Inherited and de novo biallelic pathogenic variants in COL11A1 result in type 2 Stickler syndrome with severe hearing loss.

Background: Type 2 Stickler syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly-Xaa-Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplications that typically leaves the message in-frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems.

EMQN best practice guidelines for genetic testing in dystrophinopathies.

Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010.

Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in .

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models.

PAPSS2-related brachyolmia: Clinical and radiological phenotype in 18 new cases.

Brachyolmia is a skeletal dysplasia characterized by short spine-short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity.

Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.

Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia.

Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia.

Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).

Unlabelled: Activating mutations in are associated with nephrogenic syndrome of inappropriate antidiuresis (NSIAD). NSIAD causes hyponatremia, decreased serum osmolality and clinical symptoms, which may present from birth or in infancy and include hypotonia, irritability, vomiting and/or seizures. Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache.

Evaluation of universal immunohistochemical screening of sebaceous neoplasms in a service setting.

Background: Muir-Torre syndrome (MTS) is a subtype of Lynch syndrome, which encompasses the combination of sebaceous skin tumours or keratoacanthomas and internal malignancy, due to mutations in DNA mismatch repair genes. Sebaceous neoplasms (SNs) may occur before other malignancies, and may lead to the diagnosis, which allows testing of other family members, cancer surveillance, risk-reducing surgery or prevention therapies.

Aim: To evaluate the efficacy of universal immunohistochemistry (IHC) screening of SNs in a service setting.

Association Between High-Sensitivity Cardiac Troponin I and Cardiac Events in Elderly Women.

Background: Elderly women are at high risk of coronary heart disease (CHD) and heart failure. High-sensitivity assays allow detection of cardiac troponin I (hsTnI) well below diagnostic cutoffs for acute coronary syndrome. We investigated the association between these levels with future cardiac events in community-based ambulant white women aged over 70 years initially recruited for a 5-year randomized, controlled trial of calcium supplements.

Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report.

Background: Heterozygous mutations in the gene encoding renin (REN) cause autosomal dominant tubulointerstitial kidney disease (ADTKD), early-onset anaemia and hyperuricaemia; only four different mutations have been described in the published literature to date. We report a novel dominant REN mutation discovered in an individual after forty years of renal disease.

Case Presentation: A 57 year old Caucasian woman with chronic kidney disease stage five was reviewed in a regional joint renal genetics clinic.

Immuno-nephelometric determination of group streptococcal anti-streptolysin O titres (ASOT) from dried blood spots: Method for validating a new assay.

This study was designed to determine the sensitivity and reproducibility of recovering anti-streptolysin O titres (ASOT) from dried blood spot (DBS) samples, a methodologic subcomponent of the penicillin pharmacokinetic studies in children receiving secondary prophylaxis with intramuscular benzathine penicillin for acute rheumatic fever.

Male child with somatic mosaic Osteopathia Striata with Cranial Sclerosis caused by a novel pathogenic AMER1 frameshift mutation.

Osteopathia striata with cranial sclerosis (OSCS; OMIM #300373) is a rare X-linked dominant condition caused by mutations in the AMER1 gene (also known as WTX or FAM123B). It is a condition which usually affects females in whom the clinical phenotype can be extremely variable. Conversely affected males typically die in utero or during the neonatal period [Perdu et al.

Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child.

Charcot-Marie-Tooth disease (CMT) refers to a genetically heterogeneous group of disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is 1 in 2500 individuals. Mutations in the MFN2 gene are the commonest cause for the axonal (CMT2) type.

New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study.

Background: Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs.

Objective: To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC).

Methods: Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study.

Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis.

At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse "mutation hotspots" in 50 human cancer genes.

Malignant peripheral nerve sheath tumor in cowden syndrome: a first report.

Malignant peripheral nerve sheath tumor is a rare malignancy, accounting for 3% to 10% of all soft-tissue sarcomas. We describe a previously healthy 48-year-old man who was diagnosed as having a high-grade malignant neoplasm involving the facial nerve in the right petrous canal after a 4-year history of deafness. The tumor was resected; histologic appearance and immunophenotype, including patchy but strong positivity for S100 protein, indicated a diagnosis of malignant peripheral nerve sheath tumor.

Unilateral hypoplastic kidney - a novel highly penetrant feature of familial juvenile hyperuricaemic nephropathy.

Background: Familial juvenile hyperuricaemic nephropathy is a rare inherited nephropathy with genetic heterogeneity. Categorised by genetic defect, mutations in uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1β (HNF-1β) genes as well as linkage to chromosome 2p22.1-21 have previously been identified.

COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome.

Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4.

Muscular dystrophy with large mitochondria associated with mutations in the CHKB gene in three British patients: extending the clinical and pathological phenotype.

Three patients with CHKB deficient muscular dystrophy are described which broadens the previously described phenotype. Blood smear in one patient showed Jordans anomaly (vacuolated leukocytes). Gastrointestinal features occurred in two patients and there appeared to be acute deterioration with infection/general anaesthesia.

Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.