Neural tube defects (NTDs) are very common and severe birth malformations that are caused by failure of neural tube closure. They are caused by a combination of genetic and environmental factors that remain largely unknown. Anencephaly and spina bifida are severe NTDs that affect reproductive fitness but are still prevalent across generations, suggesting a role for new or de novo mutations (DNMs) in their etiology. We have re-sequenced the exomes of 43 sporadic cases affected with either spina bifida or anencephaly and their unaffected parents and we have indeed demonstrated that loss of function DNMs play an important role in their causation. Our study also strongly implicates SHROOM3 in the pathogenesis of human NTDs. (By Philippe Lemay, http://jmg.bmj.com/content/early/2015/03/24/jmedgenet-2015-103027 )
Loss-of-function mutations of the FLNA gene cause X-linked periventricular nodular heterotopia (PNH) while gain-of-function mutations cause the Otopalatodigital (OPD) spectrum. These two conditions are known to be mutually exclusive phenotypes. We describe a family in which a woman and her three daughters exhibited a phenotype combining PNH, epilepsy and Melnick-Needles syndrome, a skeletal disorder assigned to the OPD spectrum. All affected individuals harbored a novel non-conservative missense mutation in FLNA leading to two aberrant transcripts, one of which carries the missense mutation, plus a longer transcript resulting from intron 3 retention. Co-occurring gain-of and loss-of-function appears to cause the dual phenotype. (By Elena Parrini, http://jmg.bmj.com/content/early/2015/03/09/jmedgenet-2014-102959 )
Klippel-Feil anomaly (KFA) is a rare disorder encompassing fusion of the cervical spine, as well as low posterior hair line and limited neck mobility. Here we describe a mutation in a novel gene, MYO18B, which results in KFA along with muscular weakness. This is an association that has never been reported before. High resolution microscopy reveals damage to the muscle filaments. The syndrome also results in a characteristic facial appearance which will be beneficial in identifying future cases. The mutation is predicted to cause truncation of the resulting protein, and RNA from this gene is virtually absent in the patients. (By Dr. Fowzan S Alkuraya, http://jmg.bmj.com/content/early/2015/03/06/jmedgenet-2014-102964 )
We have previously estimated that one in two million people will develop bilateral vestibular schwannomas by chance. We show for the first time molecular proof that a man who developed bilateral vestibular schwannomas aged 52 and 67 years of age had developed these by independent events in the NF2 gene with no evidence of a germline or mosaic NF2 mutation or chromosome 22q linked inherited aetiology. Furthermore we estimate that up to 50% of those presenting with bilateral vestibular schwannomas alone after 70 years of age are likely to have developed these by chance. This research will mean that people developing just vestibular schwannomas on both sides at older ages can be reassured that the risks for their children are likely even lower. (By Prof. D Gareth Evans, http://jmg.bmj.com/content/early/2015/02/27/jmedgenet-2014-102973 )
The recent discovery of a new mutation in the DNA mismatch repair gene PMS2 that is recurrent in the Inuit population surrounding Hudson Bay, Canada offers new insights suggesting that even a small, residual function of the gene in patients is sufficient to delay the age of onset of tumours. This new finding adds to existing knowledge that the disease is more severe in individuals carrying two mutated copies of PMS2 than in individuals with only one mutated copy, and could serve as a model from which to design new preventive therapies in families with defects in these genes. （By Nancy Hamel, http://jmg.bmj.com/content/early/2015/02/17/jmedgenet-2014-102934 ）
Carriers of germline pathogenic variants in BRCA1 have a significantly increased risk of breast and ovarian cancers. However, genetic testing may also uncover a variant of unknown significance (VUS). Due to the rarity of these variants clinical and family data are usually lacking to determine cancer risk association. Functional assays can be used to assess the impact of these VUS on the function of protein. We have developed a web-based visualization tool to depict all published functional data on missense VUS in BRCA1. This tool provides a comprehensive publically-available resource to aid in the assessment of BRCA1 VUS. (By Dr. Alvaro N. Monteiro, http://jmg.bmj.com/content/early/2015/02/02/jmedgenet-2014-102766 )
After completing this module you should be able to:
Be aware of the genetic heterogeneity of ID and the diagnostic yield of different approaches to investigation
Understand the challenges associated with interpreting variants identified by next generation sequencing (NGS) and the principles behind assigning causality
Understand the strengths and weaknesses of a targeted sequencing approach as compared to trio-exome analyses/ whole genome sequencing (WGS).
Redin C, Gérard B, Lauer J, Herenger Y, Muller J, Quartier A, et al. (http://learning.bmj.com/learning/module-intro/.html?moduleId=10051729&searchTerm=“Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders ”&page=1&locale=en_GB)
Leukocyte telomere length (LTL) is associated with a number of diseases. In particular, telomeres are short in patients with cardiovascular disease and long in patients with different types of cancer such as melanoma. In our study we identified a novel gene (DCAF4) associated with LTL in the general population. Our finding expands the spectrum of genes involved in the leukocyte telomere maintenance.
We also provided evidence that genes associated with LTL are enriched among genes engaged in melanoma in the general population. The model used in this research may be useful in testing the role of LTL genetics in other human cancers. (By Dr. Massimo Mangino, http://jmg.bmj.com/content/early/2015/01/23/jmedgenet-2014-102681 )
Fetal akinesia deformation sequence (FADS) is a broad spectrum of syndromes characterized by reduced or loss of fetal movement, arthrogryposis, intrauterine growth restriction and developmental abnormalities.
In this study, we identified a novel gene, MuSK (muscle-specific receptor tyrosine kinase), by whole exome sequencing in a Swedish family trio with fetuses affected by FADS. MuSK is important for the maintenance and development of the neuromuscular junction (NMJ) and the clinical phenotype of the fetuses described here is similar to many previously reported fetuses with mutations involved in the NMJ pathway. Present results can be used in prenatal screening or preimplantation genetic diagnosis when FADS associated with NMJ is suspected. (By Dr. Maria Wilbe, http://jmg.bmj.com/content/early/2015/01/23/jmedgenet-2014-102730 )Doc3
The trichothiodystrophies (TTD) are characterised by brittle, sulphur deficient hair that has an unusual tiger-tail banding pattern under polarising light microscopy. People affected by TTD can experience a range of symptoms including dry skin, short stature, intellectual disability and susceptibility to infection. About half of the patients have an inability to properly repair DNA damage following exposure to ultra-violet (UV) light and this feature categorizes photosensitive and non-photosensitive forms of the disease. Initially described as a DNA repair syndrome, photosensitive TTD is now regarded as a transcription and repair syndrome. In contrast, very little is known about non-photosensitive TTD. We identified a mutation that affects the X-linked, RNF113A gene in two male cousins with TTD that do not have any problems with UV induced DNA repair. A new gene implicated in non-photosensitive TTD! The function of RNF113A is as yet unknown though similar proteins found in fish, flies and flat worms direct the formation of the brain and central nervous system suggesting a conserved role for this protein. (By Dr. Mark Corbett, http://jmg.bmj.com/content/early/2015/01/22/jmedgenet-2014-102418 )