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.

Keywords: Case report; Lissencephaly; Novel mutation; PAFAH1B1; Rare disease; Whole-genome sequencing.

Fig. 1

MRI results. A Volumetric T1 brain MRI axial and B Sagittal planes show a diffuse lissencephaly-pachygyria spectrum predominantly in the posterior areas methylation study for Angelman syndrome was normal and the sequencing of ARX and MECP2 showed no pathogenic mutations

Fig. 2

Variant impact at genome and protein level. A IGV view of the reads mapping onto the gene PAFAH1B1. The gene’s structure is shown on top and the exon, where the mutation is located is marked with an asterisk. The reads are shown in gray and the Insertion is marked in violet. The inserted G is shown on top of the reference genome. The originated premature stop codon is also marked. B Sanger sequencing of the variant in mother (top) and patient (bottom). Mother presents no variant, while patient variant was confirmed. C Top view of the truncated LIS1 beta propeller in orange. The C-terminal region of 27 residues introduced between the frameshift and the stop codon is painted in red. For reference, the wild-type crystal structure of LIS1 (PDB access code 1VYH) is shown superimposed as a transparent grey cartoon. Also, eight crucial interacting residues  are indicated in atom sticks, completely absent from the hypothetical truncated LIS1