The authors of the brief report show a novel heterozygous SCN8A variant inducing a partial loss-of-function mutant that affected five family members with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment. Importantly, the authors concluded that SCN8A can be considered as a candidate gene for isolated non-epileptic movement disorders.
The authors report a patient with a missense mutation in TUBB2A, a neuron-specific β-tubulin isotype II impairing the binding of the corresponding protein to KIF1A, a neuron-specific kinesin required for transport of synaptic vesicle precursors and causing progressive spastic paraplegia, peripheral sensory-motor polyneuropathy and ataxia. From this, the authors draw an in vitro study and in silico analysis that suggests that loss of binding of TUBB2A to KIF1A in neurons could impair the axonal transport disrupting neuronal function and result in a gradual neuronal cell death contributing to a progressive neurodegenerative process as in the patient.
Authors report 38 unrelated individuals and two mothers, from 26 different centres in 7 different countries, affected by a distinct syndrome related to a neurodevelopmental disorder. This new syndrome seems to be due to mutations in TLK2, identified using whole-exome and whole-genome sequencing, matchmaker databases and international collaborations. Authors highlighted the importance of international data sharing that allowed the detection of this distinct syndrome caused by haploinsufficiency in TLK2.
Authors of the study identified six CHD1 heterozygous missense variants in a cohort of patients presenting autism, speech apraxia, developmental delay and facial dysmorphic features. Notably, a de novo deletion of a large portion of CHD1 was reported in a patient with no obvious neurological phenotype.
Authors identified four unrelated patients with recessive mutations in COA7, coding for cytochrome oxidase assembly factor 7. These were found among a Japanese case series of more than 1300 patients presenting Charcot-Marie Tooth disease. After a study of the patients based on MRI scans, nerve conduction studies and sural nerve biopsies, the researchers confirmed spinal cord atrophy, chronic axonal degeneration and axonal sensorimotor neuropathy. From an in cellulo study, authors concluded that mutant COA7 might affect stability of COA7 interaction partners in mitochondria. They also reproduced the patients' phenotype in Drosophila COA7 knockdown models. Authors from this study suggest that COA7 mutation is responsible for a new type of spinocerebellar ataxia with axonal neuropathy.
Seven unrelated patients with substantial phenotypic overlap were referred for exome sequencing. The patients showed developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features. The analysis detected missense mutations in TRAF7, a multi-functional protein. Authors suggest that TRAF7 might play a significant role in human development.
Using exome and whole-genome sequencing, truncating mutations in WASF1, coding for a protein part of an actin-remodeling complex, were identified. These mutations lead to moderate to profound intellectual disability with autistic features and seizures in five unrelated individuals. Researchers conclude that de novo mutations in WASF1 cause a rare form of intellectual disability associated with seizures.
Two unrelated individuals presenting ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features were found to carry the same heterozygous mutation in ELOVL1 by whole exome sequencing. Researchers suggest that this mutation is likely to cause this neurological disorder.
Authors of this study report a patient carrying a variant of EFNB2, which codes a ligand of EphB receptors involved in different developmental pathways, and a family in which ARGLU1 and EFNB2 were deleted from chromosome 13q33. The individuals presented heart defects and a mild developmental delay. Authors of this study thus conclude that haploinsufficiency of EFNB2 could explain several features of 13qter deletions.
Using whole-exome sequencing, the authors of this study identified SPTBN4 variants in six individuals from three families presenting severe hypotonia and global developmental delays. The authors postulate that the variants cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. By modelling the disease in mice, they revealed that SPTBN4 mutation impairs βIV spectrin’s capacity to interact with AnkG or phosphoinositides and possibly affect sodium and potassium channels clustering. Authors conclude that genetic assessment of βIV spectrin should be considered in children presenting with the spectrum of symptoms overlapping severe psychomotor delays, hypotonia, and epilepsy.
Two Brazilian families presented the same homozygous missense mutation in FDX2, coding for ubiquitously expressed mitochondrial ferredoxin, associated with a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness. MRI showed reversible or partially reversible leukoencephalopathy. Further analysis showed severely reduced FDX2 protein levels in muscle.
Authors of this study identified seven individuals carrying heterozygous variants of IRF2BPL, which encodes a member of the interferon regulatory factor 2 binding protein family of transcriptional regulators. Nonsense variants of IRF2BPL resulted in severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Individuals with missense variants displayed global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. Authors suggest that IRF2BPL is required in the nervous system and that its loss leads to neurological phenotypes.
The authors of the paper used massively parallel sequencing to identify 13 patients carrying germline alterations in BCL11B associated with global developmental delay with speech impairment and intellectual disability resulting in a non-syndromic neurodevelopmental delay. BCL11B is a transcription factor essential for development of the nervous and immune systems. These alterations in BCL11B were linked to a lack of peripheral type 2 innate lymphoid cells.
Through exome sequencing and world-wide collaborations, the authors identified 20 individuals with de novo variants in FBXO11, coding for a member of the F-BOX protein family, involved in ubiquitination and proteasomal degradation. These variants were associated with mild to severe developmental delay associated with a wide range of features.
Authors identified three children from two consanguineous families affected by severe psychomotor delay, intellectual disability, hypotonia, epilepsy and corpus callosum hypoplasia, and two of the three children showed also mild cerebellar hypoplasia and atrophy. This neurodevelopmental syndrome was linked to homozygous loss-of-function mutations in LNPK, which encodes the lunapark protein, a curvature-stabilizing protein within the endoplasmic reticulum (ER). Authors postulate from this study the role of ER junction stabilizer lunapark in establishing the corpus callosum.
Authors of this study identified two individuals with cochlear aplasia presenting de novo loss-of-function variants in GREB1L. The role of GREBL1 in craniofacial development was demonstred in animal models of mouse and zebrafish. Researchers suggest via this study the crucial role for GREBL1 in early inner ear and eighth cranial nerve development.
Authors performed the genetic study of a family composed of eleven unaffected and seven affected individuals with brachydactyly, overriding digits and clino-symphalangism in hands and feet and hexadactyly in feet. They also harboured skeletal defects including scoliosis, dislocated patellae and fibulae and pectus excavatum. With this study, authors postulate the crucial role of CHST11 in skeletal morphogenesis.
Authors from this study identified by exome sequencing a disease locus with variants of BMPR1B and PDHA2 linked to a unique combination of digit malformation including brachydactyly, symphalangism and zygodactyly plus infertility in males. In silico analysis indicated that both variants affect protein function. The authors suggest that the two linked variants manifest together as a novel syndrome.
Authors of the study identified two unrelated individuals presenting variants in the penultimate exon of POMP, coding for a chaperone for proteasome assembly, thereby resulting in a truncated protein. Researchers postulate that dominant-negative effect is the reason for a previously undescribed POMP-related autoinflammation and immune dysregulation found in both patients, who present early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis and autoimmunity.
Authors of the study report three consanguineous families with mutations in MYF5, a key regulator of early stages of myogenesis. Affected individuals presented congenital ophthalmoplegia with scoliosis and vertebral and rib abnormalities. Using this data, the authors argue that MYF5 is crucial for rib, spine and extraocular muscle formation in humans.
Whole-exome sequencing was allowed to find mutations in WNT2B in three individuals from two unrelated families. The affected individuals presented severe, neonatal-onset osmotic diarrhea. Ex vivo analysis was performed using enteroids generated from intestinal biopsy samples. The authors used this data to conclude that WNT2B deficiency should be considered for individuals with neonatal-onset diarrhea.
Using exome sequencing, the authors of this study revealed three homozygous missense variants in SNRPA, a splicing-related gene, in two sisters presenting an uncommon combination of phenotypes, with intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies.
Authors identified by whole exome sequencing three de novo variants in RHOBTB2, which encodes an atypical Rho GTPase. All three patients exhibited acute encephalopathy (febrile status epilepticus).