ORIGINAL ARTICLE Clinical exome sequencing in neuromuscular diseases: an experience from Turkey Esra Börklü-Yücel 1 & Çiğdem Demiriz 1 & Şahin Avcı 1 & Ebru Nur Vanlı-Yavuz 2 & Serpil Eraslan 1 & Piraye Oflazer 2 & Hülya Kayserili 3 Received: 10 October 2019 /Accepted: 20 February 2020 # Fondazione Società Italiana di Neurologia 2020 Abstract Neuromuscular diseases (NMDs) encompass a variety of ailments from muscular dystrophies to ataxias, in the course of which the functioning of the muscles is eventually either directly or indirectly impaired. The clinical diagnosis of a particular NMD is not always straightforward due to the clinical and genetic heterogeneity of the disorders under investigation. Traditional diag- nostic tools such as electrophysiological tests and muscle biopsies are both invasive and painful methods, causing the patients to be reluctant. Next-generation sequencing, on the other hand, emerged as an alternative method for the diagnosis of NMDs, both with its minimally invasive nature and fast processing period. In this study, clinical exome sequencing (CES) was applied to a cohort of 70 probands in Turkey, 44 of whom received a final diagnosis, representing a diagnostic rate of 62.9%. Out of the 50 mutations identified to be causal, 26 were novel in the known 27 NMD genes. Two probands had complex/blended phenotypes. Molecular confirmation of clinical diagnosis of NMDs has a major prognostic impact and is crucial for the management and the possibility of alternative reproductive options. CES, which has been increasingly adopted to diagnose single-gene disorders, is also a powerful tool for revealing the etiopathogenesis in complex/blended phenotypes, as observed in two probands of the cohort. Keywords Next-generation sequencing (NGS) . Clinical exome sequencing (CES) . Neuromuscular disease (NMD) . Dual diagnosis . Dysferlinopathy . Sarcoglycanopathy Introduction Neuromuscular diseases (NMDs) are a heterogeneous group of disorders affecting and impairing the muscle function, ei- ther directly by creating a muscle pathology or indirectly via nerve pathology. They are progressive disorders often charac- terized by loss of mobility and are sometimes accompanied by ocular, bulbar, respiratory and/or cardiac muscle involvement. In the rapidly progressive ones, early death is usually due to respiratory and/or cardiac failure [1–3]. Diagnosing NMDs includes a detailed clinical examination, an evaluation of fam- ily history, a measurement of serum creatine kinase (CK) levels and other relevant blood tests, according to the symp- toms, and followed by electrophysiological diagnostic tests, a muscle biopsy and histopathology and, finally, genetic testing. Although powerful and essential tools, electromyography (EMG) and muscle biopsy have limitations, that is, body mass, age, patient cooperation and technical specificity can reduce the clinical yield. Furthermore, they both rely on pain- ful and uncomfortable invasive procedures [4, 5]. It is not far-fetched to state that clinical, electrophysiological and histopathological studies cannot always distinguish be- tween NMDs, especially within the subgroups of neuropathies (e.g. Charcot-Marie-Tooth disease) or muscular dystrophies (e.g. limb-girdle muscular dystrophies) that have more than one gene associated with a phenocopy. This fact renders the traditional single-gene testing a time- and money-consuming Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10072-020-04304-w) contains supplementary material, which is available to authorized users. * Hülya Kayserili hkayserili@kuh.ku.edu.tr 1 Diagnostic Center for Genetic Diseases, Koc University Hospital, Koç University, 34010 Istanbul, Turkey 2 Neurology Department, Center for Muscle Diseases, Koç University School of Medicine (KUSoM), 34010 İstanbul, Turkey 3 Medical Genetics Department, Koç University School of Medicine (KUSoM), 34010 Istanbul, Turkey Neurological Sciences https://doi.org/10.1007/s10072-020-04304-w