Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females).

A complex case of delayed diagnosis of ornithine transcarbamylase deficiency in an adult patient with multiple comorbidities.

We report the case of a medically complex African American adult female with ornithine transcarbamylase (OTC) deficiency diagnosed after lifelong protein aversion and new onset of chronic vomiting and abdominal pain with intermittent lethargy and confusion. Symptomatology was crucial to diagnosis as genetic testing did not identify any pathogenic variants in ; however, the patient's diagnosis was delayed despite her having longstanding symptoms of a urea cycle disorder (UCD). Her symptoms improved after treatment with a modified protein-restricted diet, long-term nitrogen-scavenger therapy, and supplemental L-citrulline.

Molecular Modeling and Phenotypic Description of a Patient with a Novel Exonic Deletion of with Resultant Morquio Syndrome with Two Successful Pregnancies.

In this report, we describe phenotypic features of a patient with mucopolysaccharidosis type IVA (Morquio syndrome) harboring a novel exon 1 deletion in with enzymatic confirmation consistent with Morquio syndrome. To our knowledge, this is the first reported case of this variant. Additionally, we protein modelled wild-type GALNS and the pathogenic variant with an exon 1 deletion for comparative analysis using statistical mechanics methods described herein.

Sex differences in comorbidities associated with Sjögren's disease.

Background: Little is known about the association of comorbidities with sex and age at diagnosis in Sjögren's disease. We tested the hypothesis that sex differences occur in comorbidities in patients with Sjögren's disease.

Methods: Patients with Sjögren's disease were identified from 11/1974 to 7/2018 in the Mayo Clinic electronic medical record and assessed for 22 comorbidities according to sex and age at diagnosis.

A patient with a novel pathogenic variant in COL5A1 exhibiting prominent vascular and cardiac features.

The 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.

Importance of Family History in the Era of Exome Analysis: A Report of a Family with Multiple Concurrent Genetic Diseases.

Multiple familial diseases in a single patient often present with overlapping symptomatology that confers difficulty in delineating a clinical diagnosis. Pedigree analysis has been a long-standing practice in the field of medical genetics to discover familial diseases. In recent years, whole exome sequencing (WES) has proven to be a useful tool for aiding physicians in diagnosing and understanding disease etiology.

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study.

Background: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders.

Application of the community dialogues method to identify ethical values and priorities related to pharmacogenomics.

Given the expansion of genetics in medicine, there is a growing need to develop approaches to engage patients in understanding how genetics affects their health. Various qualitative methods have been applied to gain a deeper understanding of patient perspectives in topics related to genetics. Community dialogues (CD) are a bi-directional research method that invites community members to discuss a pertinent, challenging topic over the course of a multi-week period and the community members openly discuss their positions on the topic.

Sex Differences, Genetic and Environmental Influences on Dilated Cardiomyopathy.

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 (Titin) most frequently associated with disease.

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

Clinical description & molecular modeling of novel MAX pathogenic variant causing pheochromocytoma in family, supports paternal parent-of-origin effect.

The titular member of the MAX network of proteins, MYC-associated factor X (MAX), serves an important regulatory function in transcription of E-box genes associated with cell proliferation, differentiation, and apoptosis. Wild type MAX dimerizes with both MYC and MAD, both of which are members of the MAX network, and can promote or repress cell functions as needed. However, pathogenic variants in MAX are known to upset this balance, leading to uncontrolled oncogenic activity and disease phenotypes such as paragangliomas and pheochromocytomas.

Poirier-Bienvenu neurodevelopmental syndrome: A report of a patient with a pathogenic variant in CSNK2B with abnormal linear growth.

Casein kinase 2-related disorders have been linked to pathogenic variants in CSNK2A1 and CSNK2B. CSNK2B-related disease is predominantly associated with neurodevelopmental abnormalities affecting cognition; however, the extent of the phenotype associated with CSNK2B pathogenic variants is yet to be fully explored. Here, we describe a patient with features suggestive of Poirier-Bienvenu neurodevelopmental syndrome, harboring a novel CSNK2B pathogenic variant.

Chimerism involving a RB1 pathogenic variant in monochorionic dizygotic twins with twin-twin transfusion syndrome.

We report the first case of blood chimerism involving a pathogenic RB1 variant in naturally conceived monochorionic-dizygotic twins (MC/DZ) with the twin-twin-transfusion syndrome (TTTS), presumably caused by the exchange of stem-cells. Twin A developed bilateral retinoblastoma at 7 months of age. Initial genetic testing identified a de novo RB1 pathogenic variant, with a 20% allelic ratio in both twins' blood.

Genomics combined with a protein informatics platform to assess a novel pathogenic variant c.1024 A>G (p.K342E) in OPA1 in a patient with autosomal dominant optic atrophy.

Background: Autosomal Dominant Optic Atrophy (ADOA) is caused by mutations in the Optic Atrophy 1 Gene which disrupts the OPA1 protein. This disruption affects the normal function of the protein; impairs fusion of the mitochondrial inner membrane; and prevents normal OPA1 protein degradation. These events cause damage in retinal ganglion cells that could affect the patients with symptoms ranging from none to legally blind.

Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain.

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.

A practical approach to adult-onset white matter diseases, with illustrative cases.

Aim: To evaluate five illustrative cases and perform a literature review to identify and describe a working approach to adult-onset white matter diseases (WMD).

State Of The Art: Inherited WMD are a group of disorders often seen in childhood. In adulthood, progressive WMDs are rare, apart from the common nonspecific causes of hypertension and other cerebrovascular diseases.

Novel Pathogenic Variant in the Cys110 Residue: A Genotype-Phenotype Report of a Patient with Norrie Disease.

Norrie disease is an X-linked genetic disorder caused by pathogenic mutations in the . Here, we describe the clinical phenotype and genotype in a 19-week-old male infant with bilateral retinal detachment. Whole exome sequencing using available commercial methods on the proband revealed a hemizygous substitution in exon 3 of , which suggests the etiology behind retinal detachment.

Sex differences in inflammation, redox biology, mitochondria and autoimmunity.

Autoimmune diseases are characterized by circulating antibodies and immune complexes directed against self-tissues that result in both systemic and organ-specific inflammation and pathology. Most autoimmune diseases occur more often in women than men. One exception is myocarditis, which is an inflammation of the myocardium that is typically caused by viral infections.

A Report of a Novel Pathogenic Variant in a Family with Buschke-Ollendorf Syndrome.

Buschke-Ollendorf Syndrome (BOS) is a benign autosomal dominant disorder caused by pathogenic mutations in . Here, we describe a family diagnosed to have varied phenotypes associated with BOS. Single gene testing of detected a heterozygous frameshift pathogenic variant in both the affected family members.

A sleep modulated Channelopathy: a novel CACNA1A pathogenic variant identified in episodic Ataxia type 2 and a potential link to sleep alleviated migraine.

Background: To describe a patient with sleep alleviated episodic ataxia type 2 with a novel CACNA1A pathogenic variant and provide a possible link to sleep responsive migraine.

Case Presentation: A 26-year-old woman with recurrent attacks of dizziness, nausea, vomiting, ataxia and dysarthria presented for a possible diagnosis of vestibular migraine. Unique to her attacks was if she could fall asleep for as little as 15 min the spells would subside.

Novel Variant p.Q1248* is Associated with Developmental Delay: A Case Report.

In this report, we describe a 5-year-old boy with global developmental delay who presented for medical genetic evaluation. We performed whole exome sequencing that revealed the involvement of a heterogenous variant p.Gln1248Ter (CAG > TAG): c.