American Journal of Psychiatry, 2021 (PMID: 33384013): A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants.
Chawner SJRA, Doherty JL, Anney RJL, Antshel KM, Bearden CE, Bernier R, Chung WK, Clements CC, Curran SR, Cuturilo G, Fiksinski AM, Gallagher L, Goin-Kochel RP, Gur RE, Hanson E, Jacquemont S, Kates WR, Kushan L, Maillard AM, McDonald-McGinn DM, Mihaljevic M, Miller JS, Moss H, Pejovic-Milovancevic M, Schultz RT, Green-Snyder L, Vorstman JA, Wenger TL; IMAGINE-ID Consortium, Hall J, Owen MJ, van den Bree MBM.
Lay summary: Within autistic individuals there is great variability in terms of symptom profile, cognitive function, and developmental trajectory. In this study we investigated the extent to which genetics explains variability in autism – do different genetic variants lead to different autism sub-types? the research focused on 16p11.2 deletion, 16p11.2 duplication, 22q11.2 deletion, and 22q11.2 duplication genetic conditions, which have all been previously linked to autism. Data was combined across 8 international clinical research sites. The study results provide support for a model whereby autism profiles of these genetically defined subgroups are distinct but highly overlapping, and highlights that within a genetic condition there is still considerable variability in clinical outcomes. Also, it was found that although many individuals with a genetic condition did not meet full diagnostic criteria for autism, they nevertheless meet clinical cut-offs for autistic traits – indicating current autism diagnostic criteria is missing individuals in clinical need.
Nature Medicine, 2020 (PMID: 33169016): Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome.
Davies RW, Fiksinski AM, Breetvelt EJ, Williams NM, Hooper SR, Monfeuga T, Bassett AS, Owen MJ, Gur RE, Morrow BE, McDonald-McGinn DM, Swillen A, Chow EWC, van den Bree M, Emanuel BS, Vermeesch JR, van Amelsvoort T, Arango C, Armando M, Campbell LE, Cubells JF, Eliez S, Garcia-Minaur S, Gothelf D, Kates WR, Murphy KC, Murphy CM, Murphy DG, Philip N, Repetto GM, Shashi V, Simon TJ, Suñer DH, Vicari S, Scherer SW; International 22q11.2 Brain and Behavior Consortium, Bearden CE, Vorstman JAS.
Lay summary: A key question addressed in this study is how we can understand that there is such variability in outcomes in individuals who all have the same genetic variant, in this case a deletion of chromosome 22q11.2. The study focused on common genetic variants, summarized in polygenic scores, which were also used to elucidate certain genetic correlations between cognitive ability, cognitive decline, subclinical psychotic symptoms and schizophrenia in patients with 22q11DS.
In essence, the findings show that the rest of the genome has an important role in modifying the impact of the deletion. One important observation is that this information hidden in the rest of the genome can be used to substantially improve accuracy of prediction of outcomes – in this study schizophrenia and intellectual disability – in individual patients with 22q11DS.