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De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Autosomal recessive Charcot-Marie-Tooth disease (CMT) is considered rare and phenotypic descriptions are scarce for the different subgroups. Mutations in the SH3TC2 gene, causing recessive demyelinating CMT type 4C have been found in several Norwegian CMT patients over the last years. We aimed to estimate a minimum prevalence and to study the genotypic and phenotypic variability of CMT4C in Norway. Patients were selected from diagnostic registries in medical genetic centers in Norway for cases of CMT4C. All patients were invited to complete a questionnaire and give medical consent to the use of clinical data from medical hospital records. A total of 35 patients from 31 families were found with CMT4C, which gives a minimum prevalence of 0.7/100,000 in Norway. Six new mutations were identified. Most patients had debut in the first decade with foot deformities, distal limb paresis, sensory ataxia and scoliosis. Proximal lower limb paresis and cranial nerve involvement was seen in about half of the patients. CMT4C is the most common recessive CMT in Norway. In addition to the classic distal limb affection, early debut, scoliosis, proximal paresis, cranial nerve affection and sensory ataxia are the most prominent features of CMT4C., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: the frequency of different Charcot-Marie-Tooth (CMT) genotypes has been estimated in clinic populations, but prevalence data from the general population are lacking., Methods: our population-based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist and classified clinically, neurophysiologically and genetically., Results: two hundred and forty-five persons from 116 families had CMT. This corresponds to 1 per 1214 persons (95% CI 1062-1366) have CMT in the general population. CMT1 (motor conduction velocity (MCV) <38 m/s), CMT2 (MCV >38 m/s) and CMT intermediate (MCV 25-45 m/s) were found in 48.2%, 49.4% and 2.4% of the families. A total of 27.2% of the families and 28.6% of the affected had a mutation in the investigated CMT genes. The prevalence of the peripheral myelin protein 22 (PMP22) duplication and point mutation in the connexin32 (Cx32), myelin protein zero (MPZ) and mitofusin2 (MFN2) genes was found in 13.6%, 6.2%, 1.2%, 6.2% of the families, and in 19.6%, 4.8%, 1.1%, 3.2% of the affected, respectively. None of the families had point mutations in the early growth response 2 (EGR2), PMP22 or small integral membrane protein of lysosome/late endosome (SIMPLE) genes., Conclusions: CMT is the most common inherited neuropathy. At present, 43 CMT genes are known, and an examination of all known genes would probably only identify mutations in approximately 50% of those with CMT. Thus, it is probable that at least 30-50 CMT genes are yet to be identified.

Background: X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions., Methods: We describe two novel mutations in the connexin32 gene in two Norwegian families., Results: Family 1 had a c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247. This probably results in a shorter non-functional protein structure. Affected individuals had an early age at onset usually in the first decade. The symptoms were more severe in men than women. All had severe muscle weakness in the legs. Several abortions were observed in this family. Family 2 had a c.536 G>A (C179Y) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade. Muscle wasting was severe and correlated with muscle weakness in legs. The men and one woman also had symptom from their hands. The neuropathy is demyelinating and the nerve conduction velocities were in the intermediate range (25-49 m/s). Affected individuals had symmetrical clinical findings, while the neurophysiology revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected individuals., Conclusion: The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode.