Novel Hypomorphic Mutation in FANCD2 Gene Observed in a Fetus with Multiple Congenital Anomalies

Congenital anomalies affect 1% to 2% of the newborns. The urinary tract and the kidneys are involved in 4-5% of the cases while upper-extremities abnormalities are present in 10%. Certain anomalies occur in isolation, whereas others are associated with systemic conditions. The prenatal detection of fetal anomalies compatible with life is a challenge for both the parents and the physician. The prognosis for the fetus/newborn and the reproductive decisions of the family largely depend on the causes underlying the disease. The reported case is of a G2P1 pregnant woman referred for routine ultrasound scan at 24 weeks of gestation (w.g.). The fetus had growth retardation, right kidney agenesis, bilateral absence of radial bones and thumbs, radial deviation of the wrists, and short humeri. Nuchal fold thickness was 5 mm and there was a single umbilical artery. After termination of pregnancy, SNP array genotyping and next-generation sequencing of targeted candidate-genes were performed trying to clarify the etiology of the fetal polymalformative syndrome. A new hypomorphic mutation in FANCD2 gene was found to underlie this fetal anomaly. The case illustrates that patients/families affected by rare monogenic disorders may benefit from application of modern technologies like microarrays and NGS

Double heterozygosity of novel variants found in patients with severe clinical phenotype of cardiovascular disorders

Cardiovascular diseases (CVD) comprise a broad range of disorders of the heart and blood vessels. In this study, we used next-generation sequencing with a panel that includes 174 genes connected to CVD in order to investigate the possible genetic causes that underline some clinical phenotypes and their severity. Two patients were found with double heterozygosity, each carrying one new variant. One patient with supravalvular aortic stenosis has novel ELN: c.890-1G>A and a known variant SCN5A: p.Gly9Val in a heterozygous state, whereas another patient with hypertrophic cardiomyopathy has a heterozygous novel CACNA1C: p.Arg514Gly and a known SCN5A: p.Arg800His variant. This method proved to be useful in determining the mutation status in correlation with the severity of the clinical phenotype and can further clarify cases where the clinical status could not be explained only by single gene mutation detected by standard methods

Screening of pharmacogenetic variants associated with drug sensitivity in patients with papillary thyroid carcinoma using next generation sequencing

Thyroid cancer is the most common malignant tumour of the endocrine system. One of the most frequent types of thyroid malignancy is papillary carcinoma. In our study, we performed next generation sequencing (NGS) using a cancer panel (Illumina; Illumina, San Diego, USA) to screen for pharmacogenetic susceptibility variants in blood samples of 10 patients with papillary thyroid cancer (PTC). We report variants rs1042522 (TP53), rs2228001 (XPC), rs2227983 (EGFR), rs13181 (ERCC2), rs17655 (ERCC5) and rs1799939 (RET), which were detected in the analyzed patients either in homozygous and/or heterozygous state previously known to be connected with pharmacogenetic sensitivity to certain drugs in oncology. The results showed the TruSight Cancer Panel to be a useful clinical tool for determination of oncotherapy-associated pharmacogenetic variants in the blood of patients

SCN8A p.Arg1872Gln mutation in early infantile epileptic encephalopathy type 13: Review and case report

Early infantile epileptic encephalopathy (EIEE) is a disorder with variable genetic heterogeneity. Symptoms are mostly presented with generalised epileptic seizures with an infantile onset and progressive neurodevelopmental delay. Early infantile epileptic encephalopathy13 is caused by mutations in the SCN8A gene, which encodes the neuronal voltage-gated sodium channel α subunit (Nav1.6) and plays a major role in neuronal excitability. Describing the wide clinical variability of previously reported cases of patients carrying the same mutation, we demonstrate the complexity of the disease and the necessity of correctly correlating the phenotype with the genotype. Here, we present a minireview and a case report of EIEE13 involving the rare p.Arg1872Gln mutation in the SCN8A gene. We used targeted next-generation sequencing to examine a six-year-old girl with complex partial seizures from the left temporal lobe since 4 months of age. The condition was difficult to control with medication and the seizures evolved to generalised tonic-clonic seizures after the age of 3 years. Neurodevelopment in the child became severely delayed although seizures were as rare as 1 in every 5–10 months. А heterozygous missense mutation in the SCN8A gene (NM_014191.3:c.5616G > A, NP_055006.1:p.Arg1872Gln) was found. The variant was validated by Sanger sequencing. We suggest that this SCN8A mutation has a primary neurodegenerative effect leading to brain atrophy and intellectual disability (with or without autism) that is partially independent of its epileptogenic effect. Our results demonstrate that the application of large panels with clinically-associated genes is essential for identifying rare mutations in individuals with disorders of unknown etiology