A Novel Tool for the Analysis and Detection of Copy Number Variants Associated with Haemoglobinopathies.

Several types of haemoglobinopathies are caused by copy number variants (CNVs). While diagnosis is often based on haematological and biochemical parameters, a definitive diagnosis requires molecular DNA analysis. In some cases, the molecular characterisation of large deletions/duplications is challenging and inconclusive and often requires the use of specific diagnostic procedures, such as multiplex ligation-dependent probe amplification (MLPA).

Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies.

Haemoglobinopathies are common monogenic disorders with diverse clinical manifestations, partly attributed to the influence of modifier genes. Recent years have seen enormous growth in the amount of genetic data, instigating the need for ranking methods to identify candidate genes with strong modifying effects. Here, we present the first evidence-based gene ranking metric (IthaScore) for haemoglobinopathy-specific phenotypes by utilising curated data in the IthaGenes database.

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy.

Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding.

Deregulation of LRSAM1 expression impairs the levels of TSG101, UBE2N, VPS28, MDM2 and EGFR.

CMT is the most common hereditary neuromuscular disorder of the peripheral nervous system with a prevalence of 1/2500 individuals and it is caused by mutations in more than 80 genes. LRSAM1, a RING finger ubiquitin ligase also known as TSG101-associated ligase (TAL), has been associated with Charcot-Marie-Tooth disease type 2P (CMT2P) and to date eight causative mutations have been identified. Little is currently known on the pathogenetic mechanisms that lead to the disease.

LRSAM1 Depletion Affects Neuroblastoma SH-SY5Y Cell Growth and Morphology: The LRSAM1 c.2047-1G>A Loss-of-Function Variant Fails to Rescue The Phenotype.

Objective: Deleterious variants in LRSAM1, a RING finger ubiquitin ligase which is also known as TSG101-associated ligase (TAL), have recently been associated with Charcot-Marie-Tooth disease type 2P (CMT2P). The mechanism by which mutant LRSAM1 contributes to the development of neuropathy is currently unclear. The aim of this study was to induce LRSAM1 deficiency in a neuronal cell model, observe its effect on cell growth and morphology and attempt to rescue the phenotype with ancestral and mutant LRSAM1 transfections.

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in >30 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance.