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 )
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 )
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 )
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 )
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 )
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 )
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. 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).
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 )
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 )
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 )
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.