The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Long-Term Outcome of Symptomatic Patients Undergoing Hybrid Revascularisation for Extracranial Carotid Artery Tandem Stenosis.

OBJECTIVES: Carotid tandem lesions are a multilevel significant (>50%) atherosclerotic disease involving both the internal carotid artery (ICA) and either the ipsilateral common carotid artery (CCA) or the innominate artery (IA). These lesions may be challenging to treat. Current guidelines offer no definitive recommendation on the optimal treatment algorithm. The aim of this analysis was to assess the long-term outcome of patients undergoing surgical revascularisation for tandem lesions. METHODS: In two centres, consecutive patients who underwent carotid endarterectomy (CEA) for a symptomatic carotid artery stenosis between 2003 and 2017 were screened retrospectively for the presence of a carotid artery tandem lesion. All eligible patients were treated by a hybrid approach, consisting of retrograde stenting of the proximal CCA or IA followed by CEA. All patients had a yearly clinical check up including duplex ultrasound. The primary outcome was occurrence of any stroke, death, myocardial infarction (MI), or transient ischaemic attack (TIA) within 30 days. Secondary outcomes were any stroke, death, MI, or TIA and occurrence of restenosis ≥50% during follow up. RESULTS: Sixteen of 2368 symptomatic patients were included. Besides a high grade ICA stenosis, patients had a significant ipsilateral stenosis of the CCA (n = 13) or IA (n = 3). Within 30 days there were no deaths, strokes, or TIAs. Two patients had a clinical MI. During a median follow up of 73 (interquartile range 22-85) months, three patients died. One patient developed a symptomatic restenosis of the ICA (ipsilateral TIA). Two patients (without restenosis) developed an ipsilateral stroke and a MI. CONCLUSIONS: In this small case series, hybrid revascularisation of carotid tandem lesions in symptomatic patients seems feasible and safe. Long-term data show a relatively high number of any adverse events. These surgical outcomes need to be offset against the natural course in patients with a symptomatic carotid tandem lesion.