profile of abilities in probands (black solid lines) shows the deleterious effect of a copy number variant on the expected profile based on genetic background (dotted lines). The effect of a particular copy number variant might be different in each stream of development and is arbitrarily represented in these examples as a 2, 1·5, and 1 SD deleterious impact in the cognitive, neurobehavioural, and motor streams, respectively. The red dotted line represents the diagnostic threshold (depicted here as 2 SD below the mean). (A) In this example, the deleterious effect of the copy number variant on quantitative cognitive traits (eg, intelligence quotient) results in reaching the threshold for a diagnosis of intellectual disability, whereas neurobehavioural and motor features do not fall within the clinically impaired range. (B) In this example, because of a different starting potential (based on genetic background), the deleterious effect of the copy number variant on quantitative neurobehavioural traits (eg, social responsiveness scale score) results in reaching the threshold for a diagnosis of a neurobehavioural disorder (eg, autism spectrum disorder) without intellectual disability or motor impairment, since cognitive and motor abilities are not within the impaired range.