A journal club for GWUMC faculty, fellows, residents and students interested in genetics.
Last Updated: Feb 21, 2014
- Vitamin B12 and Pernicious Anemia — The Dawn of Molecular Medicine
“From bedside to bench and back again” is a time-honored trajectory to which many medical students, residents, and fellows aspire. Arguably the earliest and most celebrated completion of this circuit was the dietary cure of pernicious anemia that drove the discovery of vitamin B12 (cobalamin) and its physiologic role.
- Early-Onset Stroke and Vasculopathy Associated with Mutations in ADA2
"We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood."
- Mutant Adenosine Deaminase 2 in a Polyarteritis Nodosa Vasculopathy
"Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood."
- APOL1 risk variants, race, and progression of chronic kidney disease
Background: Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.
- Health disparities in kidney disease--emerging data from the human genome
Racial disparity in end-stage renal disease in the United States is well documented; hypertensive kidney disease has long been considered to be a leading cause of this disorder among black patients... Overall, nondiabetic chronic kidney disease afflicts black patients disproportionately...Research into health disparities has focused on the basis of these differences for more than 20 years, and the main emphasis in many relevant and important studies has been on social determinants of health. Yet, other observations have hinted at a role for biologic determinants, since many black patients with end-stage renal disease had close relatives who were receiving dialysis and had other family members who had so-called silent kidney disease, characterized by decreased kidney function and proteinuria. Such observations have led to the pressing question of whether there were undiscovered genetic determinants.
- PLS3 mutations in X-linked osteoporosis with fractures
Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.
- Next-Generation Sequencing for Clinical Diagnostics
Yang et al.1 report in the Journal the results of using whole-exome sequencing to make a molecular diagnosis in 62 of 250 cases (25%) sequenced by the clinical sequencing laboratory at the Baylor College of Medicine, which is accredited by the College of American Pathologists and certified through the Clinical Laboratory Improvement Amendments program. This level of success is a marked improvement over that obtained by testing single genes or gene panels currently used in standard care. The exome is the portion of the genome known to encode proteins (approximately 1% of the human genome2). Whole-exome sequencing has the advantage of reduced cost and analysis of a much smaller data set than that obtained by sequencing the entire genome. The other advantage of whole-exome sequencing is that current knowledge about functional genetic variation is largely limited to the coding sequences of genes (i.e., exons).
- Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer
tients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti–epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.
- Beyond exon 2--the developing story of RAS mutations in colorectal cancer
Initial single-agent studies of anti–epidermal growth factor receptor (anti-EGFR) antibodies in the treatment of colorectal cancer showed that these agents were marginally effective.1,2 The minority of patients derived benefit, as evidenced by progression-free survival curves that had no inflection until well after the 50% mark. However, after the determination that activating mutations in exon 2 of the gene KRAS predicted the inefficacy of anti-EGFR antibodies, reanalyses of multiple trials suggested that these agents could be more effective when administered to a more limited cohort of patients.3 Thus, mutations in exon 2 of KRAS became the first biomarkers of colorectal cancer. Even with testing of KRAS exon 2, however, a cohort of patients with colorectal cancer still do not benefit from anti-EGFR antibody therapy. Also, since the KRAS exon 2 mutations are common (appearing in approximately 40% of patients with colorectal cancer), they are the “low-hanging fruit” for analysis
- Safety and efficacy of RNAi therapy for transthyretin amyloidosis
Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.
- A new era in the treatment of amyloidosis?
Amyloidosis is a diverse group of diseases caused by extracellular accumulation of protein in a highly ordered, abnormal, insoluble fibrillar form. These diseases can be hereditary or acquired and localized or systemic. Most are progressive and fatal. Among the almost 30 different proteins that have been found to form amyloid in humans, transthyretin, a carrier molecule of thyroxine and vitamin A, is of particular interest because it may cause both hereditary and acquired amyloidosis with a diverse range of symptoms. In addition, transthyretin amyloid may be more prevalent than previously thought, and several potential new treatments are on the horizon.
- Mutations in DSTYK and dominant urinary tract malformations
ongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.
- Characterization of uterine leiomyomas by whole-genome sequencing
Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions. We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women.
- Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia
The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.
- A mechanism-driven treatment for chronic lymphocytic leukemia?
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Its prevalence is increasing largely because of extended life expectancies. CLL has a highly heterogeneous clinical course: some patients live for years or decades, never require treatment, and eventually die from a cause other than CLL, whereas others have a slowly progressive clinical picture and others have an aggressive disease course of 2 years or less. Since 1975, clinicians have relied on clinical staging systems to define prognosis and make treatment decisions. Over the past 12 years, a number of biologic markers have allowed a more refined prognostic stratification...
- Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant
Although androgen resistance has been characterized in men with a normal chromosome complement and mutations in the androgen-receptor gene, a mutation in the gene encoding estrogen receptor α (ESR1) was previously described only in one man and not, to our knowledge, in a woman. We now describe an 18-year-old woman without breast development and with markedly elevated serum levels of estrogens and bilateral multicystic ovaries. She was found to have a homozygous loss-of-function ESR1 mutation in a completely conserved residue that interferes with estrogen signaling. Her clinical presentation was similar to that in the mouse orthologue knockout. This case shows that disruption of ESR1 causes profound estrogen resistance in women. (Funded by the National Institutes of Health.).
This virtual journal club is intended to provide a way for health care practitioners to see new literature in genetics and to learn about developments in the field.
Articles on topics in medical genetics will be posted monthly, or more often if
a particularly timely article is published. To participate, read the article and then add your comments to participate in the online discussion.
The current article will be posted to the right. Please scroll down to view previous articles and discussions.
Charles J. Macri, MD, FACOG, FACMG, FACS
Professor of Obstetrics & Gynecology
Director, Division of Maternal Fetal Medicine
Director, Student Education in Obstetrics and Gynecology
GWUMC Genetics - Current, Basic & Advanced Information about Genetics
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