Atwal, Paldeep S.

AbstractThe Ehlers–Danlos Syndromes (EDS) are a group of inherited connective tissue disorders with a worldwide prevalence of 1 in 2500 to 1 in 5000 births irrespective of sex or ethnicity. Fourteen subtypes of Ehlers–Danlos Syndrome (EDS) have been described, each with characteristic phenotypes and associated genes. Pathogenic variants in COL5A1 and COL5A2 cause the classical EDS subtypes. Pathogenic variants in COL3A1 cause vascular EDS. In this case report, we describe a patient with a phenotype resembling that of vascular EDS, caused by a novel pathogenic variant in COL5A1.

Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle and impaired systolic function and is the second most common cause of heart failure after coronary heart disease. The etiology of DCM is diverse including genetic pathogenic variants, infection, inflammation, autoimmune diseases, exposure to chemicals/toxins as well as endocrine and neuromuscular causes. DCM is inherited in 20–50% of cases where more than 30 genes have been implicated in the development of DCM with pathogenic variants in TTN (Titin) most frequently associated with disease. Even though male sex is a risk factor for heart failure, few studies have examined sex differences in the pathogenesis of DCM. We searched the literature for studies examining idiopathic or familial/genetic DCM that reported data by sex in order to determine the sex ratio of disease. We found 31 studies that reported data by sex for non-genetic DCM with an average overall sex ratio of 2.5:1 male to female and 7 studies for familial/genetic DCM with an overall average sex ratio of 1.7:1 male to female. No manuscripts that we found had more females than males in their studies. We describe basic and clinical research findings that may explain the increase in DCM in males over females based on sex differences in basic physiology and the immune and fibrotic response to damage caused by mutations, infections, chemotherapy agents and autoimmune responses.

Single-minded homologue 1 (SIM1) is a transcription factor with numerous different physiological and developmental functions. SIM1 is a member of the class I basic helix-loop-helix-PER-ARNT-SIM (bHLH–PAS) transcription factor family, that includes several other conserved proteins, including the hypoxia-inducible factors, aryl hydrocarbon receptor, neuronal PAS proteins, and the CLOCK circadian regulator. Recent studies of HIF-a-ARNT and CLOCK-BMAL1 protein complexes have revealed the organization of their bHLH, PASA, and PASB domains and provided insight into how these heterodimeric protein complexes form; however, experimental structures for SIM1 have been lacking. Here, we describe the first full-length atomic structural model for human SIM1 with its binding partner ARNT in a heterodimeric complex and analyze several pathogenic variants utilizing state-of-the-art simulations and algorithms. Using local and global positional deviation metrics, deductions to the structural basis for the individual mutants are addressed in terms of the deleterious structural reorganizations that could alter protein function. We propose new experiments to probe these hypotheses and examine an interesting SIM1 dynamic behavior. The conformational dynamics demonstrates conformational changes on local and global regions that represent a mechanism for dysfunction in variants presented. In addition, we used our ab initio hybrid model for further prediction of variant hotspots that can be engineered to test for counter variant (restoration of wild-type function) or basic research probe.

We describe the phenotype of a patient with extensive aortic, carotid, and abdominal dissections. The proband was found to have a heterozygous deletion of exons 21–34 inMYLK, which is a rare finding, as deletions in this gene have been infrequently reported. We describe this finding following detection in a proband with an extensive history of aortic, carotid, and abdominal dissections. Neoteric molecular modeling techniques to help determine the impact of this deletion on protein function indicated loss of function due to lack of any kinase domain. We also provide the electrostatics calculations from the wild type and mutant variant. Through a combined multiomic approach of clinical, functional, and protein informatics, we arrive at a data fusion for determination of pathogenicity embedded within the genetic code for this particular genetic variant, which, as a platform, continues to broaden its scope across the field of variants of uncertain significance classification.

Background. The ATP-binding cassette, subfamily D, member 1 (ABCD1) protein is a peroxisomal half-transporter that allows for very long chain fatty acid (VLCFA) degradation. Pathogenic variants of ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. Methods. A newly characterized and suspected pathogenic variant in ABCD1 was analyzed using our protein informatics platform (PIP). Personalized protein-level molecular studies were completed on genetic testing data, complementing the analysis and clinical study. Results. A case of adult onset adrenomyeloneuropathy (AMN) and a novel ABCD1 variant are presented. The unique ABCD1 protein is discussed, and the proband’s case is compared to existing reports of AMN. Conclusions. Data fusion from multiple sources was combined in a comprehensive approach yielding an enriched assessment of the patient’s disease and prognosis. Molecular modeling was performed on the variant to better characterize its clinical significance and confirm pathogenicity.

AbstractBackgroundBeta‐galactosidase‐1 (GLB1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB1 cause two different lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB. In GM1 gangliosidosis, decreased β‐galactosidase‐1 enzymatic activity leads to the accumulation of GM1 gangliosides, predominantly within the CNS. We present a 22‐month‐old proband with GM1 gangliosidosis type II (late‐infantile form) in whom a novel homozygous in‐frame deletion (c.1468_1470delAAC, p.Asn490del) in GLB1 was detected.MethodsWe used an experimental protein structure of β‐galactosidase‐1 to generate a model of the p.Asn490del mutant and performed molecular dynamic simulations to determine whether this mutation leads to altered ligand positioning compared to the wild‐type protein. In addition, residual mutant enzyme activity in patient leukocytes was evaluated using a fluorometric assay.ResultsMolecular dynamics simulations showed the deletion to alter the catalytic site leading to misalignment of the catalytic residues and loss of collective motion within the model. We predict this misalignment will lead to impaired catalysis of β‐galactosidase‐1 substrates. Enzyme assays confirmed diminished GLB1 enzymatic activity (~3% of normal activity) in the proband.ConclusionsWe have described a novel, pathogenic in‐frame deletion of GLB1 in a patient with GM1 gangliosidosis type II.

AbstractBackgroundHaploinsufficiency of TAB2 is known to cause congenital heart defects and cardiomyopathy due to its important roles in cardiovascular tissue, both during development and through adult life. We report a sibling pair displaying adult‐onset cardiomyopathy, hypermobility, and mild myopia. Our proband, a 39‐year‐old male, presents only with the above symptoms, while his 36‐year‐old sister was also notable for a ventricular septal defect in her infancy.MethodsWhole‐exome sequencing was utilized to identify the molecular basis of the phenotype found in two siblings. A molecular modeling technique that takes advantage of conformational sampling advances (Maxwell's demon molecular dynamics and Monte Carlo) were used to make a model of the mutant variant for comparative analytics to the wild‐type.ResultsExome sequencing revealed a novel, heterogeneous pathogenic variant in TAB2, c.1039 C>T (p.R347X), that was present in both individuals. This pathogenic variant removes just over half the residues from the TAB2 protein and severely impacts its functional ability, which we describe in detail.ConclusionsAnalysis of the proband's family showed a history of cardiomyopathy, but no congenital heart defects or connective tissue disease. We highlight the heterogeneity in phenotype of TAB2 pathogenic variants and confirm the pathogenicity of this new variant through neoteric protein modeling techniques.

We present a 43-year-old man with aortic root dilation, mitral valve prolapse, and marfanoid appearance, who presented with acute onset left leg pain. He underwent a Doppler ultrasound that revealed left popliteal artery aneurysm with thrombus. CT angiogram showed bilateral popliteal artery aneurysms. After repairing of his left popliteal artery aneurysm, he was sent for genetic evaluation. He was diagnosed with Marfan syndrome (MFS) based on the revised Ghent criteria and then underwent FBN1 sequencing and deletion/duplication analysis, which detected a novel pathogenic variant in gene FBN1, denoted by c.5872 T>A (p.Cys1958Ser). MFS is a connective tissue disorder with an autosomal dominant inheritance due to pathogenic variants in FBN1 that encodes Fibrillin-1, a major element of the extracellular matrix, and connective tissue throughout the body. MFS involves multiple systems, most commonly the cardiovascular, musculoskeletal, and visual systems. In our case we present a rare finding of bilateral popliteal artery aneurysms in a male patient with MFS.

Chronic urticaria is a common condition characterized by recurrent hives lasting several weeks or months and is usually idiopathic. Approximately half of the individuals with chronic urticaria will present with episodes of angioedema that can be severe and debilitating. In this report, we describe a 47-year-old Hispanic male who presented initially for an evaluation of chronic hives following hospitalization due to hive-induced anaphylaxis. The individual had a history significant for urticaria and angioedema beginning in his early 30s. Interestingly, both the individual’s 41-year-old sister and 12-year-old daughter were also affected with chronic urticaria and severe angioedema. Whole exome sequencing of the proband and several family members revealed a heterozygous variant of uncertain significance in exon 2 of TNFAIP3, denoted as c.65G>A (p.R22Q), in all affected members. Variants in TNFAIP3 have been associated with multiple autoimmune diseases, susceptibility to allergy and asthma, and periodic fever syndromes, suggesting that this variant could potentially play a role in disease.

Ornithine transcarbamylase (OTC) deficiency is well known for its diagnosis in the neonatal period. Presentation often occurs after protein feeding and manifests as poor oral intake, vomiting, lethargy progressing to seizure, respiratory difficulty, and eventually coma. Presentation at adulthood is rare (and likely underdiagnosed); however, OTC deficiency can be life-threatening and requires prompt investigation and treatment. Reports and guidelines are scarce due to its rarity. Here, we present a 59-year-old woman with a past history of irritable bowel syndrome who underwent a reparative operation for rectal prolapse and enterocele. Her postoperative course was complicated by a bowel perforation (which was repaired), prolonged mechanical ventilation, tracheostomy, critical illness myopathy, protein-caloric malnutrition, and altered mental status. After standard therapy for delirium failed, further investigation showed hyperammonemia and increased urine orotic acid, ultimately leading to the diagnosis of OTC deficiency. This case highlights the importance of considering OTC deficiency in hospitalized adults, especially during the diagnostic evaluation for altered mental status.