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AimsThe review of a case of rare hereditary cardiomyopathy with severe heart failure and unfavourable prognosis.patients and methods:A boy is the second child in a family; the first child, a girl, died at the age of 2.5 years from chronic heart failure (CHF). No cardiologic observation had been performed until the age of 1.5 years, when the boy suffered from oedema, dyspnea, and wheezing. He was hospitalised and diagnosed with left ventricular non-compaction (LVNC), left ventricular dilatation cardiomyopathy (DCM), reduced myocardial contractility, EF 38%. The therapy of CHF raised EF to 46%–50%.The molecular genetic testing of the proband was carried by the new-generation sequencing (NGS) method, using cardiac panel including target regions of 404 genes, which mutations are the reason of a cardiac phenotype diseases.ResultsThe molecular genetic testing of the proband identified the novel homozygous splicing substitution c.559+ 1G>A in the MYL3 gene and heterozygous polymorphism c.649A>G in the MYBPC3 gene. Both the proband’s parents are heterozygous nucleotide substitutions c.559+ 1G>A in the MYL3 gene without clinical manifestations, indicating recessive inheritance of this mutation. The MYL3 gene encodes the myosin cardiac ventricular essential light chain; its mutations are very rare and strongly associated with heart failure and unfavourable prognosis.During the observed period of 2 years, the therapy of CHF including high doses of diuretics, aldosterone antagonists, ACE inhibitors, b-blockers and digoxin has showed the increase of heart failure.ConclusionThe molecular genetic testing determined the reason of the LVNC and DCM phenotype of a boy, it proved autosomal recessive inheritance of MYL3 gene mutations and also provided effective medical-genetic assistance to the family, including methods of preimplantation genetic diagnosis.

BackgroundDuplication 15q11.2 - q13 characterized by autism spectrum disorder (ASD), intellectual disability, motor delays and epilepsy, particularly infantile spasms. Disease frequency in the population is 2–5: 10000, among people with ASD - 1:250–1:500.The duplication described in as an interstitial duplication20% cases and as supernumerary isocentric chromosome in 80% of cases.Patients and methodsWe analyzed 5 patients 15q11-q13 duplication aged 3 to 5 years - 3 girls and 2 boys. We researched the clinical picture in 5 children with 15q11-q13 duplication syndrome. Age of children ranged from 3 years (36 months) averaging 4 years (48.2 months),3 girls and 2 boys. Array CGH was proved in 4 children, and FISH diagnostic- in one case of supernumerary isocentric chromosome 15.ResultsWe determined the duplication size from 437009 to 4914267 kb. One patients revealed two independent duplication the analyzed area - 15q11.2 (25199239_25199239) x3, 15q12 (27183835_27604796)x3. In one case identified variant - ish inv dup (15) (q11.2q13)(D15Z1++, D15S10++).All patients have development delayed and mental retardation, mild to severe. Speech disorders was varying degrees, one child had echolalia. Behavioural problems were presented with autistic features (3 children), stereotypes (4 children), hyperactivity (3 children), aggression (1 child).Elements of abdominal obesity noted in one patient. Facial features was represented flat nose, epicantic folds, broad nose tip, long filtrum.EEG was performed in 3 patients. Typical epileptiform activity was not registered. Two children had cardiac arrhythmias: recurrent ventricular tachycardia in one patient, recurrent ectopic atrial tachycardia, transient AV block- in another.ConclusionDuplication 15q11.2 - q13 was diagnosed in 5 patients with behavioral problem.Two patients have cardiac arrhythmias.

BackgroundNoonan syndrome, type 2 (NS2) is rare autosomal recessive disorder of RASopathies group, caused by mutations in the LZTR1 gene. NS2 characterized by a typical face, short stature, broad, short neck, congenital heart disease, developmental delay. The most common heart disease in children with NS2 is hypertrophic cardiomyopathy.Patients and MethodsPatient is a boy, 15 years old with short stature, developmental delay at 1 first year of life and heart disease. He had distinctive facial features of NS: downslanting palpebral fissures, epicanthic folds, hypertelorism, low-set ears short neck, wing-like folds on the neck, pectus deformity. Hypertrophic cardiomyopathy was identified at 1 month old. Now patient have obstructive, hyperthrophic cardiomyopathy, cardiac arrhythmia: ventricular extrasystoles, 4A Lown, intraventricular block combined with bundle branch block, transient WPW. Syncopal episodes.Surgical correction of obstructive hypertrophic cardiomyopathy: septal myomectomy was performed on the child due to the high risk of developing sudden death syndrome. Target areas of the exome were investigated by next generation sequencing (NGS). Bioinformatic analysis was carried out using ACMG recomendation. Validation of the identified variants was carried out by the Sanger method.ResultsWe revealed nucleotide missens VUS: c.1259A>G, p.Q420R and c.2051T>C, p.I684T in the heterozygous state in LZTR1 gene. All variants were absent in HGMD professional and gemome aggregatioonal database.ConclusionChild with severe hypertrophic cardiomyopathy and typical phenotype of Noonan syndrome was detected NS 2, caused by compound heterozygous missense variants c.2051T>C, p.I684T and c.1259A>G, p.Q420R in LZTR1 gene.

Pitt-Hopkins syndrome is rare inherited disease, characterized by mental retardation, moderate to severe, autistic disorders, breathing problems, seizures, apnea, and distinctive facial features. Frequency of disease is between 1: 34 000 – 1: 41 000 in newborn. Pitt-Hopkins syndrome (PTHS) is caused by deletions, duplication (30%), lager deletion (30%), point mutation (40%) in the TCF4 gene located at 18q21.2 and encoding Transcription Factor 4. Variants in TCF4 usually occur de novo in children with severe phenotype, milder phenotypes inherited autosomal dominant We have examined 9 patients (4 boys and 5 girls) with Pitt-Hopkins aged 1 to 12 years.Array-comparative genomic hybridization was performed in 5 children Target areas of the exome were investigated by massive parallel sequencing (NGS) in 4 cases. Validation of the identified variants was carried out by the Sanger method.De novo microdeletions 1 revealed in 5 cases: arr 18q21.2q21.32 (51266708_56293087) ×1, arr 18q21.2 (52691678_52999165) ×1, arr 18q21.2q21.1 (50029734_61654329) ×1, arr 18q21.2q21.31 (51620900_54883094) ×1, arr18q21.2q21.31 (49493248_55403360) ×1. Detected deletions was from 307 Kb to 1162 Mb.We identified 4 different mutations in the TCF4 gene in 4 patients with Pitt-Hopkins syndrome: c.961+2T>C, c.1452+1G>T, c.1634C>G, c.2033G>A.Spectrum of mutations represented by splicing site mutations, nonsense and missense mutations.All children had severe motor development delay and muscle hypotonia. Only one child was able to walk independently. All children had severe mental retardation. Expressive speech represented by vocalizations, individual words. Autistic and behavioral disorders were in 6 children. Severe episodes of hyperventilation followed by apnea observed in one child. Dysmorphic features included coarse face, protruding lower face, deep-set eyes, upslanting palpebral fissures, high, wide nose bridge, wide open mouth, cupid’s bow upper lip – thick, fleshy lips, cup-shaped ears. Three children diagnosed with myopia, scoliosis in one case. Brain MRI (in 4 children) show hypoplasia/dysplasia of the corpus callosum, atrophy/hypoplasia of the cerebellum, Dandy – Walker anomaly, hydrocephalus, small hippocampus size.ConclusionPitt-Hopkins syndrome is important for the differential diagnosis in children with severe mental retardation and behavioral disorders.

CDG Ib type is a rare autosomal recessive disorder (OMIM 154550) manifesting as coagulopathy, hypoglycemia, enteropathy, liver damage, delayed physical development etc. Approximately 20 cases of CDG Ib are described world-wide, being one of two CDG types, responding to treatment (along with CDG IIc type). CDG Ib is caused by a mutation in mannose-6-phosphate isomerase. Then, mannose-6-phosphate for protein N-glycosylation can only be synthesised from outside sources mannose. Treatment with d-mannose is the only described therapy for CDG Ib. We have extablished the diagnosis in 2 patients. Patient 1 was a 9 months old girl with exudative enteropathy, hypoproteinemia, ascites, liver fibrosis, malabsorption, multiple deficiency syndrome, hypoglycemia, coagulopathy with low antithrombin III and protein C, and right atrium thrombosis. Patient 2 was a 10 months old boy with severe physical delay and liver damage. Coagulogram studies showed low antithrombin III/protein C levels. The diagnosis was proved by molecular genetics and biochemistry in both cases. Mutation in mannose-6-phospahte isomerase gene (Ar219Trp – R219W) and abnormally structured glycoproteins (transferrin, α1-antitrypsin, haptoglobin) were discovered in patient 1. Mutation c.1252T>C in homozygotic state was found in MPI gene of patient 2. Treatment with d-mannose (150 mg/kg) resulted in stool normalisation, albumin, glucose, antithrombin III and protein C levels’ increase, intoxication symptoms and clot’s disappearance in 2 weeks. Frequent episodes of acute respiratory infections with manifested CDG symptoms demanded the increase of d-mannose (up to 230 mg/kg). The therapy revealed no side effects. Normal glucose, albumin and antithrobmin III were the criteria for adequate dose selection. We conclude that CDG Ib should be considered in patients with unexplained chronic diarrhoea, hypoglycemia, liver pathology, thromboses/haemorrhages, allowing early diagnostics/effective management for this rare disorder.

Background and aimsLast five years more than 50 novel microdeletion and microduplication syndromes were described. Sometimes we find rare chromosome anomalies, which clinical significance is not always known.Our aim was to describe the new phenotype of rare chromosome disorders in patient with mental retardation caused by genotype combined with different microdeletionMethodsBoy, 5 years old, was observed with developmental delay with the first year of life. Clinical features: upslanting palpebral fissures, epicanthal folds, short philtrum, synophrys, microstomia, low set ears, prominent forehead, high borderline of hair growth, sensorineural and conductive deafness. We used the CytoScan HD Array solution (Affymetrix) for detecting of chromosomal pathological variants lager than 50 kb. ResultsWe detected a 7,4 Mb pathogenic deletion in chromosome region 7 p21.1–7 p15.2 and a smaller one 494 kb deletion in the chromosome region 22q12.1 spanning the genes TTC28 and CHEK2. This deletion has not been described previously. According to the literature, deletions in this chromosomal region larger than 300 kb was described in patients with mental retardation and multiple malformations including conductive deafness.ConclusionsIt is known that the patients with deletions in 7 p21–p14.3 chromosome region have mental retardation and facial features similar to Greig syndrome and patients with 22q12 deletions have mental retardation, hearing loss and heart disease. All of these clinical features were present in phenotype of our patient. The results of our molecular cytogenetic research allow to reveal the combination of two microdeletions which fully explain the existing phenotype of patient. The Affymetrix microarray solutions is a powerful flexible method for detection of rare chromosomal aberrations which can help to paediatricians and clinical geneticists explain and describe new phenotype in patients with rare chromosome disorders.

Background and aimsSyndrome deletion of chromosome region 1 p36 is a chromosome syndrome with multiple anomalies, congenital heart disease and mental retardation. Frequency of this syndrome is 1 in 5000 births. Rare variant deletion p36 is deletion 1 p36.33-p36.32 include genes PRDM16 and LMNA genes. Mutations in these genes were described in patients with dilated cardiomyopathy and left ventricular noncompaction. Our aim was to determine the correlations between genotype and phenotype in patients with multiple anomalies, congenital heart disease and developmental delay, which carried different deletions in 1 p36 chromosome region.MethodsWe used MLPA method for detection of deletions in 1 p36.33-p36.32 chromosomal region and CytoScan HD microarray solutions to determine the exact borders of the deletion Case No1: Girl, 7 years old. Cardiomyopathy identified in 2009. Clinical features: mild face hypoplasia, deep set eyes, long philtrum, prominent forehead, wide nasal tip, low-set ears, brachydactyly, wide terminal phalanges, noncompaction cardiomyopathy of dilated variant and abdominal aorta hypoplasia. Case No2: Girl, 2 years old. Heart disease was detected in first year of life. Clinical features: Prominent forehead, mildface hypoplasia, short palpebral fissure, epicanthal folds, high-arched palate, irregular teeth, duodenal atresia, left ventricular noncompaction, mental retardation.ResultsWe detected in 1 p36.33-p36.32 chromosomal region the 3797 kb deletion in the first case and 2263 kb deletion in the second caseConclusionsDetection deletion of chromosomal region 1 p36 in patients with heart disease, congenital anomalies, mental retardation and developmental delay is important for the correct diagnosis, treatment and prevention this disease in families. We offer diagnostic algorithm which combines MLPA as a screening method and CytoScan HD microarray technology as a more precise method.This algorithm allowed us to find phenotype correlations on the basis of the deleted regions.

AimsThe review of a case of rare hereditary cardiomyopathy with severe heart failure and unfavourable prognosis.patients and methods:A boy is the second child in a family; the first child, a girl, died at the age of 2.5 years from chronic heart failure (CHF). No cardiologic observation had been performed until the age of 1.5 years, when the boy suffered from oedema, dyspnea, and wheezing. He was hospitalised and diagnosed with left ventricular non-compaction (LVNC), left ventricular dilatation cardiomyopathy (DCM), reduced myocardial contractility, EF 38%. The therapy of CHF raised EF to 46%-50%.The molecular genetic testing of the proband was carried by the new-generation sequencing (NGS) method, using cardiac panel including target regions of 404 genes, which mutations are the reason of a cardiac phenotype diseases.ResultsThe molecular genetic testing of the proband identified the novel homozygous splicing substitution c.559+ 1G>A in the MYL3 gene and heterozygous polymorphism c.649A>G in the MYBPC3 gene. Both the proband's parents are heterozygous nucleotide substitutions c.559+ 1G>A in the MYL3 gene without clinical manifestations, indicating recessive inheritance of this mutation. The MYL3 gene encodes the myosin cardiac ventricular essential light chain; its mutations are very rare and strongly associated with heart failure and unfavourable prognosis.During the observed period of 2 years, the therapy of CHF including high doses of diuretics, aldosterone antagonists, ACE inhibitors, b-blockers and digoxin has showed the increase of heart failure.ConclusionThe molecular genetic testing determined the reason of the LVNC and DCM phenotype of a boy, it proved autosomal recessive inheritance of MYL3 gene mutations and also provided effective medical-genetic assistance to the family, including methods of preimplantation genetic diagnosis.

BackgroundThe variability of the pharmacological response to beta 2 ( beta 2)-agonists may be due to the polymorphism of the gene of beta 2 adrenergic receptor (ADR beta 2). The objective of our research was to evaluate the significance of ADR beta 2 gene polymorphism in the 16th amino acid position in the efficiency of broncholytic therapy by beta 2-agonists among children with bronchial asthma.Materials and methodsWe defined the type of ADR beta 2 gene among 208 children with bronchial asthma of various severity by means of polymerase chain reaction. The distribution of the patients into two groups was carried out subject to the efficiency of the beta 2-agonists based short-term therapy during the exacerbation of bronchial asthma. 171 children received the inhaled glucocorticoids.ResultsSingled out statistically significant differences of the genotype distribution. The Gly/Gly16 homozygous allele was discovered twice as often in the group with an insufficient response to beta 2-agonists than in the group with a good response (66 vs 38%, P<0.001), while the distribution of heterozygous allele was detected the opposite pattern (55 vs 28%, P<0.001). In the Arg/Arg16 genotype distribution, there were no considerable differences in both groups (6% in each group). In the subgroups of children, receiving the high doses of the inhaled glucocorticoids, there was a trend for the prevalence of Gly/Gly16 homozygous allele prevalence.ConclusionWe have discovered the association of the Gly/Gly16 genotype of the ADR beta 2 gene with an insufficient effect of broncholytic therapy by means of short-term beta 2-agonists; we also revealed the participation of the Gly16 allele in the phenotype formation with the severe run of bronchial asthma and tolerance towards the therapy both by beta 2-agonists and inhaled glucocorticoids.