Mutations in FUS and TBK1 often cause aggressive early-onset amyotrophic lateral sclerosis (ALS) or a late-onset ALS and/or frontotemporal dementia (FTD) phenotype, respectively. Co-occurrence of mutations in two or more Mendelian ALS/FTD genes has been repeatedly reported. However, little is known how two pathogenic ALS/FTD mutations in the same patient interact to shape the final phenotype. We screened 28 ALS patients with a known FUS mutation by whole-exome sequencing and targeted evaluation for mutations in other known ALS genes followed by genotype–phenotype correlation analysis of FUS/TBK1 double-mutant patients. We report on new and summarize previously published FUS and TBK1 double-mutant ALS/FTD patients and their families. We found that, within a family, mutations in FUS cause ALS while TBK1 single mutations are observed in FTD patients. FUS/TBK1 double mutations manifested as ALS and without a manifest difference regarding age at onset and disease duration when compared to FUS single-mutant individuals. In conclusion, TBK1 and FUS variants do not seem to interact in a simple additive way. Rather, the phenotype of FUS/TBK1 double-mutant patients appears to be dominated by the FUS mutation.

Biallelic variants in the NARS2 gene are the cause of a continuous spectrum of neurodegenerative disorders presenting with various severity-from spastic paraplegia, progressive neurodegeneration to Leigh and Alpers syndrome. Common clinical signs result from a mitochondrial dysfunction based on OXPHOS deficiency. Here, we present a patient with infantile-onset severe epilepsy leading to fatal refractory status epilepticus. Whole exome sequencing with Exomiser analysis based on HPO terms detected two novel NARS2 variants in a compound heterozygous state. To date, 18 different NARS2 disease-causing mutations have been described. Our study adds to the understanding of this mitochondrial disorder.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease resulting from mutations in the NTRK1 gene encoding the neurotrophic tyrosine kinase-1 receptor. In this multicenter observational retrospective study, we investigated CIPA patients identified from French laboratories sequencing the NTRK1 gene, and seven patients were identified. Patients originated from France (2), Suriname (2), Mali (1), Kazakhstan (1), and Algeria (1). Mean age of patients was 9.8 years (4–20), four patients were female (57%), infant developmental milestones were delayed in four cases (57%), and four patients had a family history of consanguinity (57%). Mean age at diagnosis was 4.8 months (3–6), and all patients presented with pain insensitivity, anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, and autonomous nervous system impairment. Patients also showed an assortment of associated findings, including hyperactivity (86%), emotional lability (86%), joint deformities (71%), bone fractures (57%), abnormal sense of touch, vibration and position (50%), skin, hair and nails abnormalities (28%), and hypothermia episodes (28%). Two patients died at age 9 and 12 years from infection. In three cases, nerve conduction studies showed absent lower limbs sensory nerve action potentials. In one case, sensory nerve biopsy showed complete absence of unmyelinated fibers. Nine NTRK1 pathogenic variants were found, including three newly described mutations. This nationwide study confirms that NTRK1 gene-related CIPA is an extremely rare disorder and expands the genotypic spectrum of NTRK1 mutations.

The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia frequently in combination with dysarthria and oculomotor problems. Additional signs and symptoms are common and can include various pyramidal and extrapyramidal signs and intellectual impairment. Genetic causes of SCAs are either repeat expansions within disease genes or common mutations (point mutations, deletions, insertions etc.). Frequently the two types of mutations cause indistinguishable phenotypes (locus heterogeneity). This article focuses on SCAs caused by common mutations. It describes phenotype and genotype of the presently 27 types known and discusses the molecular pathogenesis in those 21 types where the disease gene has been identified. Apart from the dominant types, the article also summarizes findings in a variant caused by mutations in a mitochondrial gene. Possible common disease mechanisms are considered based on findings in the various SCAs described.

Mediator (MED) is a key regulator of protein-coding gene expression, and mutations in MED subunits are associated with a broad spectrum of diseases. Because mutations in MED17 result in autosomal recessive disorders, including microcephaly, intellectual disability, epilepsy, and ataxia, which are barely reported, with only three case reports to date, genotype–phenotype association should be elucidated. Here, we investigated the impact of MED17 mutations on cellular responses and found increased unfolded protein responses (UPRs) in fibroblasts derived from Japanese patients with MED17 mutations. The expression of the UPR genes CHOP and ATF4 was upregulated, and the phosphorylation of eIF2a was basally increased in patients’ cells. Based on our findings, we propose that increased UPRs caused by MED17 mutations might contribute to the clinical phenotype.

PLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

Mutations in CSNK2B lead to Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), a rare neurodevelopmental disorder. Only 14 cases of POBINDS have been reported worldwide. The main manifestations are seizures, often tonic–clonic, with or without intellectual disability, growth retardation, and developmental language retardation. We conducted a comprehensive phenotypic mining and trio-whole exome sequencing on six children with POBINDS for gene diagnosis and analyzed the different variants using bioinformatics analysis software and related experiments. This paper reviews previous literature and discusses two common missense variants that lead to structural changes. Among the six patients, four, one, and one had tonic–clonic, myoclonic, and febrile seizures, respectively. Language development disorder, motor development disorder, and developmental delay/intellectual disability (DD/ID) are the main clinical features. All children had de novo mutations in CSNK2B, including three missense variants (c.410G > T/p.(Cys137Phe), c.494A > G/p.(His165Arg), and c.3G > A/p.(Met1Ile)), two splice variants (c.292-2A > T, c.558-3 T > G), and one frameshift variant (c.499delC/p.(Leu167Serfs*60)). Three missense variants were predicted to be harmful by various software programs, and two splicing variants were found to produce new exonic splicing enhancers by the minigene assay. Western blot analysis showed that the frameshift variant resulted in decreased protein expression. According to a literature review, c.3G > A/p.(Met1Ile), c.292-2A > T, c.558-3 T > G, and c.499delC/p.(Leu167Serfs*60) are novel variants of CSNK2B. The decrease or loss of protein function caused by CSNK2B mutations may be a pathogenic factor in this cohort. The severity of the POBINDS phenotype differs, and refractory epilepsy may be accompanied by a more serious DD/ID, language disorder, and motor retardation. At present, there is no specific treatment, and antiepileptic therapy usually requires the combination of two or more anti-epileptic drugs.

Intellectual disability (ID) encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders that may present with psychiatric illness in up to 40% of cases. Despite the evidence for clinical utility of genetic panels in pediatrics, there are no published studies in adolescents/adults with ID or autism spectrum disorder (ASD). This study was approved by our institutional research ethics board. We retrospectively reviewed the medical charts of all patients evaluated between January 2017 and December 2019 in our adult neuropsychiatric genetics clinic at the McGill University Health Centre (MUHC), who had undergone a comprehensive ID/ASD gene panel. Thirty-four patients aged > 16 years, affected by ID/ASD and/or other neuropsychiatric/behavioral disorders, were identified. Pathogenic or likely pathogenic variants were identified in one-third of our cohort (32%): 8 single-nucleotide variants in 8 genes (CASK, SHANK3, IQSEC2, CHD2, ZBTB20, TREX1, SON, and TUBB2A) and 3 copy number variants (17p13.3, 16p13.12p13.11, and 9p24.3p24.1). The presence of psychiatric/behavioral disorders, regardless of the co-occurrence of ID, and, at a borderline level, the presence of ID alone were associated with positive genetic findings (p = 0.024 and p = 0.054, respectively). Moreover, seizures were associated with positive genetic results (p = 0.024). One-third of individuals presenting with psychiatric illness who met our red flags for Mendelian diseases have pathogenic or likely pathogenic variants which can be identified using a comprehensive ID/ASD gene panel (~ 2500 genes) performed on an exome backbone.