Spinal and bulbar muscular atrophy (Kennedy’s disease) is an X-linked motor neuron disorder caused by a CAG repeat expansion in the androgen receptor gene. Traditionally, alleles with 38 or more CAG repeats are considered fully penetrant in male carriers. By comparing, through systematic review and meta-analysis, the distribution of CAG repeat sizes between 2,576 patient […]
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Clinical spectrum and genetic variations of LMNA-related muscular dystrophies in a large cohort of Chinese patients
LMNA-related muscular dystrophies are a group of rare muscle diseases caused by detrimental changes (i.e. mutations) in the LMNA gene. They exhibit a wide spectrum of clinical symptoms. We reported our clinical and genetic findings from 84 patients recruited from many neuromuscular centers in China over 12 years. We found many new mutations of the […]
UKCGG Consensus Group guidelines for the management of patients with constitutional TP53 pathogenic variants
The TP53 gene is known as the “guardian of the cell” due to its crucial role in preventing cancer cells developing. Individuals with a pathogenic variant (spelling change ) in the TP53 gene are at a very high lifetime risk of developing cancer throughout childhood and adulthood, most commonly cancers of the bone and soft […]
Haploinsufficiency of the NF1 gene is associated with protection against diabetes
Neurofibromatosis type 1 (NF1) is a hereditary syndrome caused by mutations in a single gene, NF1. Kallionpää et al. used data from population-based cohort of Finnish patients with NF1 and nationwide health care registers, to study the association of NF1 and diabetes. They observed a reduced risk of diabetes, especially type 2 diabetes, among individuals […]
Rare and de novo duplications containing SHOX in clubfoot
By measuring copy number variants in 816 clubfoot probands, we identified duplications of chromosome Xp22.33 involving the SHOX gene and surrounding regions in 1.1% of cases compared to 0.07% of controls. These duplications are likely causative in some cases, as four out of six SHOX duplications were not present in the unaffected parents but were confirmed in the proband, resulting […]
Genetic and functional insights into CDA-I prevalence and pathogenesis
Congenital Dyserythropoietic Anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 (encoding Codanin-1) or C15orf41. In this study, we analyse a cohort of CDA-I patients and identify novel pathogenic variants. We predict CDA-I is five times more common than currently thought. Functional assays show Codanin-1 and C15orf41 interact and […]
NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum
Complex I deficiency is a mitochondrial disorder caused by mutations in 1 of 34 genes that encode proteins required to form the first large enzyme complex (complex I) of the energy-producing electron transport chain. In 2010, the first case of autosomal recessive NUBPL disease was reported. We report the clinical features and mutations in four […]
TMEM16A deficiency – a potentially fatal neonatal disease resulting from impaired chloride currents
In a consanguineous family, we identified a truncating pathogenic variant in TMEM16A. As a result, the patients develop a severe neonatal disorder mimicking necrotizing enterocolitis. Electrophysiological studies demonstrate absence of TMEM16A-mediated chloride currents and severe impairment of CFTR, the ion channel mutated in Cystic Fibrosis. Despite this, the patients had no respiratory symptoms but instead […]
A homozygous hypomorphic BRCA2 variant in primary ovarian insufficiency without cancer or Fanconi anemia trait
BRCA2, is a gene with a critical role in DNA repair and homologous recombination in somatic cells. Patients with biallelic alterations develop Fanconi Anemia (FA), a severe life-threatening condition with pancytopenia and multiple malformations, while women with monoallelic alteration are at high risk to develop breast or ovarian cancer (up to 60%). Here, we surprisingly uncovered […]
Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants
This study investigated the occurrence of pancreatic cancer in 172 familial melanoma families with a pathogenic CDKN2A variant. The CDKN2A gene encodes two distinct proteins (p16INK4a and p14ARF) and pathogenic variants can affect one or both. Individuals harbouring variants affecting p16INK4a are considered to be at increased risk for pancreatic cancer, but this study observed […]