Muscular dystrophies are a diverse group of inherited muscle disorders with a wide range of clinical manifestations from a severe form with early onset and early death to adult forms with later onset and minimal clinical manifestation that do not affect life-span. Overlapping clinical symptoms and the multitude of genes that need to be analyzed for an accurate characterization make the diagnosis hard. In next-generation sequencing era, a lot of used assay in molecular diagnostics must be taken into consideration for muscular dystrophy diagnosis. However, for more accurate diagnosis, muscle protein expressions analysis may have prognostic value. In this chapter, we present the most important clinical and laboratory findings in the most common forms of muscular dystrophies and molecular diagnostic approaches for a more accurate diagnosis.
Part of the book: Muscular Dystrophies
Phelan-McDermid (PMS) or 22q13 deletion syndrome (OMIM 606232) is a rare genetic disorder with highly variable clinical presentation. The phenotype includes generalized neonatal hypotonia, developmental delay with intellectual disability and delayed speech, mild dysmorphic features, and autistic behavior. The genetic defects of PMS consist of 22q13.3 deletions or chromosomal structural rearrangements involving SHANK3 gene; the loss of function mutations of SHANK3 gene was reported in a minority of cases. The 22q13.3 deletions vary in size, from 0.2 to over 9 Mb, and, although larger deletions are generally associated with more severe phenotypes, the genotype-phenotype correlations are not clear-cut for all patients. SHANK3 is considered the main candidate gene for the neurologic features of PMS. PMS is a rare disorder, often underdiagnosed. There are no established clinical diagnostic criteria for PMS. The genetic tests typically used are chromosomal microarray and multiplex ligation-dependent probe amplification (MLPA) or fluorescent in situ hybridization (FISH) for copy number analysis of SHANK3 gene; next-generation sequencing (NGS) or Sanger sequencing is used for pathogenic mutation screening of SHANK3. In this chapter, we report three cases with PMS and summarize the clinical and genetic diagnostic approaches of this condition, highlighting the role of chromosomal microarray technology in the identification of rare, but significantly impacting patient’s life, DNA copy number abnormalities.
Part of the book: Chromosomal Abnormalities