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Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B

22 Dec, 16 | by hqqu

The genetic code is degenerate. Eighteen of the twenty core amino acids are each encoded by multiple, so-called synonymous codons. The Neutral Theory of Molecular Evolution suggests that synonymous codons will be unaffected by the selective evolutionary pressure and that synonymous mutations will be inconsequential to protein quality. However, recent reports refute this prediction. A new study uncovers the mechanism(s) underlying the origin of Hemophilia B in patients harboring a single synonymous mutation in the F9 gene encoding blood coagulation factor IX. The key novel finding from this study is that a single synonymous mutation results in clinical consequences that lead to a disease via multiple mechanisms that act in concert. (By Vijaya L Simhadri, http://jmg.bmj.com/content/early/2016/12/22/jmedgenet-2016-104072 )

figure-5_proof_-jmedgenet-2016-104072

Precise long non-coding RNA modulation in visual maintenance and impairment

21 Dec, 16 | by hqqu

Long noncoding RNAs (lncRNAs), a class of DNA transcripts longer than 200 nucleotides with limited protein-coding potential, have been demonstradte to be crucial and pervasive cellular regulators in various physiological or pathological processes. Vision is a complex and vital perception that comprises 80% of the sensory information we receive. Based on current findings, our review represents a prospective and integrated illustration of lncRNAs’ modulation in visual maintenance and impairment. Furthermore, we also highlight challenges and future directions in conducting lncRNA studies, particularly in patients, to achieve diagnostic, prognostic and therapeutic applications. (By Dr. Yehong Zhuo, http://jmg.bmj.com/content/early/2016/12/21/jmedgenet-2016-104266 )

lncrnas-in-various-kinds-of-visual-impairment

LncRNAs in various kinds of visual impairment. This figure displayed lncRNAs in most visual impairments mentioned in this article, including a) Blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), b) Age related cataract, c) Glaucoma, d) Proliferative vitreoretinopathy (PVR), e) Uveal melanoma, f) Retinoblastoma, g) Age related macular degeneration (AMD), h) Retinal neurodegeneration, i) Retinopathy of prematurity (ROP), j) Diabetic retinopathy (DR).

Diagnostic value of exome and whole genome sequencing in craniosynostosis

14 Dec, 16 | by hqqu

Craniosynostosis (the premature fusion of the skull bones) is a common disorder affecting 1 in 2,250 children and so is often encountered by paediatricians and geneticists. Because of the many different genetic causes of this disease, standard diagnostic testing procedures can often miss the underlying genetic lesion. In our study we identified the genetic cause using deep sequencing of the genome in 15 patients from a cohort of 40 (37.5%), and provide specific details of 5 cases where this result has had a direct and immediate impact on the clinical decisions for the child and their families. This study highlights the impact of using these methods to identify the underlying genetic cause in cases that would otherwise have eluded routine clinical testing, in addition to identifying new disease genes to improve diagnostic and management strategies in the future. (By Dr Kerry Miller, http://jmg.bmj.com/content/early/2016/12/14/jmedgenet-2016-104215 )

Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix

13 Dec, 16 | by hqqu

Progressive symmetric erythrokeratoderma (PSEK) is a genetic condition featured by the appearance of symmetrically distributed demarcated hyperkeratotic plaques, often with associated palmoplantar hyperkeratosis, with new plaques developed over time. Previously mutation in two genes LOR and GJB4 have been implicated with PSEK, while a locus for PSEK has been mapped to 21q11.2-q21.2. In this study we identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83 gene that leads to PSEK. Heterozygous missense substitutions in KRT83 have been implicated in autosomal dominant monilethrix. Our study thus indicates that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the KRT83 gene. (By Dr. Khadim Shah, http://jmg.bmj.com/content/early/2016/12/13/jmedgenet-2016-104107 )

Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy

9 Dec, 16 | by hqqu

Tonsillectomy is one of the most common surgical procedures in children and young adults and may be recommended in patients who experience recurrent throat infections. Using Danish health register data, we screened the genomes of more than 3,000 tonsillectomy patients and 13,000 controls. Thereby, we identified variants in the gene HORMAD2 significantly associated with tonsillectomy. It is notable that the top associated genetic variant was previously reported to increase the risk of IgA nephropathy, a rare autoimmune disease that affects the kidneys, while it was also reported to decrease the risk of inflammatory bowel disease. Our results underline the complex genetic regulation of the mucosal immune system and its effect on different diseases. (By Dr. Bjarke Feenstra, http://jmg.bmj.com/content/early/2016/12/07/jmedgenet-2016-104304 )

 

hormad2_locus_for_jmg_blog

Regional association plot for the tonsillectomy locus on chromosome 22, showing SNP position (x axis) and association with tonsillectomy (-log10 p value; y axis). The top SNP, rs2412971, is represented by a purple diamond, and the other SNPs are colored to reflect their correlation (linkage disequilibrium) with the top SNP. The blue lines show estimated rates of recombination based on data from the HapMap project (right y axis). The names and positions of HORMAD2 and other genes in the region are shown in the lower part of the figure.

A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome

5 Dec, 16 | by hqqu

Progeria is a fatal premature aging disease caused by mutations in the LMNA gene, leading to production of the toxic protein progerin.    We describe a child with a mixed cell population (mosaicism) carrying two different progerin-producing mutations of the same nucleotide – one causing clinically severe Progeria and one milder Progeria.  The child possessed intermediate disease characteristics.  We postulate that the severe mutation represents the original genotype, and the milder variant arose early in embryogenesis and was subjected to positive selection.  This type of mosaicism has not been previously characterized for any disease. Such compensatory mechanisms may occur elsewhere, but go undetected by current genetic screens. (By Dr. Leslie B. Gordon, http://jmg.bmj.com/content/early/2016/12/05/jmedgenet-2016-104295 )

The importance of dynamic re-analysis in diagnostic whole exome sequencing

29 Nov, 16 | by hqqu

Exome sequencing is a method of investigating all of a person¹s genes at the same time to look for the mutation that is causing their illness. It is often used when targeted genetic testing has run into a dead end. However, half to three quarters of patients who have their exome sequenced will still not receive a Œgenetic diagnosis¹. This research by Drs. Anna Need, Vandana Shashi and colleagues explores the reasons that some families do not get a diagnosis through exome sequencing the first time, and presents three patients who received a diagnosis when their exome data was re-analysed.  (By Dr. Anna Need, http://jmg.bmj.com/content/early/2016/11/29/jmedgenet-2016-104306 )

Diagnostic value of exome and whole genome sequencing in craniosynostosis

24 Nov, 16 | by hqqu

Craniosynostosis (the premature fusion of the skull bones) is a common disorder affecting 1 in 2,250 children and so is often encountered by paediatricians and geneticists. Because of the many different genetic causes of this disease, standard diagnostic testing procedures can often miss the underlying genetic lesion. In our study we identified the genetic cause using deep sequencing of the genome in 15 patients from a cohort of 40 (37.5%), and provide specific details of 5 cases where this result has had a direct and immediate impact on the clinical decisions for the child and their families. This study highlights the impact of using these methods to identify the underlying genetic cause in cases that would otherwise have eluded routine clinical testing, in addition to identifying new disease genes to improve diagnostic and management strategies in the future. (By Dr. Kerry Miller, http://jmg.bmj.com/content/early/2016/11/24/jmedgenet-2016-104215 )

Hypersuccinylacetonemia and normal liver function in maleylacetoacetate isomerase deficiency

22 Nov, 16 | by hqqu

Tyrosinemia is a genetic disease that causes liver failure, cirrhosis and liver cancer. Succinylacetone is a substance that is elevated in tyrosinemia. Using succinylacetone for newborn screening permits early treatment of tyrosinemia, which can prevent liver disease. Six babies were detected by screening but had normal liver function. Even without special treatment, each child has maintained normal liver function. Each has a genetic deficiency of an enzyme called maleylacetoacetate isomerase, that is related to but different from the enzyme that causes tyrosinemia. Recognizing this newly-discovered condition is important for proper genetic counselling and treatment of babies detected by tyrosinemia screening. (By Dr. Grant Mitchell, http://jmg.bmj.com/content/early/2016/11/22/jmedgenet-2016-104289 )

Anxiety delivered Direct-to-Consumer: are we asking the right questions about the impacts of DTC genetic testing?

10 Nov, 16 | by hqqu

Contrarily to initial expectations about the psychological impact of Direct to Consumer genetic testing, people are substantially resilient to long-term consequences of results to genetic testing. Previous literature raised concerns on DTC focusing on anxiety levels it might cause. We claim that there are three substantial limits to be considered: non-clinical anxiety is not a negative outcome; anxiety is limitedly predictive of health related behaviors and decisions; a number of previous studies are affected by methodological errors. We promote the exploration of complex cognitive and emotional mechanisms to capture the subtle and multifaceted nature of a living-at-risk situation. (By Dr. Serena Oliveri, http://jmg.bmj.com/content/early/2016/09/19/jmedgenet-2016-104184 )

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