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When chromatin organisation floats astray: the Srcap gene and Floating–Harbor syndrome

26 Apr, 16 | by hqqu

Floating-Harbor syndrome (FHS) is a rare human disease characterized by developmental defects, often associated with mental retardation. FHS was first described at Boston’s Floating Hospital in 1973, but the causative gene, called Srcap, was identified only recently. Srcap encodes a protein with a key role in control of gene expression, however, the underlying molecular bases of FHS still need elucidating. In this review article, the authors critically examine recent studies on FHS, proposing possible mechanisms for the molecular events leading to the onset of the disease.  (By Professor Patrizio Dimitri, http://jmg.bmj.com/content/early/2016/04/26/jmedgenet-2016-103842 )

 

FHS research group

From left to right:
Maria Teresa Atterrato, Giovanni Messina, Emanuele Celauro, Patrizio Dimitri, Yuri Prozzillo.

A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype

18 Apr, 16 | by hqqu

Mitochondrial diseases occur when insufficient energy is produced, affect both adults and children and often require a muscle biopsy to help the investigation and diagnosis. We have identified the same genetic defect – a mutation within the NDUFB3 gene – in ten children from eight families with identical physical features; affected children are short, have prominent foreheads and were noted to be developing slowly during pregnancy. These children have recovered well whereas many other mitochondrial genetic defects have a fatal outcome. Early recognition of this combination of physical features could lead to other children being diagnosed without requiring an invasive muscle biopsy. (By Dr. Charlotte Alston, http://jmg.bmj.com/content/early/2016/04/18/jmedgenet-2015-103576 )

Microduplications at the Pseudoautosomal SHOX Locus in Autism Spectrum Disorders and Related Neurodevelopmental Conditions

12 Apr, 16 | by hqqu

SHOX encodes a transcription factor involved in cell-cycle and growth regulation. Here, we report the association between microduplications at the SHOX locus and autism spectrum disorders (ASD) and related neurodevelopmental conditions (NDD). The study was triggered by observations in a discovery series of 90 ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation. A link between SHOX microduplications and ASD/NDD was subsequently supported by examination of a follow-up sample of 18,857 ASD/NDD cases, compared with 12,594 controls. Our findings suggest that SHOX microduplications are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, concomitant duplication of SHOX enhancers may be required to trigger NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment. (By Dr. Maria Tropeano, http://jmg.bmj.com/content/early/2016/04/12/jmedgenet-2015-103621 )

Photo_Dr. Maria Tropeano_jpg

Dr. Maria Tropeano

Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population

11 Apr, 16 | by hqqu

The 7TM receptor for long chain fatty acids FFAR4 (GPR120) currently attracts great attention as a therapeutic target to treat metabolic diseases. A low-frequency missense variant (p.R270H, rs116454156) in FFAR4 has previously been reported to associate with obesity in European populations and to impair signaling of the receptor. Here we further examine the functional consequences of p.R270H on receptor properties, and expand the human association studies by investigating traits of relevance for obesity- and glucose metabolism. Despite impaired effects on receptor function, we found no statistically significant associations with any examined traits. (By Marie Aare Vestmar, http://jmg.bmj.com/content/early/2016/04/11/jmedgenet-2015-103728 )

Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia

11 Apr, 16 | by hqqu

Acromicric dysplasia and geleophysic dysplasia are both forms of acromelic dysplasia.  Several causative genes have been identified for the acromelic dysplasias, all of which affect TGF-β signalling and/or interactions with fibrillin.  Here, we have used massive parallel sequencing to identify a dominant mutation in latent TGF-β binding protein-3 (LTBP3) in a family with acromicric dysplasia, and de novo mutations in LTBP3 causing geleophysic dysplasia in two separate unrelated individuals. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum. (By Aideen McInerney-Leo, http://jmg.bmj.com/content/early/2016/04/11/jmedgenet-2015-103647 )

Naturally occurring BRCA2 alternate mRNA splicing events in clinically relevant samples

8 Apr, 16 | by hqqu

Genetic testing of BRCA1 and BRCA2 genes in cancer patients frequently reveals gene variations with unknown clinical effects.  Some of these variations might affect mRNA splicing, an important step in gene expression.  Aberrant splicing is typically determined by looking for novel mRNA molecules.  We wanted to know if these molecules could also occur at random.  We found there are 24 different splicing events in BRCA2 that appear in some, but not all mRNA samples examined, and may be random events.  This work shows that novel mRNA molecules are not sufficient to conclude that a gene variation is a disease-causing mutation. (By Dr. James D. Fackenthal, http://jmg.bmj.com/content/early/2016/04/08/jmedgenet-2015-103570 )

Figure 3

Germline RRAS2 Mutations are not associated with Noonan Syndrome

7 Apr, 16 | by hqqu

Mutations in a variety of Ras-MAPK pathway genes are detected in 70-80% of patients with Noonan Syndrome (NS) and related disorders, collectively referred to as RASopathies. Certain patients with RASopathies are predisposed to developing juvenile myelomonocytic leukemia (JMML), a myeloproliferative disorder of early childhood. We recently identified somatic mutations in RRAS2 in JMML and hypothesized that germline RRAS2 mutations could be an additional cause of NS. We therefore screened a cohort of 116 NS patients for mutations in RRAS2 that had no identified lesions. No recurrent mutations were found, ruling out germline mutations in RRAS2 as a cause of Noonan syndrome. (By Dr. Elliot Stieglitz, http://jmg.bmj.com/content/early/2016/04/07/jmedgenet-2016-103889 )

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

1 Apr, 16 | by hqqu

So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies. These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels by analyzing about 150,000 individuals. Our study resulted in the identification and replication of five new associations with circulating lipid levels at loci within genes that can be linked biologically to lipid metabolism. One of the variants we find associated with triglycerides, is rs116843064, a variant that changes the amino acid glutamic acid into lysine (Glu40Lys) and is predicted to be damaging for the structure and function of the protein. (By Elisa van Leeuwen, http://jmg.bmj.com/content/early/2016/04/01/jmedgenet-2015-103439 )

Fig1D

Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations

18 Mar, 16 | by hqqu

Newer genetic counselling approaches are needed to test large populations for cancer gene alterations. We compared traditional face-to-face counselling with a DVD assisted approach. This randomised study was undertaken in the London Jewish population while testing for BRCA gene alterations. We found DVD assisted counselling was not inferior to traditional face-to-face counselling for increase in knowledge and counselling satisfaction. Compared to traditional counselling it led to an equivalent number of people undergoing genetic-testing and cost savings of £14/person counselled. 98% people found the DVD length & information satisfactory, 85%-89% felt it improved their understanding and 95% would recommend it to others. (By Dr. Ranjit Manchanda, http://jmg.bmj.com/content/early/2016/03/18/jmedgenet-2015-103740 )

FINAL GCaPPS logo_sized

AKAP2 identified as a novel gene mutated in a Chinese family with adolescent idiopathic scoliosis

17 Mar, 16 | by hqqu

Adolescent idiopathic scoliosis (AIS) is a common spinal deformities found in adolescent populations, while Mendelian-inherited family cases are quite rare. An autosomal-dominant inherited AIS family has been investigated and one missense mutation harbored in AKAP2 gene was found. The AKAP2 gene is located in a previously reported linkage locus (IS4) on chromosome 9q31.2-q34.2, which could involve in the formation of bone anomalies. Bioinformatics prediction of this missense mutation and increased mRNA expression level in our AIS family suggest that the AKAP2 gene may play a potential role in the pathogenic way of AIS. (By Dr. Zheng-mao Hu, http://jmg.bmj.com/content/early/2016/03/17/jmedgenet-2015-103684 )

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