Clinical Case of Mild Tatton-Brown-Rahman Syndrome Caused by a Nonsense Variant in DNMT3A Gene.

Tatton-Brown-Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the DNMT3A gene, which is an important participant in epigenetic regulation, especially during embryonic development, and is highly expressed in all tissues. The main features of the syndrome are high growth, macrocephaly, intellectual disability, and facial dysmorphic features. We present a clinical case of Tatton-Brown-Rahman syndrome in a ten-year-old boy with macrocephaly with learning difficulties, progressive eye impairment, and fatigue suspected by a deep learning-based diagnosis assistance system, Face2Gene. The proband underwent whole-exome sequencing, which revealed a recurrent nonsense variant in the 12th exon of the DNMT3A, leading to the formation of a premature stop codon-NM_022552.5:c.1443C>A (p.Tyr481Ter), in a heterozygous state. This variant was not found in parents, confirming its de novo status. The patient case described here contributes to the understanding of the clinical diversity of Tatton-Brown-Raman syndrome with a mild clinical presentation that expands the phenotypic spectrum of the syndrome. We report the first recurrent nonsense variant in the DNMT3A gene, suggesting a mutational hot-spot. Differential diagnoses of this syndrome with Sotos syndrome, Weaver syndrome, and Cowden syndrome, as well as molecular confirmation, are extremely important, since the presence of certain types of pathogenic variants in the DNMT3A gene significantly increases the risk of developing acute myeloid leukemia.

Identification of a Novel Indel Variant in the DARS2 Gene in Russian Patients with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation.

BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. CASE PRESENTATION: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy.

New Case of Spinocerebellar Ataxia, Autosomal Recessive 4, Due to VPS13D Variants.

Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The VPS13D gene, part of the VPS13 family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of VPS13D-associated disease with two variants in the VPS13D gene in an adult female. This case contributes to our evolving understanding of VPS13D-related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions.

The Genetic Basis of the First Patient with Wiedemann-Rautenstrauch Syndrome in the Russian Federation.

Bi-allelic pathogenic variations within POLR3A have been associated with a spectrum of hereditary disorders. Among these, a less frequently observed condition is Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome. This syndrome typically manifests neonatally and is characterized by growth retardation, evident generalized lipodystrophy with distinctively localized fat accumulations, sparse scalp hair, and atypical facial features. Our objective was to elucidate the underlying molecular mechanisms of Wiedemann-Rautenstrauch syndrome (WRS). In this study, we present a clinical case of a 7-year-old female patient diagnosed with WRS. Utilizing whole-exome sequencing (WES), we identified a novel missense variant c.3677T>C (p.Leu1226Pro) in the POLR3A gene (NM_007055.4) alongside two cis intronic variants c.1909+22G>A and c.3337-11T>C. Via the analysis of mRNA derived from fibroblasts, we reconfirmed the splicing-affecting nature of the c.3337-11T>C variant. Furthermore, our investigation led to the reclassification of the c.3677T>C (p.Leu1226Pro) variant as a likely pathogenic variant. Therefore, this is the first case demonstrating the molecular genetics of a patient with Wiedemann-Rautenstrauch syndrome from the Russian Federation. A limited number of clinical cases have been documented until this moment; therefore, broadening the linkage between phenotype and molecular changes in the POLR3A gene will significantly contribute to the comprehensive understanding of the molecular basis of POLR3A-related disorders.

The first case of a point pathogenic variant in the RREB1 gene in Noonan-like Rasopathy.

The RREB1 is a zinc finger transcription factor that plays a role in regulating gene expression and inactivating MAPK signalling components. To date, no pathogenic variant in the RREB1 gene has been associated with any disease, but several cases of 6p terminal deletions affecting the RREB1 gene have been reported. In this study, we report the first case of RREB1-associated Noonan-like RASopathy caused by a pathogenic variant within this gene. Genetic testing included whole-genome sequencing (WGS) of the proband and Sanger sequencing of the proband, his parents, and his sibling. The proband had a de novo c.2677del, p.(Ala893Argfs*20) variant, likely resulting in RREB1 haploinsufficiency. Comparative analysis of patients with microdeletions, including in the RREB1 gene, confirmed shared clinical traits while highlighting unique features, such as blue sclerae and absence of cardiac anomalies. This study reinforces previous data on RREB1 haploinsufficiency as the driver of a new Noonan-like RASopathy variant, which includes intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms as key clinical indicators. These findings shed light on this RREB1-related syndrome and underscore the necessity for further investigation into the functional consequences of RREB1 mutations.

Four Novel Disease-Causing Variants in the NOTCH3 Gene in Russian Patients with CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease with unknown mechanisms and a broad phenotypic spectrum. It is caused by pathogenic variants in the NOTCH3 gene. The symptoms of the disease mainly include recurrent strokes with vascular risk factors, migraine with aura, dementia, and mood disturbances. CASE PRESENTATION: Peripheral blood samples were collected from five patients from four unrelated families to extract genomic DNA. In four patients, analysis of exons 2, 3, 4, 5, 6 and adjacent intronic regions of the NOTCH3 gene was made via Sanger sequencing. Two previously undescribed nucleotide variants were identified in two patients: missense variant c.208G>T, (p.Gly70Cys) in exon 1 and splice-site variant c.341-1G>C in intron 3. Further DNA of two other patients were analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies. Two novel missense variants in the NOTCH3 gene were identified, c.1136G>A, (p.Cys379Tyr) in exon 7 and c.1547G>A, (p.Cys516Tyr) in exon 10. The pathogenic variant c.1547G>A, (p.Cys516Tyr) was confirmed in the fifth patient (family case) by Sanger sequencing. All patients had a history of headaches, transient ischemic attacks, memory impairment, and characteristics of MRI results. Three patients had strokes and two patients had psychiatric symptoms. CONCLUSION: We found four previously undescribed pathogenic variants in the NOTCH3 gene in five patients with CADASIL and described their clinical and genetic characteristics. These results expand the mutational spectrum of CADASIL.

Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia.

Leigh syndrome (LS), also known as infantile subacute necrotizing encephalopathy, is the most frequent mitochondrial disorder in children. Recently, more than 80 genes have been associated with LS, which greatly complicates the diagnosis. In this article, we present clinical and molecular findings of 219 patients with LS and give the detailed description of three cases with rare findings in nuclear genes MORC2, NARS2 and VPS13D, demonstrating wide genetic heterogeneity of this mitochondrial disease. The most common cause of LS in Russian patients are pathogenic variants in the SURF1 gene (44.3% of patients). The most frequent pathogenic variant is c.845_846delCT (66.0% of mutant alleles; 128/192), which is also widespread in Eastern Europe. Five main LS genes, SURF1, SCO2, MT-ATP6, MT-ND5 and PDHA1, account for 70% of all LS cases in the Russian Federation. Using next generation sequencing (NGS) technique, we were able to detect pathogenic variants in other nuclear genes: NDUFV1, NDUFS2, NDUFS8, NDUFAF5, NDUFAF6, NDUFA10, SUCLG1, GFM2, COX10, PMPCB, NARS2, PDHB and SLC19A3, including two genes previously associated with Leigh-like phenotypes-MORC2 and VPS13D. We found 49 previously undescribed nucleotide variants, including two deep intronic variants which affect splicing.

[Instrumental and laboratory parameters of myocardial function in adult patients with autoimmune polyglandular syndrome type 2, 3].

BACKGRAUND: Аutoimmune polyglandular syndrome (APS) it is characterized by damage to two or more endocrine glands, which eventually results in the hormonal failure. Some clinical studies describe the development of myocardial lesion in the setting of combined autoimmune endocrine pathology. In Russia the myocardial condition in adult patients with APS types 2 and 3 was examined for the first time. AIM: To evaluate the structure and functional state of the myocardium according to magnetic resonance imaging (MRI), to analyze changes in the spectrum of specific antiheart autoantibodies and markers of heart lesion in patients with APS types 2 and 3. MATERIALS AND METHODS: 50 patients with APS types 2, 3 were studied. 45 of them were performed with delayed contrast heart MRI. All 50 patients were tested for IgG antibodies to heart muscle antigens by indirect enzymatic immunoassay (EIA), for troponin I and natriuretic peptide by chemiluminescence immunoassay (CLIA), for creatine phosphokinase (CPK) by NAC (N - acetyl-L-cysteine), and for C-reactive protein (CRP) by immunoturbidimetry. RESULTS: According to the results of heart MRI (n=45), 91% showed signs of functional changes in the left ventricular (LV) myocardium without any signs of myocarditis. 38 of 45 examined patients had deviation of 2 or more indicants of the LV functional state, MEF 68.9±6.6%, IUMm - 86 [75; 99] g, IUSV - 60.9 [50; 66] ml, IUEDVi - 52 [44; 59] ml/m2 , IUESVi - 17 [15.3; 18] ml/m2 , IUESV - 26 [23; 31] ml, IUEDV - 85 [70; 92] ml. 1 patient (2%) had positive result according to the determination of antibodies (AB) to heart muscle antigens (AG). Troponin 1 indicants did not exceed the reference values. The level of CPK exceeded the reference values in 3 patients (6%), an increase of CRP, NT-proBNP was observed in 7 patients (14%), and a combined increase was observed in 1 case. CONCLUSIONS: We obtained MRI data indicating functional changes in the myocardium in patients with APS types 2 and 3. The autoimmune cause of these changes according to the results of determining of antiheart antibodies was not confirmed in most of the examined patients, the indicants of «damage¼ to the myocardium (troponin 1 and NT-proBNP) did not deviate from the reference range.