Novel frameshift mutation in LIS1 gene is a probable cause of lissencephaly: a case report

Abstract

Background Lissencephaly (LIS) is a cortical malformation, characterized by smooth or nearly smooth cerebral surface and a shortage of gyral and sulcal development, which is caused by deficient neuronal migration during embryogenesis. Neuronal migration involves many gene products, among which is the product of the PAFAH1B1 gene, associated with this disease. LIS is a rare disease, characterized by low population frequency, and with non-specific clinical symptoms such as early epilepsy, developmental delay or cerebral palsy-like motor problems. Given that high-throughput sequencing techniques have been improving diagnosis, we have chosen this technique for addressing this patient. Case presentation We present the case of a seven years old male patient with an undiagnosed rare disease, with non-specific clinical symptoms possibly compatible with lissencephaly. The patient was enrolled in a study that included the sequencing of his whole genome. Sequence data was analyzed following a bioinformatic pipeline. The variants obtained were annotated and then subjected to different filters for prioritization. Also mitochondrial genome was analyzed. A novel candidate frameshift insertion in known PAFAH1B1 gene was found, explaining the index case phenotype. The assessment through in silico tools reported that it causes nonsense mediated mechanisms and that it is damaging with high confidence scores. The insertion causes a change in the reading frame, and produces a premature stop codon, severely affecting the protein function and probably the silencing of one allele. The healthy mother did not carry the mutation, and the unaffected father was not available for analysis. Conclusions Through this work we found a novel de novo mutation in LIS1/PAFAH1B1 gene, as a likely cause of a rare disease in a young boy with non-specific clinical symptoms. The mutation found correlates with the phenotype studied since the loss of function in the gene product has already been described in this condition. Since there are no other variants in the PAFAH1B1 gene with low population frequency and due to family history, a de novo disease mechanism is proposed.

Clinical Characteristics Suggestive of a Genetic Cause in Cerebral Palsy: A Systematic Review

“…After initial screening, 134 articles were included for data extraction and analysis based on full-text review. [66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146]…”

14‐3‐3 Family of Proteins: Biological Implications, Molecular Interactions, and Potential Intervention in Cancer, Virus and Neurodegeneration Disorders

“…LIS, also known as Agyria and Pachygyria, is a rare spectrum of malformed cortical development ranging from broad or absent cerebral convolutions (gyri), shallow grooves (sulci) or abnormal cortex and cortical structures [166][167][168]. LIS is well characterised by psychomotor impairment, muscle spasticity, seizures and developmental delays [169]. There are more than 20 types of LIS that can be separated into two categories, namely classical lissencephaly (Type I) or cobblestone lissencephaly (Type II) [170].…”

Role of Physiotherapy in Pediatric Lissencephaly: A Case Report and Therapeutic Insights

“…The genetic factors known to cause lissencephaly are DCX (double cortin), gene TUBA1A (tubulin alpha 1a), ACTB (actin beta), ACTG1 (actin gamma 1), and ARX (aristaless-related homeobox). In recent years, the development of advanced molecular genomics technologies has led to the discovery of numerous additional genes [ 5 ].…”