P440 A new nationwide initiative to explore genetic variants in a large Turkish hereditary neuropathy cohort

• Published in: Neuromuscular disorders : NMD 2023-10, Vol.33, p.S188-S188
• Main Authors: Akinci, G., Ozyilmaz, B., Parlar, O., Unalp, A., Polat, I., Baydan, F., Karaoglu, P., Gazeteci, P., Dundar, N Olgac, Ardicli, D., Koken, O Yayici, Aksoy, A., Komurcu, M., Cavusoglu, D., Yis, U., Topaloglu, H.
• Format: Article
• Language: English
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2023.07.478

Hereditary neuropathy is a term used for Mendelian-inherited neuropathies, genetically and clinically heterogeneous groups of disorders. This initiative aims to create a national network that can identify variants in subjects with hereditary neuropathy, explore the pathogenicity of these discovered variants, create deep phenotype profiles of patients with pathogenic variants in genes associated with hereditary neuropathy, and discover new genes/variants associated with hereditary neuropathies. Patients with clinically diagnosed neuropathy are tested after acquired causes are excluded. If Charcot-Marie-Tooth disease is suspected, patients are first tested for PMP22 gene copy number (usually via MLPA). A genetic panel is ordered once that has been excluded. Patients with pathogenic variants in known hereditary neuropathy genes are included in a phenotyping plan that includes multiple clinical variables such as the age of onset, ethnicity, consanguinity, inheritance pattern, family history, weakness pattern, musculoskeletal abnormalities, creatine kinase level, cognition and respiration status, nerve conduction studies, and EMG findings. The disease burden is further assessed by disease-specific instruments. In patients with negative hereditary neuropathy or neuromuscular panel results (may also include patients with negative specific single gene test), we will use WES to further analyze these pathogenic variant-negative patients. The first cohort of patients was generated from the Izmir center. All patients were diagnosed clinically between April 2020 and March 2023. These cases were either seen by our experts in our centers or their clinical information, electrophysiological and radiological records, and pathological findings were provided by local paediatric neurologists. So far, we have been able to identify 30 patients with PMP22 deletions/duplications. We have also been able to detect variants in 49 patients in 21 genes (PMP22, MFN2, MPZ, SH3TC2, GJB1, LITAF, GDAP1, HSPB1, DNM2, INF2, FGD4, DNAJB2, HINT1, MCM3AP, DYNC1H1, IGHMBP2, SACS, BSCL2, WARS, PRX, SCN9A). The pathogenicity of these variants and the phenotypes of the patients are being studied. In a very similar design to our setup, several referral centers throughout Turkey are providing service to patients and local paediatric neurologists for the diagnosis of hereditary neuropathies. As a next step, our collaborative centers in Istanbul, Ankara, Samsun, Mersin, and Afyon will start enrolling pa