Mutations in CDH1 cause the Hereditary Diffuse Gastric Cancer Syndrome. We report the largest series to date of index cases with a germline CDH1 mutation, and propose a revision of the testing criteria as a substantial proportion of our cases did not fulfil them. More specifically, we show that patients with a personal or family […]
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Refining the role of pms2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants (Contributed by Dr Gabriel Capellá and Dr Marta Pineda)
Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair genes. Borràs and collaborators assessed the pathogenicity of variants of unknown significance detected in the mutational analysis of PMS2 gene using a comprehensive strategy. Pathogenic PMS2 mutations were detected in 9 of 13 (69%) candidate patients: seven […]
Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly (Contributed by Fadi F. Hamdan, PhD)
Mutations in TSC1 or TSC2 cause Tuberous Sclerosis Complex (TSC) a multisystemic disorder with many features including intellectual disability (ID). TSC1, TSC2 and TBC1D7 form a complex that inhibits mTORC1 signaling and limits cell growth. Using homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly, we identified, in the affected individuals, […]
Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome (Contributed by Marco Tartaglia, PhD)
Kaufman oculocerebrofacial syndrome (KOS) is a rare disorder affecting development and growth originally recognized 40 years ago. KOS is characterised by microcephaly, mental retardation, ocular anomalies, distinctive facial features, generalised hypotonia, and reduced growth. In this paper, exome sequencing was employed to identify UBE3B, encoding an E3 ubiquitin-protein ligase, as the gene mutated in KOS. […]
An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor to Graves’ disease (Contributed by Professor Wei Huang)
Graves’ disease is an autoimmune illness mostly seen in female. The contribution of the X chromosomes to its risk has long been appreciated. We re-examined the X chromosome data from our recent study using a technology named genome-wide association study (GWAS). A single nucleotide polymorphism (SNP) which changes an amino acid within the G protein-coupled […]
Upregulation of RCAN1 causes Down syndrome-like immune dysfunction (Contributed by Dr. Melanie Pritchard)
People with Down syndrome (DS) (trisomy 21) have impaired immune function making them susceptible to infections and autoimmune disease. The molecular cause for this impairment is undetermined. Using mice we have found that an excess of RCAN1, a protein expressed at higher than normal levels in DS, adversely affects key immune functions, and that an […]
Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus (Contributed by Dr. Fowzan S Alkuraya)
Intellectual disability (ID) is one of the most common disabilities worldwide, affecting nearly 2% of the global population. Here we examined patients from eight families suffering from a form of ID that is coupled with squint of the eye, and in each case found the same DNA mutation, in a gene called ADAT3. This gene […]
A novel syndrome of hypohidrosis and intellectual disability is linked to COG6 deficiency (Contributed by Dr Fowzan S Alkuraya)
Intellectual disability (ID) is a common disability in humans and comprises both isolated forms as well as forms that are associated with a constellation of other clinical problems i.e. syndromic ID. In this study, we describe an apparently novel syndromic ID in which patients have decreased sweating and brittle teeth. Using positional cloning techniques in […]
A new gene for childhood-onset pulmonary arterial hypertension (Contributed by Dr. Wilhelmina S Kerstjens-Frederikse)
Pulmonary arterial hypertension (PAH) in children is a progressive and often fatal disease of the lung vessels, for which no curative therapy exists. PAH may be heritable: mutations in the BMPR2-gene have been found in about 15% of children with the disease. In a national cohort of Dutch children with unexplained PAH, we identified mutations […]
Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations (Contributed by Dr. Josine de Winter)
Nemaline myopathy (NM) is the most common non-dystrophic congenital myopathy and is most frequently caused by mutations in the nebulin gene. The sarcomeric protein nebulin plays a crucial role in skeletal muscle performance. NM patients with nebulin mutations have muscle weakness through mechanisms including a lower responsiveness to calcium. No therapy exists to treat muscle […]