Novel, homozygous RAB3GAP1 c.2606 + 1G>A, p.Glu830ValfsTer9 variant and chromosome 3q29 duplication in a Turkish individual with Warburg micro syndrome.

Warburg micro syndrome (WARBM) is a rare, autosomal recessive, neurodevelopmental disorder characterized by microcephaly, cortical dysplasia, corpus callosum hypoplasia, congenital hypotonia leading to subsequent spastic quadriplegia, severe developmental delay and hypogenitalism. Ophthalmologic findings that may affect any ocular segment including characteristic, small, atonic pupils. WARBM is known to be caused by biallelic, pathogenic variants in at least five genes although additional genetic loci may exist. The RAB3GAP1 c.748 + 1G>A, p.Asp250CysfsTer24 founder variant has been described in families of Turkish ancestry. We report the clinical and molecular findings in three, unrelated, Turkish families with WARBM. A novel c.974-2A>G variant causing WARBM in three siblings of Turkish descent was found. Functional studies of the novel, c.2606 + 1G>A variant in patients' mRNA revealed skipping of exon 22 which results in a premature stop codon in exon 23. However, the clinical consequences of this variant are blended given that the individual also had a maternally inherited chromosome 3q29 microduplication.

Dysosteosclerosis: Clinical and Radiological Evolution Reflecting Genetic Heterogeneity.

Dysosteosclerosis (DSS), the term coined in 1968 for ultrarare dysplasia of the skeleton featuring platyspondyly with focal appendicular osteosclerosis, has become generic by encompassing the genetic heterogeneity recently reported for this phenotype. We studied four unrelated Turkish patients with DSS to advance understanding of the new nosology. Patient 1 suffered femur fractures beginning at age 1 year. DSS was suspected from marked metaphyseal osteosclerosis in early childhood and subsequently platyspondyly accompanying patchy osteosclerosis of her appendicular skeleton. She harbored in SLC29A3, in 2012 the first gene associated with DSS, a unique homozygous duplication (c.303_320dup, p.102_107dupYFESYL). Patient 2 presented similarly with fractures and metaphyseal osteosclerosis but with no platyspondyly at age 2 months. She was homozygous for a novel nonsense mutation in SLC29A3 (c.1284C>G, p.Tyr428*). Patient 3 had ocular disease at age 2 years, presented for short stature at age 11 years, and did not begin to fracture until age 16 years. Radiographs showed mild platyspondyly and focal metaphyseal and femoral osteosclerosis. She was homozygous for a unique splice site mutation in TNFRSF11A (c.616+3A>G). Patient 4 at age 2 years manifested developmental delay and frequent infections but did not fracture. He had unique metadiaphyseal splaying and osteosclerosis, vertebral end-plate osteosclerosis, and cortical thinning of long bones but no mutation was detected of SLC29A3, TNFRSF11A, TCIRG1, LRRK1, or CSF1R associated with DSS. We find that DSS from defective SLC29A3 presents earliest and with fractures. DSS from compromised TNFRSF11A can lead to optic atrophy as an early finding. Negative mutation analysis in patient 4 suggests further genetic heterogeneity underlying the skeletal phenotype of DSS. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Meckel-Gruber Syndrome: Clinical and Molecular Genetic Profiles in Two Fetuses and Review of the Current Literature.

Background: Meckel-Gruber syndrome (MKS; OMIM No. 249000) is a rare, in utero lethal disease characterized by occipital encephalocele, polycystic kidneys, and polydactyly. Methodology and Results: In this study, two fetuses diagnosed as having MKS in the prenatal period were evaluated on the basis of ultrasonographic findings, postmortem autopsy findings, and molecular genetic analyses. Using exome sequencing analyses a novel homozygous frameshift variant (NM_015631: c.530delA, p.Lys177Argfs*47) was detected at exon 4 of TCTN3 gene in case 1, and a novel homozygous synonymous variant (NM_025114: c.180G>A, p Lys60Lys) was detected at exon 3 of CEP290 gene in case 2. Case 1 is the first reported case in the literature, which showed the typical MKS clinical feature with a novel frameshift variation in the TCTN3 gene. The variant in case 2 is the first reported synonymous variant of CEP290 gene in the literature, which has been shown to affect splicing in a functional study at the RNA level. Conclusion: TCTN3 gene variants that were rarely associated with the typical MKS phenotype and all cases with these variations have been discussed in the context of genotype-phenotype. The detection of the first synonymous variant of CEP290 gene and the demonstration of its effect on splicing by a functional study are likely to contribute to the molecular etiology of MKS.

Biallelic Mutations in DNAJB11 are Associated with Prenatal Polycystic Kidney Disease in a Turkish Family.

Polycystic kidney disease (PKD) is a life-threatening condition resulting in end-stage renal disease. Two major forms of PKD are defined according to the inheritance pattern. Autosomal dominant PKD (ADPKD) is characterized by renal cysts, where nearly half of the patients suffers from renal failure in the 7th decade of life. Autosomal recessive PKD (ARPKD) is a rarer and more severe form presenting in childhood. Whole-exome sequencing (WES) analyses was performed to investigate molecular causes of the disease in the fetus. In this study, we present 2 fetuses prenatally diagnosed with PKD in a consanguineous family. WES analysis of the second fetus revealed a homozygous variant (c.740+1G>A) in DNAJB11 which is related to ADPKD. This study reveals that DNAJB11 biallelic mutations may cause an antenatal severe form of ARPKD and contributes to understanding the DNAJB11-related ADPKD phenotype. The possibility of ARPKD due to biallelic mutations in ADPKD genes should be considered in genetic counseling.

Secondary findings in 622 Turkish clinical exome sequencing data.

CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in Turkish population.

Novel clinical features and pleiotropic effect in three unrelated patients with LMNA variant.

LMNA gene encodes A-type lamins and the encoded proteins join the structure of the nuclear lamina and affect the processes of nuclear homeostasis, DNA replication, repair, transcription, and apoptosis. LMNA variants cause a heterogeneous group of diseases known as laminopathies. Phenotypes associated with LMNA variants mainly affect the heart, skeleton, skin, bones, and nervous system. The affected tissues may vary depending on the site of the variant on the gene and the variation type. Complex phenotypes may also occur in some cases, in which findings of premature aging, cardiomyopathy, mandibuloacral dysplasia, lipodystrophy, renal involvement, metabolic involvement, and myopathy coexist. The pleiotropic effect of LMNA variants can result in heterogeneous phenotypes. In this study, we aimed to describe atypical phenotypic characteristics in a patient with familial partial lipodystrophy type 2 associated with LMNA variant, another with mandibuloacral dysplasia, and a third patient with a complex phenotype as well as discuss them in the context of their relationship with the genotype.

Concentrations of Serum Cyclophilin A in Patients With Bell Palsy.

BACKGROUND: Cyclophilin A (CyPA) is the responder protein to stimuli that cause inflammation. To date, no association among CyPA and Bell palsy has been reported. METHODS: The concentrations of Serum CyPA were measured in 90 healthy participants and 92 patients with Bell palsy. Serum samples of patients and the control group were compared on the basis of CyPA levels. Facial latency and amplitude values on electromyography were evaluated and compared with serum CyPA concentrations. RESULTS: A total of 28, 37, 19, and 8 patients had grade 3, 4, 5, and 6 facial palsy cases, respectively. Comparing the control group and the patient group showed significant differences in CyPA values (P < 0.001). Cyclophilin A value can be evaluated as a marker with high disease discrimination capability. The results also showed that at low CyPA, the average recovery time was shorter than that of high CyPA (41.6 ±â€Š5.7 days vs 62.8 ±â€Š10.2 days, P = 0.036). We found no statistically significant relationship between electromyography parameters and CyPA level. (Facial latency: r: -0.014, P: 0.948; facial amplitude r: -0.081, P: 0.713). CONCLUSION: Serum CyPA concentrations increased in response to inflammation in Bell palsy patients. However, CyPA could not be used as an early prognostic marker in Bell palsy, low CyPA indicates the shorter average recovery time than that of high CyPA.

O polimorfismo VNTR no gene codificador do antagonista do receptor da interleucina-1 está associado com a doença arterial coronariana / Interleukin-1 receptor antagonist gene VNTR polymorphism is associated with coronary artery disease

FUNDAMENTO: A Doença Arterial Coronariana (DAC) é a aterosclerose das artérias coronárias que transportam o sangue para o coração. A aterosclerose é uma doença inflamatória. As variações gênicas das citocinas - como as associadas à família IL1 - fazem parte da patogênese da aterosclerose. OBJETIVO: O objetivo deste estudo foi determinar a relação entre os polimorfismos da família IL1 (VNTR do IL1RN, posições -511 e +3953 do IL1B) e a DAC na população turca. MÉTODOS: Um total de 427 indivíduos foram submetidos à angiografia coronariana e em seguida divididos da seguinte forma: 170 no grupo controle e 257 no grupo de pacientes com DAC. Os sujeitos com DAC foram divididos em dois subgrupos: 91 no grupo de Doença Coronariana em um único vaso (Single Vessel Disease - SVD) e 166 no grupo Doença Coronariana em múltiplos vasos (Multiple Vessel Disease - MVD). Os genótipos de IL1RN e IL1B (-511, +3953) foram determinados por reação em cadeia da polimerase (RCP), seguida de análise da digestão por enzima de restrição. RESULTADOS: Não foram observadas diferenças significantes nas distribuições de genótipos de IL1RN e IL1B (-511 e +3953) entre os sujeitos com DAC e os controles, ou entre sujeitos com MVD e controles. No entanto, observou-se uma relação significante no genótipo IL1RN 2/2 entre sujeitos portadores de SVD e controles (P= 0,016, x2: 10,289, OR: 2,94IC 95 por cento 1,183 - 7,229). Tampouco foi observada diferença estatisticamente significante nas freqüências dos alelos de IL1RN e IL1B (-511 e +3953) entre os sujeitos com DAC e controles, os sujeitos com MVD e controles, ou ainda os sujeitos SVD e controles. CONCLUSÃO: Não foi observada nenhuma relação na freqüência alélica e nem na distribuição genotípica dos polimorfismos de IL1RN e IL1B entre sujeitos com DAC e grupos controle. No entanto, o genótipo IL1RN 2/2 pode representar um fator de risco para sujeitos com SVD na população turca.

BACKGROUND: Coronary Artery Disease (CAD) is the atherosclerosis of coronary arteries that carry blood to the heart muscle. Atherosclerosis is an inflammatory disease. Cytokine gene variations such as those associated with the IL1 family are involved in the pathogenesis of atherosclerosis. OBJECTIVE: The purpose of this study was to determine the relationship between IL1 family polymorphisms (IL1RN VNTR, IL1B positions -511 and +3953) and CAD in Turkish population. METHODS: 427 individuals were submitted to coronary angiography and were grouped as 170 control subjects and 257 CAD patients. The CAD subjects were divided into two subgroups: 91 Single Vessel Disease (SVD) and 166 Multiple Vessel Disease (MVD) subjects. The genotypes of IL1RN and of IL1B (-511, +3953) were determined by polymerase chain reaction (PCR) followed by restriction digestion analysis. RESULTS: No significant difference was found in IL1RN and IL1B (-511 and +3953) genotype distributions between CAD and control subjects or MVD and control subjects. However, significant association was seen in IL1RN 2/2 genotype between SVD and control subjects (P= 0.016, x2: 10.289, OR: 2.94, 95 percent CI: 1.183-7.229). Similarly, no statistically significant difference was found in IL1RN and IL1B (-511 and +3953) allele frequencies between CAD and control subjects, MVD and control subjects or SVD and control subjects. CONCLUSION: No association was found in either allele frequency or genotype distribution of IL1RN and IL1B polymorphisms between CAD and the control groups. However; IL1RN 2/2 genotype may be a risk factor for SVD in the Turkish population.

Interleukin 1 activates STAT3/nuclear factor-kappaB cross-talk via a unique TRAF6- and p65-dependent mechanism.

Interleukins (IL) 1 and 6 are important cytokines that function via the activation, respectively, of the transcription factors NF-kappaB and STAT3. We have observed that a specific type of kappa B DNA sequence motif supports both NF-kappaB p65 homodimer binding and cooperativity with non-tyrosine-phosphorylated STAT3. This activity, in contrast to that mediated by kappaB DNA motifs that do not efficiently bind p65 homodimers, is shown to be uniquely dependent upon signal transduction through the carboxyl terminus of TRAF6. Furthermore, STAT3 and p65 are shown to physically interact, in vivo, and this interaction appears to inhibit the function of "classical" STAT3 GAS-like binding sites. The distinct p50 form of NF-kappaB is also shown to interact with STAT3. However, in contrast to p65, p50 cooperates with STAT3 bound to GAS sites. These data argue for a novel transcription factor cross-talk mechanism that may help resolve inconsistencies previously reported regarding the mechanism of IL-1 inhibition of IL-6 activity during the acute-phase response.