AI Article Synopsis

  • Neurodevelopmental disorders (NDD) are conditions that disrupt nervous system development, with epilepsy being a common feature among them.
  • The study involved eight consanguineous families in Pakistan with recessively inherited NDD and epilepsy, utilizing MRI, EEG, and exome sequencing to analyze genetic variants associated with the disorders.
  • Findings included the identification of four novel genetic variants linked to NDD and epilepsy, with implications for treatment and better understanding of the disorders in these families.

Article Abstract

Introduction: Neurodevelopmental disorders (NDD) are a diverse group of disorders that affect the development of the nervous system. Epilepsy is a common phenotypic aspect of NDD.

Methods: We recruited eight consanguineous families from Pakistan which segregated recessively inherited NDD with epilepsy. Magnetic Resonance imaging (MRI) and Electroencephalogram (EEG) were completed. Exome sequencing was carried out for selected participants from each family. The exome data were analyzed for exonic and splice-site variants that had allele frequencies of less than 0.01 in public databases.

Results: Clinical investigations determined that developmental delay, intellectual disability and seizures were manifested by most patients in early childhood. EEG findings were abnormal in the participants of four families. MRI revealed demyelination orcerebral atrophic changes in multiple participants. We identified four novel homozygous variants including nonsense andmissense variants in OCLN, ALDH7A1, IQSEC2 and COL3A1, segregating with the phenotypes in the participants of four families. Previously reported homozygous variants of CNTNAP2, TRIT1 and NARS1 were found in individuals from three families. Clinical utility was observed in directing treatment in case of patients with an ALDH7A1 variant which included pyridoxine administration and enabling accurate counseling about the natural history and recurrence risk.

Conclusion: Our results add to the clinical and molecular delineation of very rare NDD with epilepsy. The high success rate of exome sequencing is likely attributable to the expectation of homozygous variants in patients of consanguineous families, and in one case, the availability of positional mapping data that greatly aided the variant prioritization.

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Source
http://dx.doi.org/10.1016/j.gene.2023.147599DOI Listing

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