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Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus

13 Mar, 17 | by hqqu

One of the major susceptibility loci identified for Systemic lupus erythematosus (SLE) lies within a common large inversion polymorphism region on chromosome 8p23. In this study, we further investigated the ‘extended’ 8p23 locus (~4 Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery dataset (~1,200 subjects) and a replication dataset (>10,000 subjects) comprising European-descent individuals. Our results have implicated multiple (known+novel) SLE signals/genes at the extended 8p23 locus and suggested that this broad locus contributes to SLE risk through the effects of multiple genes/pathways. Our findings underline the importance of evaluating the entire inversion region for any disease/trait linked to this 8p23 locus. (By Dr. F. Yesim Demirci, )

15 years of research on Oral-Facial-Digital syndromes: from 1 to 16 causal genes

13 Mar, 17 | by hqqu

Oral-facial-digital syndromes (OFDS) are rare genetic disorders characterized by the association of abnormalities of the face, oral cavity and extremities. Molecular bases were poorly known but we suspected the involvement of ciliary genes. Using whole-exome sequencing in 24 OFDS cases, we identified causal variants in five new genes, two genes previously implicated in OFDS and four genes previously related to other ciliopathies. Functional studies revealed the involvement of several structural or functional defects of primary cilia (centrosome, transition zone, intraflagellar transport), and characterized three ciliary protein complexes. (By Dr. Ange-Line Bruel, )

Novel and known ribosomal causes of Diamond-Blackfan anemia identified through comprehensive genomic characterization

9 Mar, 17 | by hqqu

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome primarily caused by defects in ribosome biology. It is associated with physical anomalies and high risk of specific cancers. We performed comprehensive genomic analyses of 35 genetically uncharacterized DBA families participating in the National Cancer’s Institute’s DBA cohort ( Identifier: NCT00027274). Using whole exome sequencing, copy number variation and array comparative genomic hybridization, we discovered variants in two genes not previously associated with DBA, RPL18 and RPL35. These variants caused characteristic ribosome assembly defects consistent with the DBA biology. Overall, this combination of genomic methods led to the identification the causative variant in 72% of the cohort. Efforts are underway to identify the underlying genetic cause of DBA in the remaining families. (By Dr. Payal P. Khincha, )

A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis

6 Mar, 17 | by hqqu

Hydranencephaly, a congenital anomaly caused by destruction of the cerebral hemispheres is usually found in isolation. We report a family in which three fetuses displayed multinucleated neurons, anhydramnios, renal dysplasia, and cerebellar hypoplasia together with hydranencephaly, a novel syndrome we have named MARCH. Sequencing revealed the cause to be a homozygous truncating mutation in CEP55, a cell cycle regulator. Knock-down of the CEP55 ortholog in zebrafish reproduced the brain and kidney defects, and were rescued by full-length, but not truncated human CEP55. When we expressed truncated CEP55 in human cells, the protein failed to localize properly, producing multinucleated daughter cells. Our results implicate a faulty centrosomal protein as the cause of this lethal multiple anomaly syndrome. (By Dr. Patrick Frosk, )

Zebrafish were used to model MARCH syndrome, a novel multi system disorder in humans caused by mutations in CEP55. Image credits to Carter Gunn, Julien Philippe (microscopy), and Abigaëlle Philippe (center image)

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, )

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, )

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, )

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, )

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, )

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, )

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