Noonan syndrome with multiple lentigines, (NSML) formerly known as LEOPARD syndrome, has overlapping features with other RASopathies. Except for neurofibromatosis type 1, other disorders that result from dysregulated RAS/MAPK pathway are not known to be associated with neurogenic tumors. We identified four patients from three families with NSML, progressive neuropathy, enlarged nerves, massive burden of […]
Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity
Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and distinctive brain MRI findings. Diagnosis and treatment of JS is challenging due to >28 associated genes and substantial clinical variability. This study provides a relatively unbiased view of the phenotypic range, genetic basis, and […]
Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure
Primary gonadal failure is characterized by a lack of spontaneous pubertal development, primary amenorrhea or early menopause in females, and underdeveloped testis and azoospermia in males. Its genetic causes remain mostly unknown. Variants of the minichromosome maintenance complex component 8 gene (MCM8) are significantly associated with early menopause. Mice lacking MCM8 are sterile. We sought […]
Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers
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 […]
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 […]