The amount of human long noncoding RNA (lncRNA) genes is comparable to protein-coding; however, only a small number of lncRNAs are functionally annotated. Previously, it was shown that lncRNAs can participate in many key cellular processes, including regulation of gene expression at transcriptional and post-transcriptional levels. The lncRNA genes can contain small open reading frames (sORFs), and recent studies demonstrated that some of the resulting short proteins could play an important biological role. In the present study, we investigate the widely expressed lncRNA LINC00493. We determine the structure of the LINC00493 transcript, its cell localization and influence on cell physiology. Our data demonstrate that LINC00493 has an influence on cell viability in a cell-type-specific manner. Furthermore, it was recently shown that LINC00493 has a sORF that is translated into small protein SMIM26. The results of our knockdown and overexpression experiments suggest that both LINC00493/SMIM26 transcript and protein affect cell viability, but in the opposite manner.

Meier–Gorlin syndrome (MGS) is a rare genetic developmental disorder that causes primordial proportional dwarfism, microtia, the absence of or hypoplastic patellae and other skeletal anomalies. Skeletal symptoms overlapping with other syndromes make MGS difficult to diagnose clinically. We describe a 3-year-old boy with short stature, recurrent respiratory infections, short-rib dysplasia, tower head and facial dysmorphisms who was admitted to the Tomsk Genetic Clinic to verify a clinical diagnosis of Jeune syndrome. Clinical exome sequencing revealed two variants (compound heterozygosity) in the ORC6 gene: c.2T>C(p.Met1Thr) and c.449+5G>A. In silico analysis showed the pathogenicity of these two mutations and predicted a decrease in donor splicing site strength for c.449+5G>A. An in vitro minigene assay indicated that variant c.449+5G>A causes complete skipping of exon 4 in the ORC6 gene. The parents requested urgent prenatal testing for MGS for the next pregnancy, but it ended in a miscarriage. Our results may help prevent MGS misdiagnosis in the future. We also performed in silico and functional analyses of ORC6 mutations and developed a restriction fragment length polymorphism and haplotype-based short-tandem-repeat assay for prenatal genetic testing for MGS. These findings should elucidate MGS etiology and improve the quality of genetic counselling for affected families.

Hermansky–Pudlak syndrome (HPS) is a rare disease inherited in the autosomal recessive mode, including 11 clinical genetic subtypes. They are associated with impaired function of the BLOC protein complex (Biogenesis of Lysosome-related Organelles Complexes), and the subunits of the AP-3 complex (adaptor protein complex). Each has its own clinical features, but they are all characterized by albinism, bleeding disorder, and visual abnormalities. Eleven patients from eight unrelated families with an incoming diagnosis of albinism were examined and novel and previously described genetic variants in HPS1, HPS6, and BLOC1S6 genes (types HPS1, HPS6, and HPS9) were found. To determine the optimal therapy and recommendations for further follow up, it is necessary to consider the entire clinical spectrum and genetic polymorphism of the disease. An interdisciplinary approach, combined with the use of non-routine diagnostic techniques such as RNA analysis, is essential for achieving accurate diagnoses in certain complex cases.

CONTEXT Syndrome of adrenal insufficiency, obesity, and red hair is a rare autosomal recessive disorder. The majority of disease-causing variants associated with the syndrome are located in the coding region of the POMC gene. OBJECTIVE To describe seven unrelated patients who shared a novel homozygous mutation in the 5′-untranslated region of the POMC gene and functionally characterize this novel variant. METHODS Whole exome sequencing (WES) with autozygosity mapping, Sanger sequencing, model expression system studies and RNA sequencing were used for identification of the disease causing variant and its subsequent functional characterization. PATIENTS Seven unrelated patients of Perm Tatar ethnic group presented with hypoglycemia and excessive weight gain, low plasma ACTH and cortisol. Five of seven children had red hair. Six of seven patients also showed signs of bronchial obstruction. RESULTS WES showed shared autozygosity regions overlapping the POMC gene. Sanger sequencing of POMC 5′-untranslated region detected a homozygous variant chr2:25391366C>T (hg19) at splice donor site of intron 1. As demonstrated by model expression system, the variant led to a significant decrease in the POMC mRNA level. Analyses of the patients’ haplotypes were suggestive of the founder effect. We estimated that the mutation must have occurred at least 4.27 generations ago (95% CI: 0.86–7.67). CONCLUSIONS The current report presents a new molecular mechanism of POMC deficiency and contribute to the information on phenotypic variability in patients with this disorder.

Background: Variegate porphyria is a rare heme biosynthesis disorder caused by pathogenic variants in the PPOX gene. Despite being relatively well characterized, its clinical manifestations are highly variable and can mimic a broad spectrum of neurological and systemic conditions. Case Presentation: We report the case of a young woman with recurrent episodes of muscle weakness, sometimes accompanied by respiratory dysfunction. Initially suspected to have myasthenia gravis, laboratory testing for this condition was negative. Whole‐genome sequencing identified a heterozygous pathogenic variant c.338G>C in the PPOX gene and a homozygous variant of uncertain significance c.190G>A in MYMK, with no other disease‐causing variants detected in genes associated with congenital myasthenic syndromes or periodic paralysis. Conclusion: In the described case, the patient's atypical clinical manifestations led to a prolonged and complex diagnostic workup. WGS findings suggested possible co‐occurrence of variegate porphyria with a potential overlap with a Carey–Fineman–Ziter syndrome. This case highlights the importance of comprehensive evaluation of the clinical presentation in patients with unexplained neuromuscular symptoms.

Meier–Gorlin syndrome (MGS) is a rare genetic developmental disorder that causes primordial proportional dwarfism, microtia, absent or hypoplastic patellae and other skeletal anomalies. Overlapping skeletal symptoms make MGS difficult to diagnose clinically. We describe a 3-year-old boy with short stature, recurrent respiratory infections, short-rib dysplasia, tower head and facial dysmorphisms who was admitted to the Tomsk Genetic Clinic to verify a clinical diagnosis of Jeune syndrome. Clinical Exome sequencing revealed two variants (compound heterozygosity) in the ORC6 gene: c.2T>C(p.Met1Thr) and c.449+5G>A. In silico analysis showed the pathogenicity of these two mutations and predicted a decrease in donor splicing site strength for c.449+5G>A. An in vitro minigene assay demonstrated that variant c.449+5G>A causes a complete skipping of exon 4 in ORC6 gene. The parents asked for urgent prenatal testing for MGS for the next pregnancy, but it ended in a miscarriage. Thus, this case report may help to prevent MGS misdiagnosis in the future. We also performed in silico and functional analyses of ORC6 mutations and developed a restriction fragment length polymorphism and haplotype-based short-tandem-repeat assay for prenatal genetic testing for MGS. These findings should elucidate MGS aetiology and improve the quality of genetic counselling for affected families.