Genes underscore five psychiatric disorders

A group of international doctors has uncovered the genes that contribute to the development of ADHD, autism spectrum disorder, bipolar disorder, major depression and schizophrenia. Read ScienceDaily article here

Psychiatry: Multigene test predicts depression risk

An international team has found a genetic score that reliably predicts the risk, severity and age of onset of depression in young people. The study also confirms a history of childhood abuse as a risk factor. Click here to read further.

Forty-four genomic variants linked to major depression

A new meta-analysis of more than 135,000 people with major depression and more than 344,000 controls has identified 44 genomic variants, or loci, that have a statistically significant association with depression.  Click here for further details.

Drug company says it will negotiate terms to allow children to access new treatment for rare genetic disorder

Drug company says it will negotiate terms to allow children to access new treatment for rare genetic disorder.


This preliminary decision, which is now the subject of public consultation until 5 March, comes as the company confirmed it is to negotiate with NHS England terms that could allow the drug to be made available while uncertainties in the evidence of its long term benefits are addressed.

Children with CLN2, which is also known as Batten Disease, live to between 8 years and early adolescence; the average life expectancy is 10 years. It is estimated that in the UK there are around 30 to 50 children living with the condition.

CLN2 is a progressive condition caused by the deficiency of the enzyme tripeptidyl peptidase 1. This results in the abnormal storage of proteins and lipids in neurons and other cells, preventing them from functioning normally.

Symptoms in children with CLN2 begin from around the age of 2 and can then progress rapidly with the onset of seizures, decline in speech, loss of mobility, involuntary muscle spasms, progressive dementia and visual impairment leading to blindness.

There is currently no cure or life-extending treatments for CLN2 and clinical management is limited to symptom relief and supportive and palliative care.

Costing over £500,000 for each year’s treatment, cerliponase alfa is an enzyme replacement therapy administered directly into the brain via a surgically implanted permanent access device.


See the full details from NICE at https://www.nice.org.uk/news/article/drug-company-says-it-will-negotiate-terms-to-allow-children-to-access-new-treatment-for-rare-genetic-disorder

NHS England announces new specialised treatments for patients

NHS England has announced the results of the first of two prioritisation rounds to decide which new specialised commissioning treatments and services will be made available for patients for the 2018/19 financial year.

An initial three new treatments and services were approved for funding including a treatment for HIV, a new specialised service for adults with primary ciliary dyskinesia, a genetic disorder affecting the respiratory system, and a new specialised service for Stevens-Johnson syndrome, a serious disorder of the skin.

Funding for the new treatments and services will begin from April.

Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency

Am. J. Respir. Cell Mol. Biol.  2017 doi:10.1165/rcmb.2017-0179OC

SERPINA1 gene is highly polymorphic, with more than one hundred variants described in databases. The SERPINA1 encodes alpha-1 antitrypsin (AAT) protein, and the severe deficiency of AAT is a major contributor to pulmonary emphysema and liver diseases. We report seven new variants in Spanish patients with AAT deficiency. All variants involved amino acid substitutions in different exons: PiSDonosti (S+Ser14Phe), PiTijarafe (Ile50Asn), PiSevilla (Ala58Asp), PiCadiz (Glu151Lys), PiTarragona (Phe227Cys), PiPuerto Real (Thr249Ala) and PiValencia (Lys328Glu). The effect of these variants was analyzed to investigate their contribution to the disease. Mutant proteins were overexpressed in HEK293T cells and AAT expression, polymerization, degradation and secretion as well as anti-elastase activity were analyzed by PAS staining, western blot, pulse-chase and elastase inhibition assays. When overexpressed, S+S14F, I50N, A58D, F227C and T249A mutants formed intracellular polymers and did not secrete AAT protein. Two variants (E151K and K328E) did not form polymers and secreted AAT protein. However, K328E showed intracellular retention and reduced anti-elastase activity. In conclusion, we demonstrate that deficient variants may be more frequent than previously thought, and their discovery can only be possible by the complete sequencing of the gene and subsequent functional characterization. Better knowledge of SERPINA1 variants would improve diagnosis and care of AAT deficiency carriers.

UHCW Research:  Lara Beatriz

Lenadogene Nolparvovec (GS-010) for Vision Loss from Leber’s Hereditary Optic Neuropathy Due to Mutation of the ND4 Gene

There are currently very few treatment options for LHON. Most treatment methods are used to support the patient rather than cure them. Lenadogene nolparvovec is a new gene-targeted treatment intended for vision loss caused by LHON due to an alteration in a specific gene. As a genetic medicine, lenadogene nolparvovec could be a promising option to treat LHON and if licensed, could provide a new treatment option for those with LHON.

From the NIHR Innovation Observatory

Triheptanoin (UX-007) for glucose transporter type 1 deficiency syndrome (de vivo disease) – first line

Glucose transporter type 1 deficiency syndrome (Glut1 DS) is a rare genetic disorder that affects how the body moves glucose (used for energy) into the brain. The most common symptom of this condition is seizures (epilepsy), which usually begin within the first few months of life. However, the symptoms and severity of Glut1 deficiency syndrome can vary substantially from one person to another.

Triheptanoin is a novel drug being developed to reduce seizures and other symptoms in patients with Glut1 DS. The drug acts by producing a substitute compound that can produce glucose in the brain. The safety and efficacy of triheptanion is currently being evaluated. If marketed this will become the first licensed treatment in reduction of seizures in patients with Glut1 DS.

From the NIHR Innovation Observatory

New genetic variants associated with breast cancer identified

"Do you have one of the 180 breast cancer genes? One in five women has a variant that raises her risk of the condition by a third" is the rather inaccurate headline in the Mail Online.

The story covers 2 new studies looking for genetic variations known as single nucleotide polymorphisms (SNPs).

These are small variations in our DNA, some of which are associated with an increased risk of developing a disease – in this case, breast cancer.

While the Mail Online's headline suggests the "breast cancer genes" have been pinpointed, this is not the case.

In most cases, the genetic variations identified by the researchers simply signpost regions in the DNA (loci) where the genes that affect breast cancer risk are likely to be located.

This is not the same as identifying specific genes or discovering why they increase the risk of breast cancer.

The individual variations identified are only associated with small increases in risk, and many women will carry them.

This is very different from the mutations in the BRCA1 or BRCA2 genes, which cause breast cancer – these are rare and have a bigger impact on risk.

These findings are useful steps towards understanding more about which genes influence breast cancer risk.

Larotrectinib (LOXO-101) for advanced solid cancers [with an NTRK1, NTRK2, or NTRK3 gene fusion]

Due to new technologies, rearrangement of genes in cells can be discovered which result in two normally separate genes being brought together (a fusion), which can cause abnormalities in control of cell growth leading to development of solid tumor cancers. Fusions of a family of normal genes called NTRK have been found to cause normal cells to become cancerous and can happen in cells of both adults and children. Many different solid tumor cancers have NTRK fusions. Blocking the activity of these fusions with an oral drug called larotrectinib can be a new method of cancer treatment.

From the NIHR Innovation Observatory

Asfotase alfa for treating paediatric-onset hypophosphatasia - guidance (HST6)

New Highle Specialised Technologies Guidance from NICE on asfotase alfa (Strensiq) for treating paediatric-onset hypophosphatasia in adults and children.

Asfotase alfa is recommended as an option for treating paediatric-onset hypophosphatasia only:

• for people who meet the criteria for treatment within the managed access arrangement (see section 4.18), and
• for the duration of this arrangement and in line with the other conditions it specifies, and
• when the company provides asfotase alfa with the confidential commercial terms agreed with NHS England.

Gene editing used to repair diseased genes in embryos

"Deadly gene mutations removed from human embryos in landmark study," reports The Guardian. Researchers have used a gene-editing technique to repair faults in DNA that can cause the often-fatal heart condition, hypertrophic cardiomyopathy.

This inherited heart condition is caused by a genetic change (mutation) in one or more genes. Babies born with hypertrophic cardiomyopathy have diseased and stiff heart muscles, which can lead to sudden unexpected death in childhood and in young athletes; often because they don't realise they have the condition and so put their heart under strain when exercising.

In this latest study researchers used a technique called CRISPR-cas9 to target and then remove faulty genes. CRISPR-cas9 acts like a pair of molecular scissors, allowing scientists to cut out certain sections of DNA. The technique has attracted a great deal of excitement in the scientific community since it was released in 2014. But as yet, there have been no practical applications for human health.

Eliglustat for treating type 1 Gaucher disease

Highly specialised technologies guidance from NICE.

Eliglustat is recommended within its marketing authorisation for treating type 1 Gaucher disease, that is, for long-term treatment in adults who are cytochrome P450 2D6 poor, intermediate or extensive metabolisers. Eliglustat is only recommended when the company provides it with the discount agreed in the patient access scheme

A comparative analysis of whole genome sequencing of oesophageal adenocarcinoma pre- and post-chemotherapy

Genome Res. 2017 May 2. doi: 10.1101/gr.214296.116. [Epub ahead of print]

The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.

UHCW Research: Sothi, S.

Mitochondrial disorders in children: Co-enzyme Q10

This evidence summary from NICE discusses 3 case reports in a total of 6 children with mitochondrial disorders. Because this evidence is very limited, this evidence summary also discusses the best available evidence on the use of co-enzyme Q10 in adults and young people with mitochondrial disorders.

Impact of gut hormone FGF-19 on type-2 diabetes and mitochondrial recovery in a prospective study of obese diabetic women undergoing bariatric surgery

BMC Medicine201715:34 DOI: 10.1186/s12916-017-0797-5

The ileal-derived hormone, fibroblast growth factor 19 (FGF-19), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-19 levels and the resulting impact on mitochondrial health in white adipose tissue (AT).

UHCW Research: Ioannis Kyrou, Sudhesh Kumar and Philip G. McTernan

Code of practice for histocompatibility and immunogenetics (H&I) services

Code of practice for histocompatibility and immunogenetics (H&I) services has been updated by the Royal College of Pathologists.

An inducer of glyoxalase 1 down regulates inflammatory gene expression in overweight and obese non-diabetic subjects

Diabetologia (2016) 59 (Suppl 1):S1–S581  Abstracts of 52nd EASD Annual Meeting No. 631

Glo1 deficiency was identified as a driver of cardiovascular disease in a large integrative genomics study. Induction of glyoxalase 1 (Glo1) expression is a novel strategy to prevent inflammatory signalling and decrease risk of cardiovascular disease in overweight and obese populations. Increasing Glo1 expression is unaddressed by current therapy. Glo1 is part of the glyoxalase metabolic pathway which catalyses the metabolism of the reactive metabolite and glycating agent, methylglyoxal (MG), and thereby prevents formation of advanced glycation endproducts (AGEs). We previously described a regulatory antioxidant response element in the GLO1 gene which, when bound by transcription factor Nrf2, increases basal and inducible expression of Glo1. We screened dietary bioactive compounds for Glo1 inducer activity, confirmed hits and improvement of cell function in human cell primary cultures. The aim of this study was to validate target pharmacology of an optimised Glo1 inducer formulation in Phase 1 clinical trial in overweight and obese subjects and assess inflammatory gene expression in peripheral blood mononuclear cells (PBMCs)

UHCW Research: M. O. Weickert and S Qureshi

Authentication and characterisation of a new oesophageal adenocarcinoma cell line: MFD-1

Scientific Reports 6, Article number: 32417 (2016). doi:10.1038/srep32417

New biological tools are required to understand the functional significance of genetic events revealed by whole genome sequencing (WGS) studies in oesophageal adenocarcinoma (OAC). The MFD-1 cell line was isolated from a 55-year-old male with OAC without recombinant-DNA transformation. Somatic genetic variations from MFD-1, tumour, normal oesophagus, and leucocytes were analysed with SNP6. WGS was performed in tumour and leucocytes. RNAseq was performed in MFD-1, and two classic OAC cell lines FLO1 and OE33. Transposase-accessible chromatin sequencing (ATAC-seq) was performed in MFD-1, OE33, and non-neoplastic HET1A cells. Functional studies were performed. MFD-1 had a high SNP genotype concordance with matched germline/tumour. Parental tumour and MFD-1 carried four somatically acquired mutations in three recurrent mutated genes in OAC: TP53, ABCB1 and SEMA5A, not present in FLO-1 or OE33. MFD-1 displayed high expression of epithelial and glandular markers and a unique fingerprint of open chromatin. MFD-1 was tumorigenic in SCID mouse and proliferative and invasive in 3D cultures. The clinical utility of whole genome sequencing projects will be delivered using accurate model systems to develop molecular-phenotype therapeutics. We have described the first such system to arise from the oesophageal International Cancer Genome Consortium project.

UHCW Research: OCCAMS consortium (Shamila Sothi & Sari Suortamo)