C003 The influence of CAG-CCG repeat sequence variants on the phenotype of HD patients with small expansions

<h3>Background</h3> Chorea is less frequent in patients with small CAG repeat alleles (CAG36-39).¹ Synonymous sequence variants within the HTT CAG-CCG repeat region such as the loss of the CAA interruption (LOI), are modifiers of HD onset and penetrance, particularly in symptomatic carriers with small CAG repeat alleles.² However, phenotypic differences other than earlier age at onset are not described. <h3>Aims</h3> We investigated how sequence variants influence the phenotype in patients with small CAG expansions. <h3>Methods</h3> We included 125 carriers with uninterrupted CAG36-39 in Paris (n=50) and in Vancouver (n=75). We amplified the region of interest by PCR and sequenced the amplicons with Illumina MiSeq (Paris) and clonal Sanger sequencing of the HTT repeat tract (Vancouver). <h3>Results</h3> We found 29 carriers with the LOI variant (23%). Patients with the LOI variant had a non significant earlier mean age at onset than those with the canonical sequence (59 years vs 61 years), depite comparable proportions of different CAG sizes in both groups. The full triad of motor, cognitive and psychiatric involvement was more frequent in LOI patients (100% vs. 36%; p&lt;0.05), but there was no difference regarding the absence of chorea which was frequent in both groups (17% in patients with the LOI and 28% in patients with the canonical sequence). <h3>Conclusions</h3> In the largest phenotyped small expansion cohort with DNA sequence data from two reference centers to date, the LOI is potentially a severity factor of clinical manifestations. Specific phenotypic traits like chorea frequency appear to be more related to CAG size than structure. <h3>References</h3> Heinzmann A, Sayah S, Lejeune F, Hahn V, Teichmann M, Monin M, <i>et al.</i> Huntington’s disease with small CAG repeat expansions. <i>Mov Disord</i>. 2023 Jul;<b>38</b>(7):1294–306. Findlay Black H, Wright GEB, Collins JA, Caron N, Kay C, Xia Q, <i>et al.</i> Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range. <i>Genet Med [Internet]</i>. 2020 Aug 3 [cited 2020 Oct 2]; Available from: http://www.nature.com/articles/s41436-020-0917-z.