Osteosclerotic metaphyseal dysplasia is a unique form of osteopetrosis characterized by dysplasiaof metaphyses of tubular bones with increased bone density. By exome sequencing, we found a homozygous mutation, c.5938_5944del[p.E1980Afs*66]in LRRK1 (Leucin-rich repeat kinase 1). LRRK1 was highly expressed in differentiated osteoclast. The patient’s phenotype was very similar to that of Lrrk1 knockout mice that we previously reported. In vitro transfection rescue experiments using osteoclasts from the knockout mice showed that the deletion caused a loss of bone-resorbing function of osteoclast. LRRK1 can be afascinating new drug target ofosteoporosis, like RANKL and sclerostin. (By Dr. Aritoshi Iida, http://jmg.bmj.com/content/early/2016/04/07/jmedgenet-2016-103756 )
Osteonecrosis of the femoral head is a painful and debilitating bone disease that causes bone death at the hip leading to its collapse and subsequent end-stage osteoarthritis. The disease is poorly understood limiting treatment options to invasive surgical procedures such as total hip replacement. We have identified a Canadian family of Greek origin with osteonecrosis of the femoral head in four out of six siblings with no risk factors for the disease. Genetic analysis discovered a mutation of the TRPV4 gene found only in the four affected siblings. Measurements of the mutant protein’s function found that its activity was higher than the normal protein. TRPV4-associated phenotypes involve a large spectrum of skeletal dyscrasias and neuropathies. Our findings broaden the spectrum of phenotypes caused by TRPV4 mutations and highlight the relevance of this ion channel in the physiopathology of osteonecrosis. (By Dr Chantal Séguin, http://jmg.bmj.com/content/early/2016/06/21/jmedgenet-2016-103829 )
Dr Chantal Séguin
An essential feature of successful mammalian reproduction is the fusion of a sperm with a mature oocyte. We previously found that heterozygous mutations in TUBB8 caused oocyte maturation arrest. In this study, we identified novel heterozygous and homozygous mutations in TUBB8 that cause variability in the corresponding phenotypes of human oocytes and early embryos. For example, oocyte with some mutations can exclude the first polar body and be fertilized, although the ensuing embryos became developmentally arrested. Our data substantially expand the range of dysfunctional oocyte phenotypes incurred by mutation in TUBB8, extend the class of genetic diseases known as the tubulinopathies, and provide new criteria for the qualitative evaluation of MII oocytes for IVF. (By Dr. Lei Wang, http://jmg.bmj.com/content/early/2016/06/06/jmedgenet-2016-103891 )
Common variable immunodeficiency (CVID) is an immune disorder characterized by low antibody levels and an increased susceptibility to infections and immune-related complications. It is a heterogeneous disorder with a variable clinical presentation and severity. Thus far, single gene defects have been identified in about 2-10% of patients. As more disease genes are being identified, it is becoming clear that CVID is an umbrella diagnosis and that many of these genetic defects cause separate disease entities. Moreover, it is thought that, in at least a subgroup of CVID patients, a single genetic defect does not suffice to develop the disease, meaning that additional genetic and/or environmental factors are involved. This review provides an overview of disease genes implicated in CVID and discusses current evidence on a possible multifactorial origin of this disorder. (Delfien Bogaert on behalf of all authors, http://jmg.bmj.com/content/early/2016/06/01/jmedgenet-2015-103690 )
Dentin dysplasia I (DDI) is an autosomal dominant disorder characterized by rootless teeth with abnormal pulpal morphology. The etiology of DDI still remains largely unclear. Here, we identified VPS4B as a disease-causing gene for DDI by linkage analysis followed by deep sequencing of the candidate genes in a large Chinese family with DDI. A splicing mutation (IVS7+46C>G) in VPS4B gene was found, which resulted in the aberrant transcripts with a 15-amino acid insertion and loss of function. We showed that VPS4B was identified to be linked to Wnt/beta-catenin signaling and other genes involved in odontogenesis by a functional study. (By Prof. Fu Xiong, http://jmg.bmj.com/content/early/2016/05/31/jmedgenet-2015-103619 )
mTOR is a critical effector of cell signaling, playing a pivotal role in regulating physiology of the whole body, including the brain. Mutations in genes encoding GATOR1 complex, an inhibitor of mTOR activity, have been recently implicated in the pathogenesis of a wide spectrum of focal epilepsies (FEs), occasionally associated with malformations of cortical development. Loss of mTOR inhibitor activity is the hypothesized mechanism underlying epilepsy. In this review, the authors summarize the current knowledge about GATOR1 mutations in FEs, and discuss the future therapeutic opportunities for patients. (By Sara Baldassari, http://jmg.bmj.com/content/early/2016/05/19/jmedgenet-2016-103883 )
Many women diagnosed with epithelial ovarian cancer do not access genetic testing for BRCA1/2 mutations. The reasons for this are complex but may in part be due to lack of awareness or an over-complicated referral pathway. The Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study looked at a streamlined approach led by Oncology and coordinated by Genetic services. Women did not receive formal genetic counselling and were only seen by Genetics if a mutation or variant of unknown significance was identified. Results showed this model to be feasible, cost-effective and acceptable to participants. It therefore offers new approach to increase test uptake without requiring additional resources. (By Dr. Marc Tischkowitz, http://jmg.bmj.com/content/early/2016/05/12/jmedgenet-2016-103902 )
Inga Plaskocinska, Dr Marc Tischkowitz, and Hannah Shipman.
Ciliopathies are an extensive group of disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. Our study resulted in the identification of six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy. The CEP120-associated phenotype ranges from mild classical JS in four patients, to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies. Our findings broaden the spectrum of phenotypes caused by CEP120 mutations, that account for nearly 1% of JS patients as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies. (By Dr. Susanne Roosing, http://jmg.bmj.com/content/early/2016/05/06/jmedgenet-2016-103832 )
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 )
From left to right:
Maria Teresa Atterrato, Giovanni Messina, Emanuele Celauro, Patrizio Dimitri, Yuri Prozzillo.
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 )