Detection of Germline Mutations in a Cohort of 250 Relatives of Mutation Carriers in Multigene Panel: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2.

BACKGROUND: Several hereditary-familial syndromes associated with various types of tumors have been identified to date, evidencing that hereditary cancers caused by germline mutations account for 5-10% of all tumors. Advances in genetic technology and the implementation of Next-Generation Sequencing (NGS) have accelerated the discovery of several susceptibility cancer genes, allowing for the detection of cancer-predisposing mutations in a larger number of cases. The aim of this study is to highlight how the application of an NGS-multigene panel to a group of oncological patients subsequently leads to improvement in the identification of carriers of healthy pathogenic variants/likely pathogenic variants (PVs/LPVs) and prevention of the disease in these cases. METHODS: Starting from a total of 110 cancer patients carrying PVs/LPVs in genes involved in cancer susceptibility detected via a customized NGS panel of 27 cancer-associated genes, we enrolled 250 healthy collateral family members from January 2020 to July 2022. The specific PVs/LPVs identified in each proband were tested in healthy collateral family members via Sanger sequencing. RESULTS: A total of 131 out of the 250 cases (52%) were not carriers of the mutation detected in the affected relative, while 119 were carriers. Of these, 81/250 patients carried PVs/LPVs on BRCA1/2 (33%), 35/250 harbored PVs/LPVs on other genes beyond BRCA1 and BRCA2 (14%), and 3/250 (1%) were PVs/LPVs carriers both on BRCA1/2 and on another susceptibility gene. CONCLUSION: Our results show that the analysis of BRCA1/2 genes would have only resulted in a missed diagnosis in a number of cases and in the lack of prevention of the disease in a considerable percentage of healthy carriers with a genetic mutation (14%).

Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies.

Spinal muscular atrophy (SMA) linked to 5q is a recessive motor neuron disease characterized by progressive and diffuse weakness and muscular atrophy. SMA is the most common neurodegenerative disease in childhood with an incidence of approximately 1 in 6000-10,000 live births, being long considered a leading cause of hereditary mortality in infancy, worldwide. The classification of SMA is based on the natural history of the disease, with a wide clinical spectrum of onset and severity. We are currently in a new therapeutic era, that, thanks to the widespread use of the newly approved disease-modifying therapies and the possibility of an early administration, should lead to a deep change in the clinical scenario and, thus, in the history of SMA. With the aim to achieve a new view of SMA, in this review we consider different aspects of this neuromuscular disease: the historical perspective, the clinical features, the diagnostic process, the psychological outcome, innovation in treatments and therapies, the possibility of an early identification of affected infants in the pre-symptomatic phase through newborn screening programs.

First case of two supernumerary markers derived from chromosome 5 and chromosome 8.

BACKGROUND: Small supernumerary marker chromosomes (sSMC) are additional centric chromosome fragments too small to be identified by banding cytogenetics alone. A sSMC can originate from any chromosome and it is estimated that 70% of sSMC are de novo, while 30% are inherited. Cases of sSMC derived from chromosome 5 (sSMC5) are rare, accounting for1.4% of all reported sSMC cases. In these patients, the most common reported features are macrocephaly, dysmorphic facial features, heart defects, growth retardation, hypotonia, and intellectual disability. Also sSMC derived from chromosome 8 are very rare and the phenotype of patients with sSMC8 is very variable. Common clinical features of the patients include developmental delay, mental retardation, intellectual disability, hypotonia, hypospadias, attention deficit hyperactivity disorders (ADHD), skeletal anomalies, dysmorphic facial features, and renal dysplasia. To the best of our knowledge, in literature there are no cases with coexistence of sSMC5 and sSMC8, so we reviewed the literature to compare cases with SMC5 and those with SMC8 separately. This study is aimed to highlight the unique findings of a patient with the coexistence of sSMC5 and sSMC8. CASE PRESENTATION: We describe a female patient with two supernumerary markers derived from chromosome 5 (SMC5) and chromosome 8 (SMC8). The patient was born prematurely at 30 weeks with respiratory distress and bronchodysplasia. On physical examination she presented dysmorphic features, respiratory issues, congenital heart defect, developmental delay, and intellectual disability. The G-banded chromosome analysis on cultured lymphocytes revealed in all the analyzed cells a female karyotype with the presence of two supernumerary chromosomal markers and the array-CGH highlighted the region and the size of these two duplications. We also used the fluorescent in situ hybridization analysis (FISH) using painting of chromosomes 5 and 8 to confirm the origin of the two sSMC. So, the karyotype of the patient was: 48, XX, +mar1, +mar2. CONCLUSIONS: This is the first case with two markers: one from chromosome 5 and one from chromosome 8. Based on the data reported, we can affirm that the phenotype of our patient is probably caused mainly by the presence of the sSMC.