Exome sequencing is a method of investigating all of a person¹s genes at the same time to look for the mutation that is causing their illness. It is often used when targeted genetic testing has run into a dead end. However, half to three quarters of patients who have their exome sequenced will still not receive a Œgenetic diagnosis¹. This research by Drs. Anna Need, Vandana Shashi and colleagues explores the reasons that some families do not get a diagnosis through exome sequencing the first time, and presents three patients who received a diagnosis when their exome data was re-analysed. (By Dr. Anna Need, http://jmg.bmj.com/content/early/2016/11/29/jmedgenet-2016-104306 )
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/2016/11/24/jmedgenet-2016-104215 )
Tyrosinemia is a genetic disease that causes liver failure, cirrhosis and liver cancer. Succinylacetone is a substance that is elevated in tyrosinemia. Using succinylacetone for newborn screening permits early treatment of tyrosinemia, which can prevent liver disease. Six babies were detected by screening but had normal liver function. Even without special treatment, each child has maintained normal liver function. Each has a genetic deficiency of an enzyme called maleylacetoacetate isomerase, that is related to but different from the enzyme that causes tyrosinemia. Recognizing this newly-discovered condition is important for proper genetic counselling and treatment of babies detected by tyrosinemia screening. (By Dr. Grant Mitchell, http://jmg.bmj.com/content/early/2016/11/22/jmedgenet-2016-104289 )
Contrarily to initial expectations about the psychological impact of Direct to Consumer genetic testing, people are substantially resilient to long-term consequences of results to genetic testing. Previous literature raised concerns on DTC focusing on anxiety levels it might cause. We claim that there are three substantial limits to be considered: non-clinical anxiety is not a negative outcome; anxiety is limitedly predictive of health related behaviors and decisions; a number of previous studies are affected by methodological errors. We promote the exploration of complex cognitive and emotional mechanisms to capture the subtle and multifaceted nature of a living-at-risk situation. (By Dr. Serena Oliveri, http://jmg.bmj.com/content/early/2016/09/19/jmedgenet-2016-104184 )
Fabry disease is a rare, inherited disorder due to deficiency of lysosomal α-galactosidase A leading to multisystem disease and early death.
In the 18-month randomized segment of the global ATTRACT study, orally administered migalastat, a first-in-class pharmacological chaperone, was compared with intravenous enzyme replacement therapy. Migalastat and ERT had comparable effects on renal function. Migalastat was associated with a statistically significant decrease in cardiac mass whereas ERT was associated with a smaller non-significant change. Migalastat has potential as an effective and safe oral treatment for 35-50% of patients with Fabry disease who have amenable mutations. (By Dr. Christopher Viereck, http://jmg.bmj.com/content/early/2016/11/10/jmedgenet-2016-104178 )
Familial hypercholesterolemia (FH) is a common genetic disorder frequently caused by low-density lipoprotein receptor (LDLR) gene variants. Patients with FH have high levels of LDL-cholesterol leading to cardiovascular disease including premature heart attacks. We report an update of the UCL LDLR variant database which is used widely by clinicians and researchers as a catalogue of published variant information and pathogenicity predictions. Over 1700 unique LDLR variants have been reported globally, of which we suggest that 76% are likely to be, or are probably pathogenic, 17% are unlikely to be, or are probably not pathogenic and the remaining 7% are variants of unknown significance, where additional family and in vitro studies will be required to confirm or refute their pathogenicity. (By Dr. Sarah Leigh, http://jmg.bmj.com/content/early/2016/11/07/jmedgenet-2016-104054 )
Damage to movement-related brain networks distinctively impairs processing of action verbs (words denoting bodily motion). Can genetically-based deterioration of relevant regions involve similar deficits? To address this question, we assessed lexical processing in a unique patient with cerebellar ataxia due to mutations in the STUB1 gene. By combining structural and functional MRI with genetic and behavioral analysis, we found that such genetic abnormalities are related to selective action-verb impairments, further showing the distinct role of the cerebellum and its connections to semantic- and motor-related cortical regions in processing those words. Our study opens new windows into the role of cerebellar structures and their genetic underpinnings in high-order domains. (By Dr. Agustín Ibáñez, http://jmg.bmj.com/content/early/2016/11/03/jmedgenet-2016-104148 )
Behavioral and imaging results of the patient relative to controls. (A) Behavioral performance. Lexical decision results indicate a selective deficit for action verbs. AcV: action verbs (p = .03); AbV: abstract verbs (p = .18); MaN manipulable nouns (p = .23); AbN: abstract nouns (p = .26). (B) Atrophy pattern. Voxel-based morphometry results revealed a global atrophy pattern markedly involving the left and right cerebella, in addition to insular, frontal, and temporal regions. (C) Functional connectivity alterations. Functional connectivity results revealed altered connectivity between peak atrophy site in the cerebellum (x = -17, y = -60, z = -20) and both temporo-parietal and frontal regions. (D) Gene-atrophy overlap. Overlap between atrophied areas and sites of expression of the STUB1 gene. Overlap was marked in multiple cerebellar locations, and also in the fusiform and superior temporal gyri.
Several authors have previously described a syndrome consisting of Alport Syndrome, intellectual disability, midface hypoplasia and elliptocytosis due to a large deletion involving the X chromosome. Previously published cases all had deletions of the X chromosome involving between 6 and 11 genes. We describe two maternal half-brothers who have very similar extra-renal features including midface hypoplasia, intellectual disability and elliptocytosis due to a single base-pair substitution in AMMECR1, a gene within the region of the X chromosome deleted in the previously described cases. Functional studies confirmed that the mutant protein is abnormally distributed within the nucleus of cultured cells. (By Dr. Rodney Gilbert, http://jmg.bmj.com/content/early/2016/11/03/jmedgenet-2016-104100 )
A girl suffering from neurological symptoms and vision impairment showed an accumulation of very-long-chain fatty acids (VLCFAs). VLCFA are normally degraded in peroxisomes. In this paper we show that the VLCFA accumulation in the patient is due to a defect of the peroxisomal protein ACBD5. The patient had a homozygous mutation, resulting in the complete absence of ACBD5 protein. Functional ACBD5 could rescue the defect in cells of the patient. Our study revealed ACBD5 deficiency as a novel peroxisomal disorder resulting in VLCFA accumulation. (By Dr. Sacha Ferdinandusse, http://jmg.bmj.com/content/early/2016/10/31/jmedgenet-2016-104132 )
ACBD5 expression and localization in fibroblasts from the ACBD5-deficient patient and control subjects
Early myoclonic encephalopathy (EME) is a refractory epilepsy syndrome afflicting newborns that causes severe mental and developmental retardation. EME is often considered a complication of congenital metabolic diseases. In this study, abnormal GABAA receptors were shown to cause EME. The GABAA receptor is an ion channel, which plays a cardinal role in the inhibitory neuronal network controlling hyper-excitation of the brain, i.e., seizures. We identified a mutation that hampers GABAA receptor function. This is the first report to show that an ion channel is associated with EME, and should provide clues for the treatment of this devastating disease. (By Dr. Shinichi Hirose, http://jmg.bmj.com/content/early/2016/10/27/jmedgenet-2016-104083 )