Autism and heritable bone fragility: A true association?

Abstract

ObjectivesOsteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; intelligence is reported to be normal. However, a minority of children seen also show symptomology consistent with an ‘Autism Spectrum Disorder’. A joint genetics and psychology research study was undertaken to identify these patients using ‘Gold Standard’ research tools: Autism Diagnostic Inventory Revised (ADI-R); Autism Diagnostic Observation Schedule (ADOS) and undertake genetic analyses in them.MethodA cohort of n = 7 children with autistic traits and severe/complex OI were recruited to the study. The study was set-up to explore whether there was a genetic link between bone fragility and autism in a sub-set of patients with bone fragility identified with autism traits in our complex/severe OI clinic. This was not set-up as a prevalence study but rather an exploration of genetics in association with ADI/ADOS confirmed ASD and bone fragility.ADI& ADOSStandardised tools were used to confirm autism diagnosis. ADI and ADOS were completed by the Clinical Psychologist; ADI comprises a 93 item semi-structured clinical review with a diagnostic algorithm diagnosing Autism; ADOS is a semi-structured assessment of socialisation, communication and play/imagination which also provides a diagnostic algorithm.Exome sequencingIn patients recruited, those that fulfilled research criteria for diagnosis of autism using above tools were recruited to trio whole exome sequencing (WES).Resultsone patient had compound heterozygous variants in NBAS; one patient had a variant in NRX1; one patient had a maternally inherited PLS3 variant; all the other patients in this cohort had pathogenic variants in COL1A1/COL1A2.ConclusionsAlthough, not set out as an objective, we were able to establish that identifying autism had important clinical and social benefits for patients and their families in ensuring access to services, appropriate schooling, increased understanding of behaviour and support.Lay summaryIt is important for clinicians looking after children with brittle bone disease, also referred to as Osteogenesis Imperfecta (OI) to be aware of early features of developmental delay/autistic traits especially with severe forms of OI as the emphasis is on their mobility and bone health. Ensuring appropriate assessment and access to services early-on will enable these patients to achieve their potential. Further investigations of genomics in bone fragility in relation to autism are required and dual diagnosis is essential for high quality clinical and educational provision.

Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development

“…In addition, our data shows a direct correlation between Cul3 activity and Pls3 levels, suggesting that Pls3 levels may be a good readout to test the pathogenicity of CUL3 mutations in humans. Interestingly, a pathogenic variant of PLS3 has recently also been described in a patient with idiopathic osteoporosis and ASD 53 .…”

“…As a second filtering step, regardless of P- value, ratios were also not considered if the absolute value of their base-2 logarithm did not exceed a threshold calculated as excluding all but the 5% most extreme ratios between individual controls. For functional annotation clustering, proteins found significant for a particular condition were mapped to GO terms using the DAVID Bioinformatics Resources 6.8 online tool 52 , 53 (done for proteins at 20% FDR, GO- terms filtered for P < 0.01, Benjamini-adjusted P -values are reported for significantly enriched terms).…”

Autism, Joint Hypermobility-Related Disorders and Pain

“…These results had not been reported before. Recently, Balasubramanian et al (37) reported a higher incidence of ASD in people with Osteogeneses Imperfecta (i.e., HDCTs characterized by brittle bones and blue sclerae). Ten out 102 patients in their cohort have ASD while in the general population ASD is estimated of 1 in 100.…”

Cul3regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development

“…Pls3 is altered in the developing and adult cortex, the adult hippocampus, but not in the adult striatum 31,32 . Interestingly, a pathogenic variant of PLS3 has recently also been described in a patient with idiopathic osteoporosis and ASD 38 . Thus, our analysis points to a central role of Cul3 in the homeostatic regulation of cytoskeletal proteins of which the most significant might be Plastin 3.…”