Goldberg-Shprintzen megacolon syndrome with associated sensory motor axonal neuropathy.

Goldberg-Shprintzen megacolon syndrome (GOSHS) (OMIM 609460) is characterized by a combination of learning difficulties, characteristic dysmorphic features and Hirschsprung's disease. Variable clinical features include iris coloboma, congenital heart defects and central nervous system abnormalities, in particular polymicrogyria. GOSHS has been attributed to recessive mutations in KIAA1279, encoding kinesin family member (KIF)-binding protein (KBP) with a crucial role in neuronal microtubule dynamics. Here we report on a 7-year-old girl with GOSHS as a result of a homozygous deletion of exons 5 and 6 of the KIAA1279 gene. She had been referred with the suspicion of an underlying neuromuscular disorder before the genetic diagnosis was established, prompted by the findings of motor developmental delay, hypotonia, ptosis and absent reflexes. Neurophysiological studies revealed unequivocal evidence of a peripheral axonal sensory motor neuropathy. We hypothesize that an axonal sensory motor neuropathy may be part of the phenotypical spectrum of KIAA1279-related GOSHS, probably reflecting the effects of reduced KBP protein expression on peripheral neuronal function.

New clinical molecular diagnostic methods for congenital and inherited heart disease.

IMPORTANCE OF THE FIELD: For patients with congenital and inherited heart disorders, causative mutations are often not identified owing to limitations of current screening techniques. Identifying the mutation is of major importance for genetic counseling of patients and families, facilitating the diagnosis in people at risk and directing clinical management. Next-generation sequencing (NGS) provides unprecedented opportunities to maximize mutation yields and improve clinical management, genetic counseling and monitoring of patients. AREAS COVERED IN THIS REVIEW: Recent NGS applications are reviewed, focusing on methods relevant for molecular diagnostics in cardiogenetics. Requirements for reliable implementation in clinical practice and challenges that clinicians, bioinfomaticians and molecular diagnosticians must deal with in analyzing resulting data are discussed. WHAT THE READER WILL GAIN: Readers will be introduced to recent developments, techniques and applications in NGS. They will learn about possibilities of using it in clinical diagnostics. They will become acquainted with difficulties and challenges in interpreting the data and considerations around communicating these issues to patients and the community. TAKE HOME MESSAGE: Although several obstacles are still to be overcome and there is much still to learn, NGS will revolutionize clinical molecular diagnostics of inherited and congenital cardiac diseases, maximizing mutation yields and leading to optimized diagnostic and clinical care.

Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon?

PURPOSE OF REVIEW: Recent developments in the elucidation of genes underlying arrhythmogenic right ventricular cardiomyopathy and possible pathogenic mechanisms will be highlighted. RECENT FINDINGS: The cardiac desmosome is a multiprotein structure involved in cell-cell interactions. Mutations in genes encoding desmosomal proteins such as PKP2, DSP, JUP, DSC2 and DSG2 underlie arrhythmogenic right ventricular cardiomyopathy, which can therefore be considered a desmosome cardiomyopathy. Mutations in the plakophilin-2 gene are most prevalent. Current pathophysiological insights suggest a final common pathway in which plakoglobin release from the desmosome, independent of the primarily affected desmosomal protein, results in desmosome impairment, intercalated disc remodeling and Wnt/beta-catenin pathway signaling defects. The recognition of left ventricular involvement associated with mutations in desmosomal protein genes and low penetrance suggests that formal criteria should not be followed too closely in selecting patients for DNA analysis, because finding a mutation may have important implications for clinical practice. SUMMARY: Recent developments have demonstrated that arrhythmogenic right ventricular cardiomyopathy can be considered a desmosome cardiomyopathy. Left ventricular involvement is not uncommon in this type of cardiomyopathy. Such findings are important for diagnostics and family screening and form a starting-point for the elucidation of other (non)-genetic factors influencing disease progression and outcome.