Leigh syndrome (LS) is a progressive neurodegenerative disease caused by either mitochondrial or nuclear DNA mutations resulting in dysfunctional mitochondrial energy metabolism. The onset of ...clinical features is typically between 3 and 12 months of age; however, a later onset has been described in a few patients. Complex I deficiency is reported to be the most common cause of mitochondrial disorders. We described a patient with a late-onset LS, who presented with gait ataxia, caused by complex I deficiency (NDUFV1 gene).
Nonaka myopathy (MIM 605820) is caused by homozygous pathogenic variants in the
GNE
gene. It is a recessively inherited early adult-onset myopathy that usually preserves the quadriceps and presents ...with bilateral foot drop, usually caused by anterior tibialis weakness. In patients with Nonaka myopathy, serum creatine kinases are slightly elevated, muscle weakness progresses slowly, and ambulation loss develops after 15–20 yr. The current study aims to raise awareness of Nonaka myopathy that occurs as a rare phenotype due to pathogenic variants in
GNE
gene. Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family were done by Sanger sequencing. Also the homology model of the mutant protein was created with the ProMod3 algorithm. We identified a bialelic pathogenic variant (c.830G>A) in
GNE
gene, which explain the patients' clinical status. We present the main findings of two siblings with Nonaka myopathy together with detailed clinical and genetic profiles of the patients together with a three-dimensional mutant GNE protein model. We think that the clinical characteristics and the effect of the (c.830G>A) variant will facilitate our understanding of
GNE
gene in Nonaka myopathy pathogenesis.
We aimed to examine the association between plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism and early spontaneous recanalization in patients presenting with acute ST-elevation ...myocardial infarction.
Patients admitted to our emergency department with ST-elevation myocardial infarction in the first 6 h of symptom onset were included. An immediate primary percutaneous coronary intervention was performed. Patients were grouped according to the initial patency of the infarct-related artery (IRA) as follows: total occlusion (TO) group Thrombolysis in Myocardial Infarction (TIMI) 0-1 flow in the IRA, partial recanalization group (TIMI 2 flow in the IRA), and complete recanalization (CR) group (TIMI 3 flow in the IRA). PAI-1 4G/5G polymorphism was detected using the real-time PCR method.
There were 107 patients in the TO group, 30 patients in the partial recanalization group, and 45 patients in the CR group. When we evaluated degrees of patency according to the PAI-1 genotype, TO of the IRA was the highest in patients with the PAI 4G/4G genotype (PAI-1 4G/4G: 66.7%, PAI-1 4G/5G: 65.9%, PAI-1 5G/5G: 40.4%) and CR of the IRA was the highest in patients with the PAI 5G/5G genotype (PAI-1 5G/5G: 38.5%, PAI-1 4G/5G: 19.8%, PAI-1 4G/4G: 17.9%). The distribution of genotypes in different degrees of patency of IRA was statistically significant (P=0.029). In logistic regression analysis, the PAI-1 5G/5G genotype was associated independently with the spontaneous CR of the IRA (odds ratio: 2.875, 95% confidence interval 1.059-7.086, P=0.038).
Patients with the PAI-1 5G/5G genotype seem to be luckier than others in terms of early spontaneous recanalization of the IRA. Further prospective studies with large patient populations are required for more precise results.
Variance-component methods that estimate the aggregate contribution of large sets of variants to the heritability of complex traits have yielded important insights into the genetic architecture of ...common diseases. Here, we introduce methods that estimate the total trait variance explained by the typed variants at a single locus in the genome (local SNP heritability) from genome-wide association study (GWAS) summary data while accounting for linkage disequilibrium among variants. We applied our estimator to ultra-large-scale GWAS summary data of 30 common traits and diseases to gain insights into their local genetic architecture. First, we found that common SNPs have a high contribution to the heritability of all studied traits. Second, we identified traits for which the majority of the SNP heritability can be confined to a small percentage of the genome. Third, we identified GWAS risk loci where the entire locus explains significantly more variance in the trait than the GWAS reported variants. Finally, we identified loci that explain a significant amount of heritability across multiple traits.
Gaucher disease (GD) is the most frequent lysosomal storage disorder due to biallelic pathogenic variants in GBA gene. Only homozygous D409H variant has been associated with the cardiovascular ...phenotype which is also known as Gaucher disease type 3c. In this descriptive study, we presented phenotypic heterogeneity and a novel clinical finding among 13 patients with GD type 3c. Patients presented with varying degrees of cardiac valve and/or aortic calcifications (84,6%) and corneal opacities (76,9%) in addition to visceral (100%), hematological (92,3%), neurological (92,3%), and skeletal (30%) manifestations. Also, cervical dystonia (38,4%) and psychiatric disorders (46,1%) were not infrequent entities with respect to neurological involvement in GD type 3c. In this report, we highlight transient neonatal cholestasis (38,4%) as a novel finding in GD type 3c. Neonatal cholestasis is a finding associated with Gaucher type 2, but transient neonatal cholestasis has not been reported in GD patients, so far. The clinical features of GD type 3c are highly heterogeneous, from disease severity or age of onset to disease progression. Also, we concluded that phenotypic spectrum may be associated with age at onset of clinical symptoms. As, patients presenting in infancy or childhood had mainly visceral and hematological involvement and patients presenting in adolescence and adulthood had mainly cardiac, neurological involvement, and psychiatric behavioral disorders. Identifying the heterogeneous clinical course of these patients in this fatal disease, may lead a sufficient understanding of the pathophysiology which will enable targeted therapeutic interventions.
In this study, we examined the relationship between PAI-1 4G/5G polymorphism and patency of the infarct-related artery after thrombolysis in patients with ST-elevation myocardial infarction (STEMI).
...Acute STEMI patients who received thrombolytic therapy within first 12 h were included in our study. The PAI-1 4G/5G promoter region insertion/deletion polymorphism was studied from venous blood samples. Patients with the PAI-1 4G/5G gene polymorphism were included in group 1 and the others were included in group 2. Coronary angiography was performed in all patients in the first 24 h after receiving thrombolytic therapy. Thrombolysis in myocardial infarction (TIMI) 0-1 flow in the infarct-related artery was considered as 'no flow', TIMI 2 flow as 'slow flow', and TIMI 3 flow as 'normal flow'.
A total of 61 patients were included in our study. Thirty patients (49.2%) were positive for the PAI-1 4G/5G gene polymorphism, whereas 31 of them (50.8%) were in the control group. There were significantly more patients with 'no flow' (14 vs. 6; P=0.02) and less patients with 'normal flow' (8 vs. 19; P=0.02) in group 1. In addition, time to thrombolytic therapy (TTT) was maximum in the 'no flow' group and minimum in the 'normal flow' group (P=0.005). In the logistic regression analysis, TTT (odds ratio: 0.9898; 95% confidence interval: 0.982-0.997; P=0.004) and the PAI-1 4G/5G gene polymorphism (odds ratio: 4.621; 95% confidence interval: 1.399-15.268; P<0.01) were found to be independently associated with post-thrombolytic 'no flow'.
The PAI-1 4G/5G gene polymorphism and TTT are associated independently with 'no flow' after thrombolysis in patients with STEMI.
Shprintzen-Goldberg Syndrome: Case Report Yalçıntepe, Sinem; Özalp Yüreğir, Özge; Tuğ Bozdoğan, Sevcan ...
Meandros medical and dental journal,
08/2018, Volume:
19, Issue:
2
Journal Article
Peer reviewed
Open access
Shprintzen-Goldberg syndrome is a rare syndrome with craniosynostosis of
coronal, sagittal or lambdoidal sutures, dolichocephaly, typical craniofacial
features, skeletal abnormalities, scoliosis, ...joint hyperextensibility or contractures,
neurological findings and brain malformations. Fifteen months old male patient
with hydrocephalus and dysmorphic facial appearance was referred to our clinic
for genetical evaluation. In his dysmorphic examination, the findings were
dolichocephaly, prominent forehead and glabella, hypertelorism, prominent
eyes, proptosis, depressed nasal root, anteverted nostrils, small nose, low-set and
posteriorly rotated, dysplastic ears, microretrognathia, short philtrum, fish mouth
of mouth, plump cheeks, high and narrow palate, secondary alveolar arch, pectus
carinatum. Hands were small and he had arachnodactyly. Toes were thin. He had also
hypotonia and umbilical hernia. With these findings, he was clinically diagnosed
as Shprintzen-Goldberg syndrome. This is the first reported case of Shprintzen-
Goldberg syndrome from Turkey according to literature review.
Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 ...and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.
Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual ...disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.
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