In March 2014 the International Gastric Cancer Linkage Consortium, a group of worldwide experts in the field of Hereditary Diffuse Gastric Cancer, held a consensus meeting in the Radboudumc in Nijmegen, The Netherlands. During this three-day meeting, the current evidence and world-wide experience for managing individuals with a family history of diffuse type gastric cancer […]
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A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life
Hypertrophic Cardiomyopathy (HCM) is one of the most common inherited cardiac disorders with a prevalence of 1:500. It is characterized by unexplained left ventricular hypertrophy (from 13 mm to more than 35 mm) that develops in the absence of an underlying systemic condition or other cardiac disease. The most serious manifestations of HCM are sudden […]
Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients
Neurofibromatosis 2 is an inherited condition that predisposes to tumours of the nerve sheath (schwanomas) and brain lining (meningiomas). Most patients develop deafness and other handicaps that reduce life expectancy. In 1192 NF2 patients followed for an average of over 9 years, we confirmed that life expectancy was reduced when NF2 was diagnosed at a […]
IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype
Ciliopathies are diseases accounted for by alterations of cilia-dependent cellular functions. The clinical expression of ciliopathies is mostly limited to retina, kidney, brain, and bone. These organs can be affected individually or in multiple combinations, defining a wide spectrum of devastating overlapping syndromes. Studying 1,628 candidate individuals we identified homozygous IFT81 mutations in two individuals […]
Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients
Up to 70% of patients with pheochromocytoma or paraganglioma (PPGL) harbor a somatic or germline mutation in one of the 22 genes described so far as related to the disease. However, patients with apparently sporadic PPGL tend to be excluded from genetic testing. This study should bring to an end years of controversy and debate, […]
WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome
Mutations in the WAC gene have been recently reported in large screening cohorts of patients with intellectual disability or autism. We used whole exome sequencing to evaluate 6 patients with developmental delay, hypotonia, behavioral problems, constipation/feeding difficulties and common dysmorphic features including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. […]
Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses
Heparan sulfate proteoglycans are essential for human development. Many genes are involved in producing heparan sulfate and when these genes are mutated, they can lead to early-onset developmental disorders affecting multiple body systems. Our group identified a family with a disease designated as seizures-scoliosis-macrocephaly syndrome, which is characterized by seizures, intellectual disability, scoliosis, and prominent […]
Charcot–Marie–Tooth diseases: an update and some new proposals for the classification
Charcot-Marie-Tooth (CMT) disease is the most frequent form of inherited neuropathy. To date, more than 60 genes have been implicated in this heterogeneous group of neuropathies, and the recent advances in genetic technologies are promising. In this review, we discuss the diagnostic approaches and the underlying complex molecular processes. We also suggest a modification of […]
Mutations in COQ4, an Essential Component of Coenzyme Q Biosynthesis, Cause Lethal Neonatal Mitochondrial Encephalomyopathy
Coenzyme Q10 is an essential cofactor for mitochondrial function and other biochemical pathways. Mutations in genes involved in CoQ10 biosynthesis cause primary CoQ10 deficiency syndromes that can be treated with oral ubiquinone. We used exome sequencing to evaluate 6 patients with clinical findings suggestive of a mitochondrial disorder. All patients were female and presented on […]
Whole exome sequencing identifies LRP1 as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans
Keratosis pilaris atrophicans (KPA) is a group of related skin disorders characterized by inflammatory keratotic skin-papules and hair loss on the scalp, eyebrows and eye-lashes. Facial scarring is a complication. A consanguineous family with four members affected by KPA was subject to extensive genetic investigation. The analysis revealed that affected individuals had inherited a unique […]