A Familial Form of Epidermolysis Bullosa Simplex Associated with a Pathogenic Variant in KRT5

Epidermolysis bullosa simplex is a disease that belongs to a group of genodermatoses characterised by the formation of superficial bullous lesions caused by minor mechanical trauma to the skin. The skin fragility observed in the EBS is mainly caused by pathogenic variants in the KRT5 and KRT14 genes that compromise the mechanical stability of epithelial cells. By performing DNA sequencing in a female patient with EBS, we found the pathogenic variant c.967G>A (p.Val323Met) in the KRT5 gene. This variant co-segregated with EBS in the family pedigree and was transmitted in an autosomal dominant inheritance manner. This is the first report showing a familial form of EBS due to this pathogenic variant.

Case Report: Identification of a Novel Pathogenic Germline TP53 Variant in a Family With Li–Fraumeni Syndrome

Li–Fraumeni syndrome (LFS) is an inherited autosomal dominant disease characterized by a predisposition to many cancers. Germline pathogenic variants in TP53 are primarily responsible for LFS. By performing a targeted sequencing panel in a proband with liver carcinoma having a deceased son affected by osteosarcoma, we found the novel heterozygous frameshift variant c.645del (p.Ser215Argfs*32) in the TP53 gene. This variant co-segregated with typical LFS cancers in the family pedigree, consistent with the pathogenicity of this novel and previously undescribed TP53 variant.

Intelligent Citizenship Identity Through Family Pedigree Using Graph-Signature Based Random-Forest Model

There has been a global upsurge of interest in the topic of citizenship identity over the past decades, specifically in the world dominated by profound insecurity, inequalities, proliferation of identities, and rise of identity politics,engendered by capitalism. However finding effective solution to these problems has been rendered difficult. To alleviate these problems, this paper presents an analytical Machine learning model that suitably combined the graph signature with random forest techniques. This study presents the design and realization of a novel Intelligent Citizenship Identity through family pedigree using Graph Signature based random forest (GSB-RF) model. The study also showcases the development of a novel graph signature technique referred to as Canonical Code Signature(CCS) method. The CCS method is used at the pre-processing stage of the identification process to build signature for any given tuple. Performance comparisim between the present system and the baseline techniques which includes: the K-Nearest Neighbour and the traditional Random Forest shows that the present system outperformed the baseline method studied. The proposed system shows capability to perform continuous re-identification of Citizens based on their family pedigree with ability to select best sample with low computational complexity, high identification accuracy and speed. Our experimental result shows that the precision rate and identification quality of our system in most cases are equal to or greater than 70%. Therefore, the proposed Citizenship Identification machine is capable of providing usable, consistent, efficient, faster and accurate identification, to the users, security agents, government agents and institutions on-line, real-time and at any-time.Keywords- Canonical code,Citizenship Identity, Family pedigree,Graph-Signature,Machine learning, Random-forest

Infant inhibited temperament in primates predicts adult behavior, is heritable, and is associated with anxiety-relevant genetic variation

An anxious or inhibited temperament (IT) early in life is a major risk factor for the later development of stress-related psychopathology. Starting in infancy, nonhuman primates, like humans, begin to reveal their temperament when exposed to novel situations. Here, in Study 1 we demonstrate this infant IT predicts adult behavior. Specifically, in over 600 monkeys, we found that individuals scored as inhibited during infancy were more likely to refuse treats offered by potentially-threatening human experimenters as adults. In Study 2, using a sample of over 4000 monkeys from a large multi-generational family pedigree, we demonstrate that infant IT is partially heritable. The data revealed infant IT to reflect a co-inherited substrate that manifests across multiple latent variables. Finally, in Study 3 we performed whole-genome sequencing in 106 monkeys to identify IT-associated single-nucleotide variations (SNVs). Results demonstrated a genome-wide significant SNV near CTNNA2, suggesting a molecular target worthy of additional investigation. Moreover, we observed lower p values in genes implicated in human association studies of neuroticism and depression. Together, these data demonstrate the utility of our model of infant inhibited temperament in the rhesus monkey to facilitate discovery of genes that are relevant to the long-term inherited risk to develop anxiety and depressive disorders.

Case Report: First Two Identified Cases of Fabry Disease in Central Asia

Background: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked inherited, genetic disease due to the functional deficiency of lysosomal α-galactosidase (α-GAL) that leads to the accumulation of glycosphingolipids (mainly globotriaosylceramide or Gb3) and its derivative globotriaosylsphingosine or lyso-Gb3. Classic FD is a multisystem disorder which initially presents in childhood with neuropathic pain and dermatological, gastrointestinal, ocular, and cochleo-vestibular manifestations. Over time, end-organ damage such as renal failure, cardiac arrhythmia and early stroke may develop leading to reduced life expectancy in the absence of specific treatment.Case presentation: We describe two Kazakh patients who presented in adulthood with a delayed diagnosis. We conducted also a family screening through cascade genotyping.Conclusion: This is the first description of cases of Fabry disease in Central Asia. An extensive family pedigree enabled the identification of ten additional family members. Patients with rare genetic diseases often experience substantial delays in diagnosis due to their rarity and non-specific symptoms, which can negatively impact their management and delay treatment. FD may be difficult to diagnose because of the non-specificity of its early and later-onset symptoms and its X-linked inheritance. Raising awareness of clinicians is important for earlier diagnosis and optimal outcome of specific therapies.

Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.

Hereditary Paraganglioma in an Omani Family

Pheochromocytomas are tumors derived from chromaffin cells within the medulla of adrenal glands, whereas paragangliomas are tumors derived from extra-adrenal chromaffin cells of the sympathetic prevertebral and paravertebral ganglia. The growing deployment of genetic testing has shown that approximately 30% of pheochromocytoma and paraganglioma (PPGL) patients carry familial pathogenic germline mutations in known PPGL-susceptibility genes. This prompts genetic screening of their family members and leads to an increase in the detection of asymptomatic PPGLs or non-secreting tumors reported in familial cases discovered after the index patient work-up. Here, we present three case reports of affected members of a single Omani family with a history of paraganglioma and highly variable clinical presentations among the affected members. Eight out of the 16 siblings (50.0%) in the second generation of the reported family pedigree were carriers of the succinate dehydrogenase B:c.574T>C mutation, reflecting the autosomal dominant inheritance risk of paraganglioma and other associated tumors. This report highlights the complexity of managing such families and encourages further discussion regarding the management of asymptomatic PPGL-associated mutation carriers. Genetic screening has enabled the early detection of PPGLs, for which early surgical intervention can significantly impact prognosis and treatment strategies to reduce morbidity and mortality. Although PPGLs are similar tumors, they warrant distinction from each other with respect to their differences in locations, manifestations, secretory functions, genetic syndromes, and propensity to metastasize. While current guidelines are clear concerning symptomatic PPGL cases, the management of asymptomatic mutation carriers requires further elucidation.