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

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.

Lissencephaly, abnormal genitalia and refractory epilepsy: case report of XLAG syndrome / Lisencefalia, genitália ambígua e epilepsia refratária: relato de caso da síndrome XLAG

INTRODUCTION: X-linked lissencephaly with ambiguous genitalia (XLAG) is a recently described genetic disorder caused by mutation in the aristaless-related homeobox (ARX) gene (Xp22.13). Patients present with lissencephaly, agenesis of the corpus callosum, refractory epilepsy of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia. CASE REPORT: Second child born to healthy nonconsanguineous parents, presented with seizures within the first hour of life that remained refractory to phenobarbital, phenytoin and midazolam. Examination identified microcephaly, axial hypotonia, pyramidal signs and ambiguous genitalia. EEG showed disorganized background activity and seizures starting at the right midtemporal, central and occipital regions. MRI showed diffuse pachygyria, moderate thickening of the cortex, enlarged ventricles, agenesis of the corpus callosum and septum pellucidum. Karyotype showed a 46,XY genotype. Additional findings were hypercalciuria, vesicoureteral reflux, patent ductus arteriosus and chronic diarrhea.

INTRODUÇÃO: Lisencefalia com genitália ambígua ligada ao X (XLAG) é doença genética recentemente descrita, causada por mutação no gene aristaless-related homeobox (ARX) (Xp22.13). Os pacientes apresentam lisencefalia, agenesia de corpo caloso, epilepsia refratária com início no período neonatal, microcefalia adquirida e genótipo masculino com genitália ambígua. RELATO DE CASO: Segundo filho de pais não-consangüíneos, apresentou crises na primeira hora de vida que permaneceram refratárias a fenobarbital, fenitoína e midazolam. Apresentava microcefalia, hipotonia axial, sinais de liberação piramidal e genitália ambígua. EEG demonstrou atividade de base desorganizada, crises convulsivas com início nas regiões temporal-média, central e occipital direitas. RNM demonstrou paquigiria difusa, moderado espessamento do córtex, ventrículos aumentados, agenesia de corpo caloso e septo pelúcido. Cariótipo evidenciou genótipo 46,XY. Achados adicionais foram: hipercalciúria, refluxo vésico-ureteral, ducto arterioso persistente e diarréia crônica.

Lissencephaly, abnormal genitalia and refractory epilepsy: case report of XLAG syndrome.

INTRODUCTION: X-linked lissencephaly with ambiguous genitalia (XLAG) is a recently described genetic disorder caused by mutation in the aristaless-related homeobox (ARX) gene (Xp22.13). Patients present with lissencephaly, agenesis of the corpus callosum, refractory epilepsy of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia. CASE REPORT: Second child born to healthy nonconsanguineous parents, presented with seizures within the first hour of life that remained refractory to phenobarbital, phenytoin and midazolam. Examination identified microcephaly, axial hypotonia, pyramidal signs and ambiguous genitalia. EEG showed disorganized background activity and seizures starting at the right midtemporal, central and occipital regions. MRI showed diffuse pachygyria, moderate thickening of the cortex, enlarged ventricles, agenesis of the corpus callosum and septum pellucidum. Karyotype showed a 46,XY genotype. Additional findings were hypercalciuria, vesicoureteral reflux, patent ductus arteriosus and chronic diarrhea.