Prospective evaluation of NGS-based sequencing in epilepsy patients: results of seven NASGE-associated diagnostic laboratories.

Background: Epilepsy is one of the most common and disabling neurological disorders. It is highly prevalent in children with neurodevelopmental delay and syndromic diseases. However, epilepsy can also be the only disease-determining symptom.

Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.

Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.

Methods: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases.

PIGN encephalopathy: Characterizing the epileptology.

Objective: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy.

Methods: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment.

Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies.

Background: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies.

Kir2.2 p.Thr140Met: a genetic susceptibility to sporadic periodic paralysis.

Introduction: Periodic paralyses (PP) are recurrent episodes of flaccid limb muscle weakness. Next to autosomal dominant forms, sporadic PP (SPP) cases are known but their genetics are unclear.

Methods: In a patient with hypokalemic SPP, we performed exome sequencing to identify a candidate gene.

SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy.

Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state.

Utility of a next-generation sequencing-based gene panel investigation in German patients with genetically unclassified limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophies (LGMDs) are genetically heterogeneous and the diagnostic work-up including conventional genetic testing using Sanger sequencing remains complex and often unsatisfactory. We performed targeted sequencing of 23 LGMD-related genes and 15 genes in which alterations result in a similar phenotype in 58 patients with genetically unclassified LGMDs. A genetic diagnosis was possible in 19 of 58 patients (33 %).

Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum.

Homozygosity for the common Caucasian splice site mutation c.-32-13T>G in intron 1 of the GAA gene is rather rare in Pompe patients. We report on the clinical, biochemical, morphological, muscle imaging, and genetic findings of six adult Pompe patients from five unrelated families with the c.

Long-Term Observations in an Affected Family with Neurogenic Scapuloperoneal Syndrome Caused by Mutation R269C in the TRPV4 Gene.

Mutations in the TRPV4 gene, encoding a polymodal Ca(2+) permeable channel, are causative for several human diseases, affecting the skeletal and the peripheral nervous system with highly variable phenotypes. We report on a family with two affected individuals. The father clinically suffered from a classical scapuloperoneal syndrome, while the son presented with a severe neonatal onset with congenital respiratory distress, feeding problems and arthrogryposis multiplex.

Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients.

Objective: To examine rare KCNJ18 variations recently reported to cause sporadic and thyrotoxic hypokalaemic periodic paralysis (TPP).

Methods: We sequenced KCNJ18 in 474 controls (400 Caucasians, 74 male Asians) and 263 unrelated patients with periodic paralysis (PP), including 30 patients with TPP without mutations in established PP genes.

Results: In 10 patients without TPP, we identified 9 heterozygous, novel variations (c.

Overlap phenotype between CMT1A and hereditary neuropathy with liability to pressure palsies caused by the novel small in-frame deletion c.407_418del12 in PMP22 gene.

We report monozygotic twins, who presented with a clinical picture of Charcot-Marie-Tooth disease type 1 (CMT1) with bilateral foot drop, pes cavus, thoracic kyphosis, and scoliosis. Hereditary neuropathy with liability to pressure palsies (HNPP) showed up in one of them. Neurography showed demyelinating neuropathy, typical for CMT1, and transient conduction block in the ulnar nerve correlating with clinical ulnar palsy due to minor mechanical stress in only one of them.

Early infantile sensory-motor neuropathy with late onset respiratory distress.

Children with spinal muscular atrophy with respiratory distress (SMARD1) usually present within their first year of life, with respiratory failure due to diaphragmatic paralysis and progressive distal limb weakness. We present a child with a confirmed compound heterozygous IGHMBP2 mutation c.[676G>T];[2083A>T] in whom severe sensory-motor neuropathy preceded diaphragmatic paralysis by almost 3years.

Palladium-catalyzed C-S coupling: access to thioethers, benzo[b]thiophenes, and thieno[3,2-b]thiophenes.

The first C-S bond formation/cross-coupling/cyclization domino reaction using thiourea as a cheap and easy to handle dihydrosulfide surrogate has been developed. Structurally important biarylthioether, benzo[b]thiophenes, and thieno[3,2-b]thiophene scaffolds are provided in high yield.