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 […]
Category: Uncategorized
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 […]
Prevalence of BRCA1/BRCA2 pathogenic variation in Chinese Han population
Mutation in BRCA1 and BRCA2 genes increases the risk of breast and ovarian cancer. Identifying the mutation is a key to prevent and treat the mutation-caused cancer. China has the largest population of 1.4 billion in the world. By testing BRCA1/2 genes in 11,386 non-cancer Chinese Han individuals, we determined there is one BRCA mutation […]
Paternal 132 bp deletion affecting KCNQ1OT1 in 11p15.5 is associated with growth retardation but does not affect imprinting
A girl suffering from growth retardation inherited a small genetic deletion on chromosome 11p15.5 from her healthy father. By molecular genetic tests the region was characterised, and it turned out that the deletion affected the imprinted KCNQ1OT1 gene, i.e. a gene which is expressed only from the paternal allele. Since the father inherited the same […]
Hypomethylation of a centromeric block of ICR1 is sufficient to cause Silver-Russell syndrome
A major cause of an imprinting disorder, Silver-Russell syndrome (SRS), is the loss of DNA methylation (LOM) of imprinting control region 1 (ICR1) within the IGF2/H19 domain. ICR1-LOM on the paternal allele reduces IGF2 repression and makes H19 express biallelically. Majority of the patients showed consistent hypomethylation of ICR1; however, one exhibited LOM at the centromeric block of ICR1 but […]
Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability
The overlapping and non-specific symptoms observed in patients with intellectual disability syndromes can make diagnosis difficult. Here, we report a new genetic intellectual disability syndrome in 8 patients characterized by moderate to severe intellectual disability, delayed verbal and motor milestones, and hypotonia. All patients have pathogenic variants in TTC5, a scaffold protein linked to many […]