Association of Serum 25-Hydroxyvitamin D and Chronic Periodontitis in Postmenopausal Women after Non-Surgical Periodontal Therapy.

Objectives: Vitamin D deficiency appears to have a major effect on periodontal tissue health. The present study aimed to assess the association of the serum level of 25-hydroxyvitamin D and chronic periodontitis in postmenopausal women. Materials and Methods: This research was done on 30 postmenopausal women with chronic periodontitis who all had at least 20 natural teeth. Intravenous blood samples were taken from the study population at baseline and after completion of non-surgical periodontal treatment. This was followed by assessment of serum levels of 25-hydroxyvitamin D. Next, clinical parameters of all teeth except for third molars were measured, which included pocket depth (PD), gingival index (GI), and plaque index (PI). Data were analyzed by paired t-test and its non-parametric equivalent, the Wilcoxon test. P<0.05 was considered significant. Results: The mean PD, PI and GI before and after the intervention were significantly different (P<0.05). There was, however, no significant difference between the mean vitamin D concentrations before and after treatment (P>0.05). Conclusion: According to the results obtained in the present study, there is no association between serum vitamin D concentrations and chronic periodontitis in postmenopausal women.

A novel nonsense variant in the ATL3 gene is associated with disturbed pain sensitivity, numbness of distal limbs and muscle weakness.

Introduction Hereditary sensory neuropathy (HSN) describes as a heterogeneous group of peripheral neuropathies. HSN type 1 (HSN1) is one subtype characterized by distal sensory impairment that occurs in the form of numbness, tingling, or pain. To date, only two variants in the atlastin GTPase 3 (ATL3) gene have been identified that result in hereditary sensory neuropathy type 1F (HSN1F) with autosomal dominantinheritance. Methods We sudied and examined who present with sensory disturbances and muscle weakness in their lower limb. Patients underwent Whole Exome Sequencing and Sanger sequencing was performed in families for validation of detected variant. Results Here, we identified two Iranian families carrying the novel heterozygous stop variant NM_015459.5: c.16C>T, p.Arg6Ter in ATL3 that led to disturbed pain and touch sensitivity. This variant in the ATL3 gene was detected in both families (NM_015459.5: c.16C>T, p.Arg6Ter) by whole-exome sequencing and confirmed by Sanger sequencing. Conclusion In this study, the subjects manifested weakness of distal limb muscles and numbness of the lower extremities. In addition, some unusual features, including hearing problems and inability to sit and walk presented in one of the patients. Eventually, we provide a case-based review of the clinical features associated with HSN1F. Hitherto, only 11 patients with HSN1F have been reported. We compared our findings to previously reported cases, suggesting that the clinical features are generally variable in the HSN1F patients.

Intronic OTOF mutation causes an atypical splicing defect resulting in auditory neuropathy spectrum disorder.

Pathogenic variants in OTOF cause auditory neuropathy spectrum disorder (ANSD), namely prelingual nonsyndromic ANSD and temperature-sensitive ANSD (TS-ANSD). All study subjects provided blood sample for genetic analysis and sequencing. Wholeexome sequencing was carried out to identify the causative pathogenic variant. RNAwas extracted to analyse the messenger RNA (mRNA) resulting from the transcription of OTOF. Here, we identified a family with OTOF-related ANSD. This disorder was caused by an intronic mutation in OTOF (NM_194248: c.2406>4A[G). In further analysis, we proved that this variant causes a splicing defect resulting in the omission of exon 20 from the mRNA transcribed from OTOF. In this study, we demonstrated that the variant is four nucleotides away from the conventional splicing site, and our findings suggest that splicing mechanisms need to be better understood, as well as how neighbouring regions may impact splicing.

The salivary exosomal microRNA as a potential biomarker in patients with periodontitis and oral cancers.

Periodontitis and oral cancers are the most common oral diseases in the human population. The early diagnosis of oral diseases allows the efficient therapy of the patient. During oral diseases, resident cells in the affected tissue secrete exosomal microRNAs (miRNAs) into saliva. As these miRNAs have a crucial role in the pathogenesis of oral diseases, they have been suggested as non-invasive and validated biomarkers in predicting periodontitis severity and cancer progression. Several attempts have been performed to evaluate the expression of salivary exosomal miRNAs in patients with periodontitis and oral cancers. Some miRNAs are differentially expressed in the saliva of the affected patients when compared to healthy individuals. These miRNAs are reviewed in this narrative review. Collectively, it seems that salivary exosomal microRNAs could be used as a diagnostic biomarker in oral diseases. However, further studies are required to validate them.

Signature pattern of gene expression and signaling pathway in premature diabetic patients uncover their correlation to early age coronary heart disease.

BACKGROUND: Coronary Heart Disease (CHD) is the leading cause of death in industrialized countries. There is currently no direct relation between CHD and type 2 diabetes mellitus (T2D), one of the major modifiable risk factors for CHD. This study was carried out for genes expression profiling of T2D associated genes to identify related biological processes/es and modulated signaling pathway/s of male subjects with CHD. METHOD: the subjects were divided into four groups based on their disease, including control, type 2 diabetes mellitus (T2D), CHD, and CHD + T2D groups. The RNA was extracted from their blood, and RT2 Profiler™ PCR Array was utilized to determine gene profiling between groups. Finally, the PCR Array results were validated by using Q-RT-PCR in a more extensive and independent population. RESULT: PCR Array results revealed that the T2D and T2D + CHD groups shared 11 genes significantly up-regulated in both groups. Further analysis showed that the mRNA levels of AKT2, IL12B, IL6, IRS1, IRS2, MAPK14, and NFKB1 increased. Consequently, the mRNA levels of AQP2, FOXP3, G6PD, and PIK3R1 declined in the T2D + CHD group compared to the T2D group. Furthermore, in silico analysis indicated 36 Gene Ontology terms and 59 signaling pathways were significantly enriched in both groups, which may be a culprit in susceptibility of diabetic patients to CHD development. CONCLUSION: Finally, the results revealed six genes as a hub gene in altering various biological processes and signaling pathways. The expression trend of these identified genes might be used as potential markers and diagnostic tools for the early identification of the vulnerability of T2D patients to develop premature CHD.

MCM2 mutation causes autosomal dominant nonsyndromic hearing loss (DFNA70): novel variant in the second family.

Pathogenic variants in MCM2 could result in mild to severe sensorineural hearing loss in the affected individuals (deafness, autosomal dominant 70; DFNA70; OMIM: 616968), an extremely rare autosomal dominant progressive disorder. Here, we report a novel missense variant (NM_004526:c.388C>T, p.R130C; Clinvar: SCV002072508) in MCM2 in an Iranian family identified by whole-exome sequencing and confirmed by Sanger sequencing. The heterozygous variant (NM_004526:c.388C>T, p.R130C) in MCM2 was identified in the proband and his mother. The proband is a nine-year-old male born to nonconsanguineous parents. The proband was characterized by nonsyndromic hearing loss, while his mother showed a mild form of the disorder. This study reports the second disease-causing variant in MCM2 in the world and confirms that hearing loss arising from variants in MCM2 is nonsyndromic. Nevertheless, as was reported in the previous family, phenotype could vary among the patients with the same variant.

Genotypic and phenotypic spectrum of Myofibrillar Myopathy 7 as a result of Kyphoscoliosis Peptidase deficiency: The first description of a missense mutation in KY and literature review.

KY is located on chromosome 3 and encodes a transglutaminase-like protein in the skeletal muscles, namely Kyphoscoliosis Peptidase. KY is primarily involved in the formation and stabilization of neuromuscular intersections making it essential for the development of the musculoskeletal system. Mutations in KY cause Myofibrillar Myopathy-7 (MFM-7) and Hereditary Spastic Paraplegia (HSP). MFM-7 is an early onset muscle disorder with an autosomal recessive inheritance marked by progressive muscle weakness and joint contractures. Herein, we describe an Iranian family with MFM-7 caused by a homozygous novel variant in KY. We identified a homozygous variant (NM_178554.6:c.1247T > A, p. Ile416Asn) in KY in two patients born to consanguineous parents and the same heterozygous mutation in their parent by Whole-Exome Sequencing. The patients manifest muscle weakness, muscle atrophy, mobility restriction, and hyporeflexia. Lastly, we reviewed the phenotype and corresponding genotype of the previously reported cases with pathogenic variants in KY.

Recurrent Infections and Immunodeficiency Caused by Severe Pancytopenia Associated with a Novel Life-Threatening Mutation in Hypoxia-Upregulated Protein 1.

HYOU1 encodes a protein from the endoplasmic reticulum chaperone proteins, expressed to protect cellular mechanisms from stress such as hypoxia, insufficient energy and excessive or insufficient substances, and to restore cell homeostasis. In this study, we report a novel pathogenic variant in HYOU1. The proband, the second patient with pathogenic variant in HYOU1, was a female born to consanguineous parents. A novel homozygous pathogenic variant in HYOU1 (NM_001130991.3: c.1456C>T; p.Arg486Cys) was identified, causing anemia, thrombocytopenia and severe panleukopenia and immunodeficiency in the second month of age, leading to consistent high-grade fever, regression of brain functions and recurrent infections; ultimately resulting in the patient expiring at three and half months of age. Both parents are heterozygous for this variant and have no issues related to this study.

ZNF142 mutation causes neurodevelopmental disorder with speech impairment and seizures: Novel variants and literature review.

The ZNF142 gene on chromosome 2q35 contains ten exons and encodes a zinc finger protein 142 with 31 C2H2-type zinc fingers domain. Pathogenic variants in ZNF142 result in an autosomal recessive neurodevelopmental disorder with impaired speech and developmental delay. Here, we report two novel variants (NM_001105537: c.25C > T/c.1741C > T, p.Gln9*/p.Arg581Cys) in ZNF142 in an Iranian family identified by Whole-Exome sequencing and confirmed by Sanger sequencing. These variants are categorized as "pathogenic" and "variant of unknown significance" based on the standards for the interpretation of sequence variations recommended by ACMG, respectively. The proband is a five-year-old male born to consanguineous parents. The compound heterozygous variant (NM_001105537: c.25C > T/c.1741C > T, p.Gln9*/p.Arg581Cys) in ZNF142 was identified in the proband with moderate intellectual disability, global developmental delay, speech impairment, and seizures. This paper reported the sixth family in the world with novel pathogenic variants in the ZNF142 gene as the reason for neurodevelopmental Disorder with Impaired Speech and Hyperkinetic Movements (NEDISHM) and determining the phenotype spectrum of this disease. In this study, we also reviewed the phenotype of the former cases. In contrast to the Malaysian cases, proband in the present paper does not manifest any facial features similar to the patients in the initial study. Further studies on the NEDISHM patients could be valuable to determine the phenotype precisely.

Clinical features of patients with Yin Yang 1 deficiency causing Gabriele-de Vries syndrome: A new case and review of the literature.

BACKGROUND: Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease caused by de novo pathogenic variants in YY1. In this study, we report a 10-year-old boy with a de novo novel pathogenic variant in YY1, the first Iranian patient with Gabriele-de Vries Syndrome. METHODS: The novel de novo pathogenic variant detected in this study (NM_003403:c.690delA, p.Glu231Ilefs*25) was identified by whole-exome sequencing and confirmed by Sanger sequencing. RESULTS: The proband presented with delayed motor and speech development, ataxia, abnormal gait, autistic behavior, brain atrophy, and severe learning disability. Finally, we provide a case-based review of the clinical features associated with Gabriele-de Vries Syndrome. Thus far, merely 13 Gabriele-de Vries Syndrome patients have been reported in the literature. CONCLUSION: The investigations for a suspected case of Gabriele-de Vries Syndrome must involve molecular diagnosis of the disease and its underlying genetic defect because the clinical investigations are generally variable and nonspecific.

Clinical Features of Okur-Chung Neurodevelopmental Syndrome: Case Report and Literature Review.

Introduction: Autosomal dominant pathogenic variations in the CSNK2A1 gene cause Okur-Chung neurodevelopmental syndrome (OCNDS). Methods: The proband and her parents were examined thoroughly and observed for any issues related to OCNDS. Furthermore, peripheral blood samples were collected from each subject for further investigations. Whole-exome sequencing identified a pathogenic variant in CSNK2A1 (NM_001895: c.62G>A, p.R21Q; rs1402734448). Results: The proband has global developmental delay, speech disorders, epilepsy, and behavioral issues. Despite the previously reported cases, she manifested both atonic and myoclonic seizures simultaneously. Lastly, we provide a review of the reported cases with OCNDS. Discussion: p.R21Q causes OCNDS. Further studies are highly recommended concerning this mutation to validate the results of this study and expand the knowledge regarding CSNK2A1 and the phenotypic spectrum of OCNDS.

Exome sequencing identified a de novo frameshift pathogenic variant of CTBP1 in an extremely rare case of HADDTS.

Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (HADDTS) is an extremely rare autosomal dominant genetic disease caused by disruptive pathogenic variants in CTBP1. There are merely 12 cases reported to have pathogenic variants in the CTBP1 gene. Here, we report the first case with HADDTS in the Middle-Eastern population. In the present study, wholeexome sequencing was deployed to identify the variant(s) causing this condition. Subsequently, Sanger sequencing was performed to confirm the variant. The clinical evaluation of the patient is written according to the thoroughly carried out examinations and clinical investigations. A novel single frameshift pathogenic variant in CTBP1 (NM_001328.3:c.1315_1316delCA, p.Gln439ValfsTer84) was identified as the cause for HADDTS in the proband. Our findings enhance the knowledge of poorly studied CTBP1. The newly reported patient is phenotypically different in comparison to the previously reported cases. He has no sign of hypotonia, difficulty in walking or standing.

A novel frameshift pathogenic variant in ST3GAL5 causing salt and pepper developmental regression syndrome (SPDRS): A case report.

GM3 synthase deficiency is associated with salt and pepper developmental regression syndrome (SPDRS), a rare genetic disorder. Herein, we report the first Iranian patient with SPDRS. We detected a novel pathogenic variant of ST3GAL5 (NM_003896.4: c.1030_1031del, p.Ile344Cysfs*11). The proband had intellectual disability (ID), failure to thrive, cerebral atrophy, microcephaly, and atonic seizures. The main future challenge proceeding from the results of this study is the prenatal detection of the newly discovered variant; the next step would involve further studies to elucidate the phenotypic spectrum of SPDRS and detect new variants that could cause symptoms ranging from mild to severe.

A novel PTRH2 missense mutation causing IMNEPD: a case report.

PTRH2 deficiency is associated with an extremely rare disease, infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We report the first Iranian patient with IMNEPD. We detected a pathogenic variant in the PTRH2 gene (NM_016077.5: c.68T > C, p.V23A). The proband has myopia, spastic diplegic cerebral palsy, urolithiasis, and a history of seizures.

Phenotype of ST3GAL3 deficient patients: A case and review of the literature.

ST3GAL3 deficiency is an extremely rare autosomal recessive disorder caused by pathogenic mutations in the ST3GAL3 gene. Epilepsy, motor development delay, severe intellectual disability, and behavioral disorders have been reported to be associated with ST3GAL3 deficiency. In the present study, ST3GAL3 deficiency was caused by a homozygous splice-site mutation (NM_174964.4: c.936+1delG) in ST3GAL3. The patient described in this study was clinically similar to previously reported cases; nevertheless, we were able to detect repetitive behavior, previously not reported manifestations.

Two novel mutations in the MECP2 gene in patients with Rett syndrome.

Rett syndrome (RTT) is an X-linked severe neurological disorder. Mutations in Methyl-CpG-Binding Protein2 (MECP2) gene are the main cause of RTT disease. In this study, we report the results of screening the MECP2 gene for mutations in 7 Iranian patients with RTT syndrome. MECP2 sequencing identified two novel mutations in the heterozygous state, a splice mutation, c.354G>T, p.Gly119Gly, resulting in a premature splice-donor site and a 20-bp deletion, c.1167-1186del20 (p.P390Rfs), leading to modifying the c-terminal parts of the protein and it also changes the reading frames of all coding sequence downstream of the mutation. Multiple sequence alignment showed that amino acid changes occurred in the well conserved protein regions across species. Based on the results of this study and literature reviews, about 70% of mutations are found in exon 3 and 4 of the MECP2 gene, and mutations in exon 4 are more common than other exons. Therefore, it is recommended that exon 4 to be a priority for screening the genetic analysis of RTT patients.

Identification of mutations in HEXA and HEXB in Sandhoff and Tay-Sachs diseases: a new large deletion caused by Alu elements in HEXA.

GM2 gangliosides are a group of lysosomal lipid storage disorders that are due to mutations in HEXA, HEXB and GM2A. In our study, 10 patients with these diseases were enrolled, and Sanger sequencing was performed for the HEXA and HEXB genes. The results revealed one known splice site mutation (c.346+1G>A, IVS2+1G>A) and three novel mutations (a large deletion involving exons 6-10; one nucleotide deletion, c.622delG [p.D208Ifsx15]; and a missense mutation, c.919G>A [p.E307K]) in HEXA. In HEXB, one known mutation (c.1597C>T [p.R533C]) and one variant of uncertain significance (c.619A>G [p.I207V]) were identified. Five patients had c.1597C>T in HEXB, indicating a common mutation in south Iran. In this study, a unique large deletion in HEXA was identified as a homozygous state. To predict the cause of the large deletion in HEXA, RepeatMasker was used to investigate the Alu elements. In addition, to identify the breakpoint of this deletion, PCR was performed around these elements. Using Repeat masker, different Alu elements were identified across HEXA, mainly in intron 5 and intron 10 adjacent to the deleted exons. PCR around the Alu elements and Sanger sequencing revealed the start point of a large deletion in AluSz6 in the intron 6 and the end of its breakpoint 73 nucleotides downstream of AluJo in intron 10. Our study showed that HEXA is an Alu-rich gene that predisposes individuals to disease-associated large deletions due to these elements.

A Novel Mutation in ERCC8 Gene Causing Cockayne Syndrome.

Cockayne syndrome (CS) is a rare autosomal recessive multisystem disorder characterized by impaired neurological and sensory functions, cachectic dwarfism, microcephaly, and photosensitivity. This syndrome shows a variable age of onset and rate of progression, and its phenotypic spectrum include a wide range of severity. Due to the progressive nature of this disorder, diagnosis can be more important when additional signs and symptoms appear gradually and become steadily worse over time. Therefore, mutation analysis of genes involved in CS pathogenesis can be helpful to confirm the suspected clinical diagnosis. Here, we report a novel mutation in ERCC8 gene in a 16-year-old boy who suffers from poor weight gain, short stature, microcephaly, intellectual disability, and photosensitivity. The patient was born to consanguineous family with no previous documented disease in his parents. To identify disease-causing mutation in the patient, whole exome sequencing utilizing next-generation sequencing on an Illumina HiSeq 2000 platform was performed. Results revealed a novel homozygote mutation in ERCC8 gene (NM_000082: exon 11, c.1122G>C) in our patient. Another gene (ERCC6), which is also involved in CS did not have any disease-causing mutations in the proband. The new identified mutation was then confirmed by Sanger sequencing in the proband, his parents, and extended family members, confirming co-segregation with the disease. In addition, different bioinformatics programs which included MutationTaster, I-Mutant v2.0, NNSplice, Combined Annotation Dependent Depletion, The PhastCons, Genomic Evolutationary Rate Profiling conservation score, and T-Coffee Multiple Sequence Alignment predicted the pathogenicity of the mutation. Our study identified a rare novel mutation in ERCC8 gene and help to provide accurate genetic counseling and prenatal diagnosis to minimize new affected individuals in this family.