Structural and sequence variants in patients with Silver‐Russell syndrome or similar features—Curation of a disease database

Silver‐Russell syndrome (SRS) is a clinically and molecularly heterogeneous disorder involving prenatal and postnatal growth retardation, and the term SRS‐like is broadly used to describe individuals with clinical features resembling SRS. The main molecular subgroups are loss of methylation of the distal imprinting control region (H19/IGF2:IG‐DMR) on 11p15.5 (50%) and maternal uniparental disomy of chromosome 7 (5%–10%). Through a comprehensive literature search, we identified 91 patients/families with various structural and small sequence variants, which were suggested as additional molecular defects leading to SRS/SRS‐like phenotypes. However, the molecular and phenotypic data of these patients were not standardized and therefore not comparable, rendering difficulties in phenotype–genotype comparisons. To overcome this challenge, we curated a disease database including (epi)genetic phenotypic data of these patients. The clinical features are scored according to the Netchine‐Harbison clinical scoring system (NH‐CSS), which has recently been accepted as standard by consensus. The structural and sequence variations are reviewed and where necessary redescribed according to recent recommendations. Our study provides a framework for both research and diagnostic purposes through facilitating a standardized comparison of (epi)genotypes with phenotypes of patients with structural/sequence variants.     

Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth,pulmonary hypertension,microcephaly, and spasticity

The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.     

Spontaneous external jugular vein pseudoaneurysm treated by thrombin injection: Case report and literature review

Although external jugular vein (EJV) aneurysms are infrequent, regardless of etiology, spontaneous pseudoaneurysms (PAs) are extremely rare and generally require surgery. We describe a case of spontaneous PA of the EJV, which was successfully treated by percutaneous thrombin injection.     

Prevalence of hepatitis B infection in the southeastern region of Turkey: comparison of risk factors for HBV infection in rural and urban areas

Although hepatitis B has been well studied, there are still aspects of its epidemiology that remain to be clarified. There are many regions with high seroprevalence, particularly in the developing regions of the world, and these regions are known to have different epidemiologic patterns. Nonetheless, there are currently no data on the differences in hepatitis B seroprevalence between urban and rural areas of Turkey. In the present study, therefore, we used 30-cluster sampling to determine and compare the prevalence of hepatitis B in the urban and rural areas of the least developed region of Turkey, the southeastern region. From 2,888 adults living in the region, blood samples were obtained from house visits, and screened for HBsAg, anti-HBs, and anti-HBcIgG. Factors associated with hepatitis B seroprevalence, particularly living in rural areas, were analyzed with multivariate methods. The seroprevalence of HBsAg was 8.2% in the rural and 6.2% in the urban areas. There was a statistically significant difference between urban and rural regions in terms of HBsAg positivity (crude OR: 0.74; 95% CI: 0.55 - 0.98). Exposure to hepatitis B virus (HBV) increased with age both in urban and rural areas. Lower education level was also an important risk factor for hepatitis B seropositivity in urban areas (adjusted OR: 1.66; 95% CI: 1.26 - 2.19) but not in rural ones (adjusted OR: 0.77; 95% CI: 0.36 - 1.69). Familial jaundice history was a statistically significant risk factor for HBsAg positivity in rural areas (adjusted OR: 2.15; 95% CI: 1.30 - 3.56) but not in urban ones (adjusted OR: 1.48; 95% CI: 0.96 - 2.27). This study shows that the prevalence of HBV infection in the southeastern region of Turkey is intermediate among the levels reported for the European region of the World Health Organization.     

The role of angiotensin converting enzyme genotype in coronary artery ectasia

Coronary artery ectasia (CAE) is characterised by irregular, diffuse, saccular, or fusiform dilatation of the coronary arteries. Although the underlying mechanisms are not fully understood, CAE is considered to be an original form of vascular remodelling in response to atherosclerosis. However, it is not clear why some patients develop CAE while most do not. Experimental data suggest that activation of the renin angiotensin system may lead to an increased inflammatory response in the vessel wall or to an activation of matrix metalloproteinases. In addition, an insertion/deletion (ID) polymorphism of angiotensin converting enzyme (ACE) has been associated with coronary vascular tone and the development of aneurysms. Accordingly, we hypothesised that the gene polymorphism of ACE may be a potential factor influencing the genesis of CAE. We retrospectively evaluated 112 patients who underwent coronary angiography. ACE ID genotype was determined in two groups of patients. Group 1 consisted of 56 patients who were found to have CAE. Group 2 consisted of 56 patients with significant coronary artery disease (CAD) (> 50% stenosis in any of the major epicardial coronary arteries or their branches) but without any evidence of coronary ectasia. Polymerase Chain Reaction (PCR) was used to detect ACE genotype. The ratio of DD genotype was found to be greater in group 1 than group in 2 (39% versus 18%, respectively, P < 0.05). When assessed according to the presence of the I allele, it was greater was greater in group 2 than in group 1 (82.1% versus 60.7%, respectively, P < 0.05). The results indicate that an ACE DD genotype may be a risk factor for CAE.     

Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty.     

Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations

Hepatocellular carcinoma (HCC) rarely occurs in childhood. We describe a patient with new onset of pruritus at 8 months of age who at 17 months of age was found to have a 2.5 cm HCC. To delineate the possible genetic basis of this tumour, we performed whole exome sequencing (WES) of the germline DNA and identified two novel predictably deleterious missense mutations in ABCB11, encoding bile salt export pump (BSEP), confirmed in the parental DNA as bi-allelic and inherited. Although inherited ABCB11 mutations have previously been linked to HCC in a small number of cases, the molecular mechanisms of hepatocellular carcinogenesis in ABCB11 disease are unknown. WES of the HCC tissue uncovered somatic driver mutations in the beta-catenin (CTNNB1) and nuclear-factor-erythroid-2-related-factor-2 (NFE2L2) genes. Moreover, clonality analysis predicted that the CTNNB1 mutation was clonal and occurred earlier during carcinogenesis, whereas the NFE2L2 mutation was acquired later. Interestingly, background liver parenchyma showed no inflammation or fibrosis and BSEP expression was preserved. This is the first study to identify somatic CTNNB1 and NFE2L2 mutations in early childhood arisen in the setting of inherited bi-allelic ABCB11 mutations. Rapid WES analysis expedited this child’s diagnosis and treatment, and likely improved her prognosis.     

Balanced translocation in a patient with severe myoclonic epilepsy of infancy disrupts the sodium channel gene SCN1A

In a patient with severe myoclonic epilepsy of infancy (SMEI), we identified a de novo balanced translocation, t(2;5)(q24.3,q34). The breakpoint on chromosome 2q24.3 truncated the SCN1A gene and the 5q34 breakpoint was within a highly conserved genomic region. Point mutations or microdeletions of SCN1A have previously been identified in SMEI patients, but this is the first report of a balanced translocation disrupting the SCN1A gene in an epilepsy patient. We therefore recommend that SMEI patients without SCN1A microdeletions or point mutations should be investigated for chromosomal rearrangements.     

Time and frequency domain methods for quantifying common modulation of motor unit firing patterns

Background  

In investigations of the human motor system, two approaches are generally employed toward the identification of common modulating drives from motor unit recordings. One is a frequency domain method and uses the coherence function to determine the degree of linear correlation between each frequency component of the signals. The other is a time domain method that has been developed to determine the strength of low frequency common modulations between motor unit spike trains, often referred to in the literature as 'common drive'.