Clinical genetics has an important role in the healthcare system to provide a definitive diagnosis for many rare syndromes. It also can have an influence over genetics prevention, disease prognosis and assisting the selection of the best options of care/treatment for patients. Next-generation sequencing (NGS) has transformed clinical genetics making possible to analyze hundreds of genes at an unprecedented speed and at a lower price when comparing to conventional Sanger sequencing. Despite the growing literature concerning NGS in a clinical setting, this review aims to fill the gap that exists among (bio)informaticians, molecular geneticists and clinicians, by presenting a general overview of the NGS technology and workflow. First, we will review the current NGS platforms, focusing on the two main platforms Illumina and Ion Torrent, and discussing the major strong points and weaknesses intrinsic to each platform. Next, the NGS analytical bioinformatic pipelines are dissected, giving some emphasis to the algorithms commonly used to generate process data and to analyze sequence variants. Finally, the main challenges around NGS bioinformatics are placed in perspective for future developments. Even with the huge achievements made in NGS technology and bioinformatics, further improvements in bioinformatic algorithms are still required to deal with complex and genetically heterogeneous disorders.

Congenital muscular dystrophy type 1A (MDC1A) is one of the main subtypes of early‐onset muscle disease, caused by disease‐associated variants in the laminin‐α2 (LAMA2) gene. MDC1A usually presents as a severe neonatal hypotonia and failure to thrive. Muscle weakness compromises normal motor development, leading to the inability to sit unsupported or to walk independently. The phenotype associated with LAMA2 defects has been expanded to include milder and atypical cases, being now collectively known as LAMA2‐related muscular dystrophies (LAMA2‐MD). Through an international multicenter collaborative effort, 61 new LAMA2 disease‐associated variants were identified in 86 patients, representing the largest number of patients and new disease‐causing variants in a single report. The collaborative variant collection was supported by the LOVD‐powered LAMA2 gene variant database (https://www.LOVD.nl/LAMA2), updated as part of this work. As of December 2017, the database contains 486 unique LAMA2 variants (309 disease‐associated), obtained from direct submissions and literature reports. Database content was systematically reviewed and further insights concerning LAMA2‐MD are presented. We focus on the impact of missense changes, especially the c.2461A > C (p.Thr821Pro) variant and its association with late‐onset LAMA2‐MD. Finally, we report diagnostically challenging cases, highlighting the relevance of modern genetic analysis in the characterization of clinically heterogeneous muscle diseases.

Duchenne muscular dystrophy (DMD) is an X‐linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT‐NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT‐NMD. For the DMD registries within TREAT‐NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT‐NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.