Neurodevelopmental disorders are lifelong debilitating conditions that affect cognition and originate during embryonic development. Being heterogeneous and with a variety of etiologies, most of these disorders have no targeted treatment or cures, due to our lack of knowledge on the underlying molecular mechanisms disrupted in their pathogenesis. An emerging epigenetic mechanism recently associated with neurodevelopmental disorders is ubiquitylation of histone H2B. This posttranslational modification controls gene expression during neurodevelopment, where histone H2B ubiquitylation levels are tightly regulated by multiple deubiquitylase protein complexes ensuring correct gene expression. Components of deubiquitylase complexes regulating histone H2B ubiquitylation are the protein scaffolds ATXN7L3 and ENY2, and the deubiquitylating enzymes USP22, USP27X, and USP51. Recent clinical studies have highlighted a potential role of H2B ubiquitylation in human neurodevelopment, including the identification of neurodevelopmental disorders associated with gene variants in the ATXN7L3, USP27X and USP51 genes. Here, we summarize our knowledge of the functions of deubiquitylase complexes that regulate histone H2B ubiquitylation and their components in neurodevelopment, and describe ATXN7L3, USP27X, and USP51-associated disorders, proposing future directions on the required research on their fundamental biology that could lead to targeted therapies.
Spinocerebellar Ataxia Type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATXN2 gene. Endogamous populations may exhibit clustering of inherited disorders because of founder effects and restricted gene flow. This study aimed to characterize the clinical and genetic features of SCA2 in multigenerational Banjara families from North India. A total of 141 individuals from 23 multigenerational Banjara families were clinically evaluated. 55 clinically affected individuals and at-risk family members underwent molecular testing for ATXN2 CAG repeat expansions using flanking PCR followed by capillary electrophoresis. Clinical characteristics were summarized using descriptive statistics, and the relationship between CAG repeat length and age at onset was assessed by linear regression. Pathogenic ATXN2 CAG repeat expansions were identified in 39 of the 55 individuals who underwent genetic testing (70.9
Inherited peripheral neuropathies (IPNs) represent a clinically and genetically heterogeneous group of disorders affecting sensory, motor, autonomic functions, and can also present as a part of complex neurogenetic syndromes. Charcot-Marie-Tooth disease (CMT) is the most prevalent type of IPN. Despite advances in genetic testing, the diagnostic process remains challenging due to genetic heterogeneity and overlapping clinical phenotypes. We performed a comprehensive genetic evaluation of 126 patients presenting with symptoms of IPN. Nineteen patients with a typical CMT phenotype were initially screened for PMP22 copy number variations using Multiplex Ligation-dependent Probe Amplification (MLPA). Whole-exome sequencing (WES) was subsequently performed in 107 patients. Of these, 72 (63.7
SPG7 encodes paraplegin, a mitochondrial AAA-metalloprotease critical for inner mitochondrial membrane protein quality control. Pathogenic variants most commonly cause autosomal recessive hereditary spastic paraplegia (HSP) but its phenotypic spectrum includes cerebellar ataxia, progressive external ophthalmoplegia, myopathy and parkinsonism. We report a 47 year old man presenting with a progressive external ophthalmoplegia, ptosis, progressive gait disturbance, and spasticity. Ten-year follow-up of this individual showed slowly progressive spastic ataxia with ocular motor involvement and neurogenic bladder. His mother and maternal aunt both had marked spasticity, ataxia, ptosis and external ophthalmoplegia. Genetic testing demonstrated compound heterozygous pathogenic variants in paraplegin in this individual. Genetic testing in his mother and aunt revealed homozygous canonical splice-site variants (c.2182–2 A > G). Cascade testing of his asymptomatic father showed a common pathogenic missense variant p.(Ala510Val) in the same gene. This family demonstrates a pseudodominant inheritance pattern, instead of the expected autosomal recessive trait that applies to paraplegin. We highlight diagnostic pitfalls in relying on family history and assumed inheritance traits. We emphasise the importance of segregation analysis and comprehensive genomic testing. Recognition of pseudodominance inheritance has important implications for genetic counselling, family planning and cascade testing.
Developmental epilepsy (DE) and developmental and epileptic encephalopathy (DEE) comprise neurodevelopmental disorders in which epilepsy occurs alongside developmental impairment of varying contributions from the underlying etiology and epileptic activity. Advances in genetic testing, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and chromosomal microarray analysis (CMA), have facilitated the identification of copy number variants (CNVs); however, data on CNV-associated epilepsy and neurodevelopmental disorders remain limited in Southeast Asia, including Indonesia. This retrospective case series describes the clinical and genetic characteristics of four Indonesian children across the DE–DEE spectrum with pathogenic CNVs identified at a tertiary referral hospital in Yogyakarta, Indonesia. Among 48 patients who underwent WES, CNVs were identified in five; four underwent further genetic characterization and were included in this case series, while one patient died before additional testing could be performed. Clinical manifestations included early-onset seizures, developmental delay or intellectual impairment, and abnormal EEG and/or neuroimaging findings. Genetic findings included a 2q24.3 deletion involving SCN1A in a patient with Dravet syndrome and 15q11.2–q13.1 deletions involving UBE3A in three patients with clinical features of Angelman syndrome. Confirmatory testing using WGS or CMA further characterized the identified CNVs. This case series expands the clinical and molecular data on pathogenic CNVs associated with pediatric epilepsy and neurodevelopmental disorders in an underrepresented Southeast Asian population and illustrates the complementary roles of sequencing and chromosomal analysis in genetic diagnosis.
