Huntington’s disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington’s disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. We developed a method for calling perfect and imperfect repeats from exome-sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington’s disease via regression analysis. We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1 × 10−9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.

Background: Huntington's disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington's disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. Methods: We developed a novel method for calling perfect and imperfect repeats from exome sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington's disease via regression analysis. Results: We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1x10-9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. Conclusions: The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.

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AimsBackground: The Driving & Vehicle Licensing Agency (DVLA) states: “Doctors and other healthcare professionals should: advise individuals on the impact of their medical condition for safe driving ability and also advise the individual on their legal requirement to notify DVLA of any relevant condition”. Within mental health, the guidance states that depression or anxiety associated with “Significant memory or concentration problems, agitation, behavioural disturbance or suicidal thoughts” must be reported to the DVLA. Aims: Identify whether information was collected on driving status of patients presenting with depression/anxiety and self harm. Identify whether accurate advice was provided and documented. Implement changes that would improve compliance with guidance.MethodsWe reviewed notes to collect baseline data for 3 weeks prior to commencing interventions, then weekly for 2 months from November 2021. Cases were defined as: those presenting to Liaison Psychiatry (LP) with an act of self-harm either on antidepressants or with a confirmed diagnosis of depression/anxiety on their record. Each week, the notes of 10 cases were reviewed for evidence of documentation of driving status and advice regarding DVLA guidelines.Weekly InterventionsWeek 1: Email communication to team highlighting the guidance, responsibilities and where to document.Week 2: Driving status discussed in handover daily to increase awareness and identify/address concerns.Week 3: Repeat email to team.Week 4: DVLA guidance posters placed in LP office.Week 12: Teaching session by Occupational therapist from regional driving assessment centre.ResultsData were analysed for 90 patients over 9 weeks. 52% were female, and average age was 33 years. Relevant documentation was only made on week 1 (10%) and week 4 (20%). No documentation of either driving status or advice given were made in any of the other weeks analysed.ConclusionAchieving compliance with guidance was difficult. Email communication was the most effective intervention. A group discussion to identify drivers of poor compliance found that clinicians failed to ask as the questions were not routine practice, and some voiced concerns about the potential implications of advice (worsening therapeutic relationship or increasing social isolation/implications for employment). Future plans include adding a prompt about driving on the electronic risk assessment, and specific training in the staff induction.