Coenzyme Q10 is an essential cofactor for mitochondrial function and other biochemical pathways. Mutations in genes involved in CoQ10 biosynthesis cause primary CoQ10 deficiency syndromes that can be treated with oral ubiquinone. We used exome sequencing to evaluate 6 patients with clinical findings suggestive of a mitochondrial disorder. All patients were female and presented on the first day of life and died in the neonatal period or early infancy. Other clinical findings included hypotonia, encephalopathy, neonatal seizures, cerebellar atrophy, cardiomyopathy, and lactic acidosis. We identified recessive mutations in COQ4 gene in all patients studied; one was a founder mutation in the Ashkenazi Jewish population (By Marwan Shinawi, M.D., http://jmg.bmj.com/content/early/2015/07/16/jmedgenet-2015-103140 ).
Keratosis pilaris atrophicans (KPA) is a group of related skin disorders characterized by inflammatory keratotic skin-papules and hair loss on the scalp, eyebrows and eye-lashes. Facial scarring is a complication.
A consanguineous family with four members affected by KPA was subject to extensive genetic investigation. The analysis revealed that affected individuals had inherited a unique DNA variant in a gene encoding the protein LRP1. Further studies showed that patients had reduced levels of LRP1 and one of its binding partners. Among multiple functions, LRP1 mediates inflammatory responses. Thus, the authors’ findings suggest perturbed immunoregulation as one pathophysiological mechanism behind KPA. (By Dr. Niklas Dahl, http://jmg.bmj.com/content/early/2015/07/03/jmedgenet-2014-102931 )
Dahl Group: From back left- Joakim Klar, Jens Schuster, Niklas Dahl, Muhammad Jameel. Front- Maria Sobol.
Chronic elevation of serum creatine kinase (CK) is a common manifestation of neuromuscular disorders and may precede disease clinical expression, or remain asymptomatic. In 3 Italian families having high CK, mild myopathy, and calsequestrin-positive inclusions in muscle fibers, exome and Sanger sequencing and linkage analysis revealed a founder mutation in the CASQ1 gene. Immunocytochemistry, electron microscopy, biochemistry, and transfected cell line investigations showed a tendency of the mutated calsequestrin to form aggregates. CASQ1 mutations may go undiagnosed if a muscle biopsy is not taken, and the condition could be more frequent than supposed in patients with familial hyperCKemia. (By Dr. Marina Mora, http://jmg.bmj.com/content/early/2015/07/01/jmedgenet-2014-102882 )
(Muscle histopathology. in CASQ1 mutated patients (A) Gomori trichrome and (B) H&E staining show several sarcoplasmic vacuoles, that, by electron microscopy (C,D) appear as large, often membrane-limited inclusions of variable size, shape and electron density, forming aggregations often lobular; (E) immunohistochemistry shows positivity of vacuoles to calsequestrin and SERCA1.)
Neonatal diabetes (diagnosed under 6 months of age) is usually caused by a disruption (mutation) in one of over twenty diabetes-related genes. One of the most common causes of neonatal diabetes is mutations in the insulin gene that result in production of a misshaped insulin protein that leads to death of the insulin producing beta cells. We describe a new type of mutation, deep in the non-coding part of the insulin gene, that causes diabetes through a previously undescribed mechanism. This discovery extends our understanding of diabetes and may have broader implications for those with insulin deficiency later in life. (By Dr. David Carmody, http://jmg.bmj.com/content/early/2015/06/21/jmedgenet-2015-103220 )
Coenzyme Q (CoQ10) is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. A range of metabolic diseases, as well as the ageing process and prolonged statin treatments have been associated with CoQ10 deficiency. Here the first case of a primary CoQ10 defect due to a mutation in COQ7, necessary for CoQ10 biosynthesis, is presented. For accurate diagnosis a novel and highly sensitive method for CoQ10 quantification by UPLC – mass spectrometry was developed. By applying the COQ10 analogue, 2,4-dihydroxybenzoic acid, a potentially effective treatment strategy for CoQ10 deficiencies is introduced. (By Dr. Christoph Freyer, http://jmg.bmj.com/content/early/2015/06/16/jmedgenet-2015-102986 )
Bardet Biedl syndrome (BBS) is a recessive rare disorder included in the ciliopathies disease family. The patient´s phenotype is very important in order to go deeper into the physiopathology of the disease. The clinical description of the patients could give us some clues about the pathways that are involved in the disease. Besides, the more clinical information we have, the more accurate the diagnosis will be, also highlighting non-common BBS features. This approach will be interesting for considering groups of patients candidate for different therapeutical options. (By Dr. Diana Valverde Pérez, http://jmg.bmj.com/content/early/2015/06/16/jmedgenet-2015-103099 )
The novel and ancestral NNT mutation, p.G200S, which was identified in two unrelated consanguineous families, expands the glucocorticoid deficiency phenotype of NNT mutations to include also mineralocorticoid deficiency; and thus present in early life with severe salt loss, low blood pressure and hypoglycemia. We provide the first patient-based evidence that NNT mutations induce oxidative stress which result in morphological and functional mitochondrial defects – the energy producing factory in each cell. Thus, NNT is crucial for mitochondrial function in the human adrenal gland and NNT mutations should be considered in diagnosis of early life adrenal crisis. (By Dr. Ariella Weinberg-Shukron, http://jmg.bmj.com/content/early/2015/06/12/jmedgenet-2015-103078 )
Craniosynostosis (CRS) is premature closure of cranial sutures, which is caused by either a gene mutation or environmental factors or both. Herein we found a gene mutation causing midline non-syndromic craniosynostosis in a 15-month-old boy. Conventional chromosome study revealed a complex paracentric inversion involving 2q14.3 and 2q34, and multicolor banding refined breakpoints to 2q14 and 2q34. An intronic break of the PTH2R gene was detected by whole genome sequencing and fluorescence in situ hybridization analysis finally confirmed disruption of PTH2R. This addition of PTH2R to the list of genes associated with CRS expands our understanding of the development of CRS. (By Dr. Juwon Kim, http://jmg.bmj.com/content/early/2015/06/04/jmedgenet-2015-103001 )
A brief conference report documents a gathering, sponsored by the University of Toronto’s McLaughlin Centre, of representatives of the Canadian medical genetics community. They were invited to consider issues concerning new genomic technologies in prenatal clinical practice, as a precursor to practice guidelines and recommendations for policy makers. Invited guests provided international experience and insight. As microarrays and whole-exome or -genome sequencing transition from the postnatal context and are applied for prenatal screening or diagnosis, the related issues become more acute. Participants agreed that national coordination and sharing of resources and experience should be advocated. (By Janet Buchanan, http://jmg.bmj.com/content/early/2015/06/03/jmedgenet-2015-103223 )
Research ethics and data access review are two important milestones that rest on the path from clinical innovation to clinical care. Research ethics review ensures the protection of all research participants, while the data access review facilitates collaboration and data sharing among researchers worldwide. Both reviews, however, can pose significant practical challenges when studies involve multiple research sites and across multiple jurisdictions. The adoption of more efficient models for research ethics and data access reviews for these studies is therefore critical to clinical progress, and is supported by illustrating two Canadian examples in this paper. (By Ma’n H. Zawati, http://jmg.bmj.com/content/early/2015/06/03/jmedgenet-2014-102640 )