Clare A. Gibbons

Structural Variation of Chromosomes in Autism Spectrum Disorder

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

Feasibility of computerized working memory training in individuals with Huntington disease

Objectives Huntington disease (HD) is associated with a variety of cognitive deficits, with prominent difficulties in working memory (WM). WM deficits are notably compromised in early-onset and prodromal HD patients. This study aimed to determine the feasibility of a computerized WM training program (Cogmed QM), novel to the HD population. Methods Nine patients, aged 26–62, with early stage HD underwent a 25-session (5 days/week for 5 weeks) WM training program (Cogmed QM). Training exercises involved the manipulation and storage of verbal and visuospatial information, with difficulty adapted as a function of individual performance. Neuropsychological testing was conducted before and after training, and performance on criterion WM measures (Digit Span and Spatial Span), near-transfer WM measures (Symbol Span and Auditory WM), and control measures were evaluated. Post-training interviews about patient experience were thematically analyzed using NVivo software. Results Seven of nine patients demonstrated adherence to the training and completed all sessions within the recommended timeframe of 5 weeks. All adherent patients showed improvement on the Cogmed tasks as defined by the Improvement Index (M = 22.17, SD = 8.84, range = 13–36). All adherent patients reported that they found training helpful (n = 7), and almost all felt that their memory improved (n = 6). Participants also expressed that the training was difficult, sometimes frustrating, and time consuming. Conclusions This pilot study provides support for feasibility of computerized WM training in early-stage patients with HD. Results suggest that HD patients perceive benefits of intensive WM training, though a full-scale and controlled intervention project is needed to understand the size of the effect and reliability of changes over time. Trial registration ClinicalTrials.gov, Registry number NCT02926820

J8 Two case studies demonstrating transmission of unstable huntington’s disease intermediate alleles and the implications for genetic counselling practice

Background Huntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat within the Huntingin gene, with affected individuals inheriting >36 CAG repeats. Intermediate alleles (IAs) are classed as 27–35 CAG repeats. Although IAs do not fall within the disease causing range, they are susceptible to paternal germline instability, and so may expand into the reduced penetrance or full mutation range upon transmission to the next generation. There are several factors which are thought to influence CAG repeat instability. However, the risk of IAs expanding into the HD disease causing range has been difficult to establish. Case history and conclusions We present two cases, where intermediate alleles have expanded into the full mutation range. The first case describes a family where a paternally inherited intermediate allele of 29 CAG repeats has expanded into a full mutation of 45 CAG repeats. This finding has been confirmed by PCR and linkage analysis and as far as we are aware, this degree of expansion has not been described in the literature before. The second case describes a family where an intermediate allele of 32 has expanded to 44 CAG repeats. We discuss the implications of this both for the family, and the genetic counsellor involved and present some of the challenges associated with genetic counselling for IAs.

M15 Computerised cognitive training for individuals with early stage huntington’s disease

Background Huntington’s disease (HD) is associated with a variety of cognitive deficits, with prominent deficits in working memory (WM). These deficits can occur in the early stage of the disease and undermine quality of life. Currently, there are no established treatments for these symptoms. Aims The feasibility of implementing a home-based, computerised WM training program was examined in HD patients who reported WM difficulties in daily life. A secondary aim was to assess the patient experience with this training program. Methods Nine patients, aged 26–62, with early stage HD underwent a 25-session (5 days/week for 5 weeks) WM training program (Cogmed QM). Training exercises involved the manipulation and storage of verbal and visuospatial information, with difficulty adapted as a function of individual performance. Neuropsychological testing was conducted before and after training, to evaluate changes in performance on criterion WM measures (Digit Span and Spatial Span) and near-transfer WM measures (Symbol Span and Auditory WM). Post-training interviews about patient experience were thematically analysed using NVivo software. Results Seven of nine (77%) patients completed the program within the recommended timeframe (M = 36 ± 12.35 days). Compared to baseline scores, patients showed significant improvement on both measures of verbal WM (Digit Span, p = 0.047; Auditory WM, p = 0.041). Each of these patients reported that they found training helpful, and almost all (n = 6) felt that their memory improved. Conclusions This pilot study provides support for feasibility of computerised WM training in early-stage patients with HD. Results suggest that HD patients can improve WM with intensive training, though a full-scale intervention project is needed to understand the reliability of changes over time.