Morphological variants in neurodevelopmental disorders

Abstract

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are diagnosed in a significant minority of children, adolescents, and adults worldwide. Physical examinations are recommended for children undergoing assessment of NDDs, including evaluation of the presence of morphological variants, which are altered physical features of the body such as low-set ears, curved finger digits, narrow lips, etc. Morphological variants have been shown to appear more frequently in children with some NDDs, such as ASD, and in children with genetic syndromes. Physical examinations for morphological variants may help identify children undergoing assessment for NDDs who would benefit from further screening or testing (i.e., genetic). However, these physical examinations are often subjective, timeconsuming, and require a high level of expertise to perform. The thesis uses a cohort of twins recruited in the Roots of Autism and ADHD Twin Study in Sweden (RATSS) who received detailed in-person clinical and automated morphological assessments, neuroimaging, and molecular genetic testing. The aims of the studies in this thesis are to identify characteristics of morphological variants that can support NDD screening and risk assessment, to test whether it is possible to obtain reliable morphological assessments using low-cost, automated technology, and to utilize the twin design to explore the potential genetic and environmental influences on the development of morphological variants. Overall, it was hypothesized that individuals with NDDs would have increased numbers of morphological variants compared to those with typical development.

Study I explored the presence of minor physical anomalies (MPAs) in twin pairs in RATSS who received in-person clinical assessments and compared MPAs found in twins with NDDs to those with typical development. This study found that individuals with ASD in particular had increased numbers of MPAs, as well as those with increasing scores on a measure for autistic traits and those with lower IQs. Monozygotic twins, regardless of NDD diagnosis, had similar numbers and types of MPAs. Study II explored the relationship of the 2nd and 4th finger digit ratio (2D:4D) in individuals with diagnoses of various NDDs and found a small decrease in the ratio in individuals with NDDs overall, but not for any particular NDD. Additionally, the study confirmed the results of previous studies on 2D:4D ratios by finding lower ratios in males compared with females. Study III detailed the presence of morphological variants, as well as diagnostic and behavioral findings, in a twin pair with an identified genetic mutation (i.e., duplication on Chromosome 12) and NDD diagnoses of ASD and ADHD. The study compared phenotypic findings in this twin pair with other individuals worldwide identified with a similar size and location of duplication. The twin pair, along with the other individuals with the duplication, were reported to have learning difficulties, cognitive impairment, language and gross motor delays, and at least one NDD (i.e., intellectual disability, ADHD, ASD). The twin pair and other individuals identified were primarily males and had morphological variants present in head shape, forehead, eyes, vision, ears, nose, oral-facial region, and toe digits. Finally, Study IV compared in-person clinical assessments of facial morphological variants (FMVs) with automated assessments using Face2Gene (F2G), and described findings from the automated assessments in a large sample of twins with either typical development or NDDs. The study also explored differences in FMVs by presence of NDD diagnosis. The study found high to nearly complete agreement between clinical and automated assessments of FMVs. However, FMVs were neither increased, nor distinguishable, between individuals with NDD diagnoses versus those with typical development.

The studies in this thesis point to the potential value of morphological assessment as part of the physical examination in individuals with NDDs, particularly for those who may have NDDs such as ASD, increased autistic traits, lower IQs, or genetic variants. In general, the studies in this thesis found increased numbers of morphological variants in individuals with NDDs and in some with genetic variations (i.e., 12q12 duplication), but significant differences in the number of variants in individuals diagnosed with NDDs versus typical development were not always identified. Although automated assessments are now available to detect morphological variants, they are limited to just certain body regions (i.e., face). In contrast, in-person clinical assessments allow for a full, head-to-toe examination and appear to be better at identifying individuals with morphological variants. In conclusion, identification of morphological variants may point to individuals with possible NDDs or underlying genetic alterations and have the potential to help determine individuals undergoing diagnosis for NDDs who would most benefit from further screening or testing, such as genetic testing.