Exome sequencing and optical genome mapping in molecularly unsolved cases of duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to $\it X$-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding $\it DMD$ gene. However, in a small subset of patients clinically diagnosed with DMD, the molecular cause is not identified with these routine methods. Evaluation of the 60 DMD patients in our center revealed three cases without a known genetic cause. DNA samples of these patients were analyzed using whole-exome sequencing (WES) and, if unconclusive, optical genome mapping (OGM). WES led to a diagnosis in two cases: one patient was found to carry a splice mutation in the $\it DMD$ gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene $\it (FKTN)$ that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the $\it DMD$ gene (~1.28 Mb) that was subsequently confirmed with long-read sequencing. These results highlight the importance of reanalyzing unsolved cases using WES and demonstrate that OGM is a useful method for identifying large structural variants in cases with unremarkable exome sequencing

Biochemical and molecular genetics of cystic fibrosis

Cystic fibrosis (CF) is the most common severe recessive genetic disorder in the Caucasian population. In 1938, D. H. Anderson provided the first comprehensive description of the disease and also introduced the name “cystic fibrosis of the pancreas.” Patients with CF suffer from excessive mucus accumulation resulting in severe clinical consequences in the respiratory, gastrointestinal, and genitourinary tracts (see Table I). All these symptoms are consistent with defects of exocrine glands, as suggested by S. Farber in 1945; he called the disease “mucoviscidosis,” a name still popular in some parts of continental Europe. CF patients also have elevated electrolyte levels in their sweat, an observation which, first described by di Sant’Agnese et al. (1953), became the hallmark for CF diagnosis.link_to_subscribed_fulltex