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The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile‐onset epilepsy was noted in 81% of these families (61/74). Fifty‐five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single‐nucleotide variants/small insertion‐deletions, 1 (2%) copy‐number variant, and 1 (2%) triplet‐repeat expansion in 53 epilepsy‐associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty‐one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence. [ABSTRACT FROM AUTHOR]

The evolutionarily conserved mevalonate pathway plays an important role in the synthesis of cholesterol and isoprenoid compounds. Mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) enzymes regulate key rate‐limiting steps in this pathway by sequentially phosphorylating mevalonic acid to yield downstream metabolites that regulate protein prenylation and cell signaling. Biallelic pathogenic variants in MVK cause a spectrum of rare autoinflammatory disorders that encompass milder forms of hyper‐IgD syndrome (HIDS) at one end and the more severe mevalonic aciduria on the other. In contrast, pathogenic variants reported in PMVK are heterozygous and associated with porokeratosis, a skin disorder with no systemic manifestations. Recently, biallelic variants in PMVK were reported as a cause for an autoinflammatory disorder for the first time in two unrelated patients. In this study, we describe a child with recurrent arthritis and a HIDS‐like phenotype harboring a novel homozygous variant c.398 C>T (p.Ala133Val) in PMVK. Mononuclear cells isolated from the patient showed significantly elevated production of interleukin 1β, a key cytokine that shapes the inflammatory response in HIDS. Protein modeling studies suggested potential defects in PMVK enzyme activity. These results posit a further expanding of the genotypic spectrum of autoinflammatory disease to include biallelic PMVK variants. [ABSTRACT FROM AUTHOR]

Heterozygous disease‐causing variants in BCL11B are the basis of a rare neurodevelopmental syndrome with craniofacial and immunological involvement. Isolated craniosynostosis, without systemic or immunological findings, has been reported in one of the 17 individuals reported with this disorder till date. We report three additional individuals harboring de novo heterozygous frameshift variants, all lying in the exon 4 of BCL11B. All three individuals presented with the common findings of this disorder i.e. developmental delay, recurrent infections with immunologic abnormalities and facial dysmorphism. Notably, craniosynostosis of variable degree was seen in all three individuals. We, thus add to the evolving genotypes and phenotypes of BCL11B‐related BAFopathy and also review the clinical, genomic spectrum along with the underlying disease mechanisms of this disorder. [ABSTRACT FROM AUTHOR]

The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly. Using structural molecular modelling and functional testing of the variants in a cell-based Saccharomyces cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly. [ABSTRACT FROM AUTHOR]

Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders. [ABSTRACT FROM AUTHOR]

Objective: To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization. Methods: A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype–based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES. Results: In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype‐phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies. Conclusion: Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype‐phenotype associations in perinatal cohorts undergoing ES. What's already known about this topic Exome sequencing has a variable diagnostic yield of 6% to 80% in fetuses with abnormal perinatal phenotypes.There are various challenges in clinical translation of this technology.ES also helps in identification of novel Mendelian phenotypes and expansion of prenatal phenotypes of known disorders. What this study adds Careful selection of cases and robust bioinformatics analysis is important for improving diagnostic yield of ES for perinatal phenotypes.Interpretation of ES results may be erroneous on basis of prenatal findings alone.Deep phenotyping by postnatal evaluation is essential for gene discovery and prenatal phenotype expansion. [ABSTRACT FROM AUTHOR]

Several genetic disorders are associated with either a permanent deficit or a delay in central nervous system myelination. We investigated 24 unrelated families (25 individuals) with deficient myelination after clinical and radiological evaluation. A combinatorial approach of targeting and/or genomic testing was employed. Molecular diagnosis was achieved in 22 out of 24 families (92%). Four families (4/9, 44%) were diagnosed with targeted testing and 18 families (18/23, 78%) were diagnosed using broad genomic testing. Overall, 14 monogenic disorders were identified. Twenty disease-causing variants were identified in 14 genes including PLP1, GJC2, POLR1C, TUBB4A, UFM1, NKX6-2, DEGS1, RNASEH2C, HEXA, ATP7A, SETBP1, GRIN2B, OCLN, and ZBTB18. Among these, nine (45%) variants are novel. Fourteen families (82%, 14/17) were diagnosed using proband-only exome sequencing (ES) complemented with deep phenotyping, thus highlighting the utility of singleton ES as a valuable diagnostic tool for identifying these disorders in resource-limited settings., (© 2024 Wiley Periodicals LLC.)