Autistic Traits and Cognitive Abilities Associated with Two Molecular Causes of Silver-Russell Syndrome

Background: Silver-Russell syndrome (SRS) is a rare condition associated with restricted growth, estimated prevalence 1 in 30,000. A molecular cause has been identified in approximately 60% of individuals with a clinical diagnosis of SRS. Specifically, 30 – 60% of individuals with SRS have loss of methylation on chromosome 11p15 (SRS 11p15) and 5 – 10% have maternal uniparental disomy for chromosome 7 (SRS mUPD7). Previous research has indicated that autistic traits and intellectual disability may be prevalent in SRS and particularly in SRS mUPD7. However, to date, autistic traits and cognitive abilities associated with the SRS molecular subtypes have not been systematically investigated using standardised assessments.

Objectives: The primary aim of this study was to identify and compare the prevalence of autistic traits associated with two molecular causes of SRS (SRS 11p15 and SRS mUPD7). A secondary aim of this study was to assess cognitive abilities in order to establish and compare the intellectual ability of individuals with SRS 11p15 and individuals with SRS mUPD7.

Methods: The Social Responsiveness Scale, second edition (SRS-2) was used to assess autistic traits via parental report. The parent/caregiver of each participant completed the SRS-2 for 47 individuals with SRS 11p15 (mean age = 8.17 years, SD = 4.24) and 32 individuals with SRS mUPD7 (mean age = 11.63 years, SD = 7.12). The Autism Diagnostic Observation Schedule, second edition (ADOS-2) and the British Ability Scales, third edition (BAS3) were used to assess autistic behaviours and cognitive abilities, respectively. These in-person assessments were completed by a subset of participants: 18 individuals with SRS 11p15 (mean age = 8.63 years, SD = 3.44) and 15 individuals with SRS mUPD7 (mean age = 14.27 years, SD = 6.37).

Results: As assessed by the SRS-2, 45% of participants with SRS 11p15 and 53% of participants with SRS mUPD7 scored above clinical cut-off for ASD (total T-score ≥ 60). In addition, 10% of participants with SRS 11p15 and 38% of participants with SRS mUPD7 scored in the severe clinical range (total T-score ≥ 76). Comparison of SRS-2 mean total T-scores revealed that the SRS mUPD7 group were reported as displaying more autistic traits than the SRS 11p15 group. As assessed by the ADOS-2, 33% of participants with SRS mUPD7 scored in the autism spectrum or autism range, compared to 11% of participants with SRS 11p15. Based on general conceptual ability (GCA) scores, the majority of participants with SRS 11p15 had average intellectual ability (M = 98.56, SD = 19.23), whereas the majority of participants with SRS mUPD7 had borderline intellectual ability (M = 79.86, SD = 8.72). There was no association between SRS-2 total T-scores and GCA or ADOS-2 total scores and GCA for either group.

Conclusions: Overall, the findings demonstrate that individuals with SRS 11p15 and SRS mUPD7 display increased prevalence of autistic traits and these are particularly pronounced in SRS mUPD7. In addition, SRS mUPD7 is associated with increased risk of intellectual disability but autistic traits and intellectual ability are not associated in either of these groups.