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Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder

18 May, 15 | by hqqu

Auditory neuropathy spectrum disorder (ANSD) is a type of hearing loss in which transmission of auditory signals from the inner ear to the brain stem is distorted, giving rise to speech perception difficulties beyond that expected for the observed degree of hearing loss. Although its prevalence is high – ANSD has an incidence of 13% in children with severe-to-profound hearing loss – in many cases, the molecular pathology remains unclear.  Underlying etiologies include toxic/metabolic derangements, infections, immunological causes, drugs and genetic abnormalities, with 40% of ANSD having a genetic basis.   We now implicate mutation of AIFM1 as a common cause of familial and sporadic ANSD in male, often occured at adolescence.  Our finding of cochlear nerve hypoplasia in some patients implies that magnetic resonance imaging may be of value in localizing the site of lesion and suggests that cochlea implantation in these patients may be chosen carefully.  (By Dr. Qiuju Wang , http://jmg.bmj.com/content/early/2015/05/17/jmedgenet-2014-102961 )

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A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome

7 May, 15 | by hqqu

Silver Russell Syndrome (SRS) includes pre and postnatal growth retardation, severe feeding difficulties, protruding forehead, relative macrocephaly at birth and body asymmetry. A simple clinical definition of SRS is important to establish its prevalence, propose clinical guidelines and common clinical trials for this group of patients and allow research to progress for patients with no molecular cause identified yet. We validate, on a prospective study, a new scoring system very sensitive (98%) for the detection of SRS patients with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum. (By Salah Azzi, http://jmg.bmj.com/content/early/2015/05/07/jmedgenet-2014-102979 )

MET variant and human hearing loss

4 May, 15 | by hqqu

Hearing loss is a common phenotype. We mapped DFNB97, a new recessively inherited deafness locus, to chromosome 7q31.2. The DFNB97 phenotype is segregating in a consanguineous family with 9 affected individuals. Whole-exome sequencing (WES) identified a missense mutation in MET (Mesenchymal Epithelial Transition factor) which is the receptor for HGF (hepatocyte growth factor). The p.F841V variant co-segregated with deafness in this family, and affects a highly conserved amino acid in MET in a domain that forms an HGF binding site. It is predicted to be disease causing by different software programs. Although the requirement of HGF for normal hearing has been reported, this is the first study to directly implicate its receptor MET in human hearing. (By Dr. Sadaf Naz, http://jmg.bmj.com/content/early/2015/05/03/jmedgenet-2015-103023 )

Mujtaba et al. JMG blog

A germline mutation in PBRM1 predisposes to renal cell carcinoma

24 Apr, 15 | by hqqu

Many cases of familial renal cell carcinoma (RCC) are unexplained by mutations in known predisposing genes or shared environmental factors. We have shown that PBRM1, a tumor supressor gene with frequent somatic mutations in clear cell RCC, is also a RCC susceptibility gene. Indeed, four members from the same family, all with a history of RCC, carried the same germline pathogenic mutation in PBRM1, whereas an unaffected relative did not. Complementary analyses supported our findings as there was loss of the wild-type allele and absence of expression of the normal protein in tumoral tissue extracted from the patients RCCs. (By Patrick R Benusiglio, http://jmg.bmj.com/content/early/2015/04/23/jmedgenet-2014-102912 )

Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer

23 Apr, 15 | by hqqu

Lynch syndrome is a hereditary condition which predispose to colorectal cancer and other tumors. A particular cause of this syndrome is the MLH1 constitutional methylation (epimutation). Universal tumor testing is recommended as the best strategy to identify Lynch syndrome patients. This screening renders a considerable number of cases with MLH1 methylation in tumors raising the question to test or not, for constitutional epimutation. Our results suggest that the prevalence of constitutional epimutation is negligible in colorectal cancer patients who do not fulfil the risk criteria, rendering this testing unnecessary in members of the general population who lack cancer history or are aged at the time of diagnosis. (By Dr. José Luis Soto, http://jmg.bmj.com/content/early/2015/04/23/jmedgenet-2015-103076 )

Canadian Open Genetics Repository (COGR): a unified clinical genomics database as a community resource for standardising and sharing genetic interpretations

22 Apr, 15 | by hqqu

Genomic medicine is still an emerging field. Scientists working at different institutions have developed naming systems and checklists and specialized databases that differ significantly from one to another; their utility is compromised by the many differences between them. The result is that sharing such data across the biomedical community has been difficult if not impossible. To unlock the benefits of these resources, the project team has created a unified, open-access, clinical-grade genetic database, a repository based on a commonly shared platform designed to hold genetic information and their relationship to disease. This database draws from the holdings in place at hospitals from across Canada. (By Marina Wang, http://jmg.bmj.com/content/early/2015/04/22/jmedgenet-2014-102933 ) COGR_WebsiteFrontPage

Loss-of-function de novo mutations play an important role in severe human neural tube defects

24 Mar, 15 | by hqqu

Neural tube defects (NTDs) are very common and severe birth malformations that are caused by failure of neural tube closure. They are caused by a combination of genetic and environmental factors that remain largely unknown. Anencephaly and spina bifida are severe NTDs that affect reproductive fitness but are still prevalent across generations, suggesting a role for new or de novo mutations (DNMs) in their etiology. We have re-sequenced the exomes of 43 sporadic cases affected with either spina bifida or anencephaly and their unaffected parents and we have indeed demonstrated that loss of function DNMs play an important role in their causation. Our study also strongly implicates SHROOM3 in the pathogenesis of human NTDs. (By Philippe Lemay, http://jmg.bmj.com/content/early/2015/03/24/jmedgenet-2015-103027 )

Familial periventricular nodular heterotopia, epilepsy and Melnick-Needles Syndrome caused by a single FLNA mutation with combined gain-of-function and loss-of-function effects

10 Mar, 15 | by hqqu

Loss-of-function mutations of the FLNA gene cause X-linked periventricular nodular heterotopia (PNH) while gain-of-function mutations cause the Otopalatodigital (OPD) spectrum. These two conditions are known to be mutually exclusive phenotypes. We describe a family in which a woman and her three daughters exhibited a phenotype combining PNH, epilepsy and Melnick-Needles syndrome, a skeletal disorder assigned to the OPD spectrum. All affected individuals harbored a novel non-conservative missense mutation in FLNA leading to two aberrant transcripts, one of which carries the missense mutation, plus a longer transcript resulting from intron 3 retention. Co-occurring gain-of and loss-of-function appears to cause the dual phenotype. (By Elena Parrini, http://jmg.bmj.com/content/early/2015/03/09/jmedgenet-2014-102959 )DSC_0114

A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B

6 Mar, 15 | by hqqu

Klippel-Feil anomaly (KFA) is a rare disorder encompassing fusion of the cervical spine, as well as low posterior hair line and limited neck mobility. Here we describe a mutation in a novel gene, MYO18B, which results in KFA along with muscular weakness. This is an association that has never been reported before. High resolution microscopy reveals damage to the muscle filaments. The syndrome also results in a characteristic facial appearance which will be beneficial in identifying future cases. The mutation is predicted to cause truncation of the resulting protein, and RNA from this gene is virtually absent in the patients. (By Dr. Fowzan S Alkuraya, http://jmg.bmj.com/content/early/2015/03/06/jmedgenet-2014-102964 )

Bilateral vestibular schwannomas in older patients: NF2 or chance?

27 Feb, 15 | by hqqu

We have previously estimated that one in two million people will develop bilateral vestibular schwannomas by chance. We show for the first time molecular proof that a man who developed bilateral vestibular schwannomas aged 52 and 67 years of age had developed these by independent events in the NF2 gene with no evidence of a germline or mosaic NF2 mutation or chromosome 22q linked inherited aetiology. Furthermore we estimate that up to 50% of those presenting with bilateral vestibular schwannomas alone after 70 years of age are likely to have developed these by chance. This research will mean that people developing just vestibular schwannomas on both sides at older ages can be reassured that the risks for their children are likely even lower. (By Prof. D Gareth Evans, http://jmg.bmj.com/content/early/2015/02/27/jmedgenet-2014-102973 )

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