Biallelic protein truncating EXOSC6 variants cause a neurodevelopmental disorder with cerebellar atrophy, ataxia, and global developmental delay

Hemizygous loss-of-function variants of EIF1AX are associated with a syndromic neurodevelopmental disorder

Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males, and its pathogenicity was evaluated using a molecular dynamic simulation and transgenic Drosophila models.

Exome Sequencing uncovers Homozygous Stop-Gained variant in the SYNE1 Gene Leading to Spinocerebellar Ataxia

ABSTRACT Background &Objective: Spectrin Repeat-Containing Nuclear Envelope Protein 1 (SYNE1) is important gene for maintaining neuronal structure and function, particularly in the cerebellum, the brain region responsible for coordinating movement. The genetic mutation in SYNE1 gene, which encodes Nesprin-1 protein leads to autosomal recessive form of spinocerebellar Ataxia OMIM (608441). This cerebellar dysfunction causes progressive balance and coordination problems, including reflexes and cognitive impairment. To understand genetic mutations in SYNE1 gene that are linked with Autosomal Recessive Spinocerebellar Ataxia type 8 (SCAR8) and Autosomal Recessive Cerebellar Ataxia type 1 (ARCA1). Methodology: The study was done in the Center of Excellence in Genomic Medicine and Research (CEGMR) during 2023-2024. Firstly, Whole Exome Sequencing (WES) was carried out to identify the mutation, followed by Sanger sequencing to validate the WES results. Results: WES identified a novel homozygous stop-gained variant, NM_182961.3:c.352C>T (p.Arg118Ter), in the SYNE1 gene in a 32-year-old Saudi patient. This alteration was associated with progressive cerebellar atrophy, impaired fine motor skills, muscular weakness, and speech and learning deficits. The variant was independently confirmed by Sanger sequencing. Conclusions: The patient’s phenotype was consistent with previously reported ARCA1 and SCAR8. To our knowledge and based on the currently available literature, this may represent the first reported Saudi family with a SYNE1 mutation associated with these conditions. This finding advances the genetic and molecular characterization of these rare disorders, highlights the utility of molecular diagnostics, and supports the establishment of a local database of disease-associated variants to improve diagnosis, management, and future research in the Saudi population.

BHLHE22 monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, abnormal muscle tone and movement abnormalities.

BACKGROUND BHLHE22 encodes a basic helix-loop-helix transcription factor expressed exclusively in the retina and central nervous system and functions as an important regulator of neuronal differentiation. However, BHLHE22 has not yet been associated with a Mendelian neurodevelopmental or neurological disorder. METHODS 15 individuals from 13 unrelated families carrying BHLHE22 variants identified by exome sequencing were collected through an international collaboration. RESULTS De novo missense variants located in the highly conserved helix-loop-helix domain of the protein were found in six individuals, and one recurrent homozygous frameshift variant, NP_689627.1:p.Gly74AlafsTer18, was found in nine individuals. Frequent clinical features include absent or limited speech (10/13), delayed or impaired motor abilities (11/13), intellectual disability (ID; 9/12), partial or complete agenesis of the corpus callosum (12/15), involuntary movements and/or stereotypies (11/13) and abnormal muscle tone (13/13), depending on data availability. Two individuals developed spastic paraplegia, without ID or callosal anomalies. One individual had moderate developmental delay and ID but without callosal anomalies. CONCLUSION Collectively, our data establish BHLHE22 as a previously unrecognized neurodevelopmental disease gene. Disruption of BHLHE22, through either dominant or recessive variants, results in a distinct syndrome characterised by abnormalities in brain development, cognition, tone and movement.

Heterozygous RNF13 Truncating Variants Are Associated With Developmental and Epileptic Encephalopathy.

A case series of an additional 13 affected individuals with RNF13 variants (2 missense, 11 truncating) supports and broadens previous reports and helps to define a narrow but critical region of the protein that is intolerant to truncating variation, although the gene is not highly constrained.

TTC14 dysfunction contributing to microcephaly and lissencephaly spectrum features through protein mislocalization and impaired RNA processing

Neuropathy With Demyelinating Features in a Patient With Biallelic HARS1 Variants

ABSTRACT Background and Aims The HARS1 gene encodes cytoplasmic histidyl‐tRNA synthetase, which catalyzes the ligation of histidine to tRNAHIS in the cytoplasm as an early step in protein biosynthesis and is essential for cell viability. Pathogenic variants in HARS1 have been associated with three phenotypes: autosomal dominant Charcot–Marie–Tooth (CMT) disease, a multisystem recessive syndrome with prominent ataxia, and autosomal recessive Usher syndrome. Here, we present a patient who is compound heterozygous for HARS1 variants and who has a complex recessive phenotype that includes a neuropathy with demyelinating features and active denervation. Our computational and functional analyses support the pathogenicity of these alleles, suggesting that our findings expand the allelic and clinical heterogeneity of HARS1‐related disease. Methods The individual found to have pathogenic compound heterozygous HARS1 variants was evaluated in a neuromuscular clinic and was further investigated in research studies. Functional consequences of the HARS1 variants were tested in yeast complementation assays; the phase of these alleles was confirmed via long‐range PCR and long‐read sequencing on DNA isolated from the proband, the mother, and the father. Results A 25‐year‐old male with CMT1 and mild intellectual disability had a maternally inherited variant (p.Q410*) and a de novo variant in the HARS1 gene (p.R375C) identified via trio exome sequencing. Studies in yeast revealed ablated function for p.Q410* and reduced function for p.R375C. Of 2480 informative sequencing reads generated from the proband: (a) 1765 (71%) included only p.R375C or only p.Q410*; (b) 237 (10%) included both alleles; and (c) 478 (19%) included neither allele. Interpretation Studies in yeast revealed loss‐of‐function characteristics for both p.Q410* and p.R375C HARS1, consistent with these variants being pathogenic. Allele‐specific sequencing analyses are consistent with the proband having a compound heterozygous genotype and with p.R375C being a de novo variant that arose on the chromosome 5 transmitted by the father. There is therefore moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype. This case report expands the allelic and phenotypic heterogeneity of biallelic HARS1 pathogenic variants.