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Bi-allelic variants in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts

3 Mar, 17 | by hqqu

Collagens are important constituents of connective tissue but are also present in the membrane lining the surface of the brain. The COL3A1 gene encodes the chains of type III procollagen. Mutation of one copy of this gene results in vascular Ehlers Danlos syndrome (EDS), a connective tissue disorder. We now have discovered that mutations of both copies of this gene, so-called bi-allelic mutations, result in a complex brain malformation with or without signs of vascular EDS. This brain malformation is very similar to that associated with mutations in the gene encoding the receptor of type III collagen, G protein-coupled receptor 56 (GPR56), also known as Adhesion G protein-coupled Receptor G1 (ADGRG1). (By Prof. Anna Jansen, http://jmg.bmj.com/content/early/2017/03/03/jmedgenet-2016-104421 )

A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi Family

31 Jan, 17 | by hqqu

Here, we report five members affected with severe intellectual disability, developmental delays, seizures, and self-mutilation in a large consanguineous family from Saudi Arabia. Clinical whole-exome sequencing in the proband revealed a pathogenic variant in the CRBN gene, which segregated in the family. CRBN protein is known to play a role in memory and learning by regulating the assembly and expression of large-conductance, calcium-activated potassium channels involved in severe neurological disorders. Our study expands the role of CRBN in severe intellectual disability, with an additional feature of self-mutilation reflecting the heterogeneity in the clinical features exhibited by the patients with CRBN mutations. Studies are ongoing to understand the function of the CRBN variant.

(By Atia Sheereen, http://jmg.bmj.com/content/early/2017/01/30/jmedgenet-2016-104117 )

GPRASP2, a Novel Causative Gene implicated in an X-Linked Recessive Syndromic Hearing Loss

17 Jan, 17 | by hqqu

We reported a novel X-linked recessive syndromic hearing loss (SHL) combined with unique and unrecognized clinical features in a five-generation Chinese family. To identify the genetic cause of X-linked SHL, targeted X-chromosome exome sequencing (XES) was conducted. A 2-base pair missense mutation (c.1717_1718GC>AA, p.A573N) in the G protein-coupled receptor associated sorting protein 2 (GPRASP2) gene was identified by XES and cosegregation analysis. In silico analysis and the expression of homologous Gprasp2 in the mouse cochlea strongly suggested the implication of GPRASP2 in hearing function, and its role in the occurrence of X-linked SHL was still needed to be further investigated. (By Professor Xin Cao, http://jmg.bmj.com/content/early/2017/01/17/jmedgenet-2016-104320 )

A liminal stage after predictive testing for Huntington disease

13 Jan, 17 | by hqqu

Does knowledge of being a carrier of the pathological Huntington disease mutation trigger onset of the disease, influence self-awareness and allow carriers to identify symptoms of disease onset? These are questions raised by persons who requested presymptomatic testing and we went back to 75 of them. We showed that having motor signs on examination did not correlate with subjective recognition of them. In carriers without motor signs, self-observation was high despite the lack of objective signs. The view of carriers was not always concordant with the medically defined onset, highlighting difficulties for its use as an outcome in future trials. (By Dr. Alexandra Durr, http://jmg.bmj.com/content/early/2017/01/12/jmedgenet-2016-104199 )

No correlation between mtDNA amount and methylation levels at the CpG island of POLG exon 2 in wild-type and mutant human differentiated cells

9 Jan, 17 | by hqqu

Mechanisms regulating mitochondrial DNA (mtDNA) amount according to developmental stage and tissue origin are still unknown. Recent works have suggested the role of epigenetic modification at a CpG island located in POLG gene, encoding the polymerase responsible for mtDNA synthesis. We found that this CpG island is highly methylated in human tissues, whatever developmental stages (after 12 weeks) or tissue energy-demand. This methylation level is not modified by the presence of genetic mutations that can alter the mtDNA amount (mtDNA or inactivating POLG mutations). Mechanisms involved in mtDNA amount control in human differenciated cells remain to be identified. (By Dr. Julie STEFFANN, http://jmg.bmj.com/content/early/2017/01/09/jmedgenet-2016-104335 )

Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy

28 Dec, 16 | by hqqu

Hereditary optic neuropathies (HON) are blinding conditions that affect the optic nerve which connects the eye to the brain. Mitochondrial (mt) and nuclear DNA mutations can cause HON. mtDNA mutations in complex I subunits of the respiratory chain cause a bilateral, painless, subacute disease known as Leber HON (LHON). Here, we report for the first time a LHON-like phenotype associated with a nuclear gene, NDUFS2. Consistent with the pathomechanism of LHON, NDUFS2 is required for the assembly of Complex I. Severe NDUFS2 mutations were previously reported to cause Leigh syndrome. Our results suggest milder mutations can cause isolated HON. (By Dr. Jean-Michel ROZET, http://jmg.bmj.com/content/early/2016/12/28/jmedgenet-2016-104212 )

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 )

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