Characterization of intragenic tandem duplication in the PAFAH1B1 gene leading to isolated lissencephaly sequence

Background Genetic aberrations in PAFAH1B1 result in isolated lissencephaly sequence (ILS), a neuronal migration disorder associated with severe mental retardation and intractable epilepsy. Approximately 60 % of patients with ILS show a 17p13.3 deletion or an intragenic variation of PAFAH1B1 that can be identified by fluorescence in situ hybridization (FISH) analysis or gene sequencing. Using multiplex ligation-dependent probe amplification (MLPA), 40–80 % of the remaining patients show small genomic deletions or duplications of PAFAH1B1 . The intragenic duplications within PAFAH1B1 are predicted to abolish the PAFAH1B1 function, although a detailed characterization of the duplication regions have not been reported. Results Here we describe a female patient with ILS occurring predominantly in the posterior brain regions. MLPA was used to identify a small duplication within PAFAH1B1 . This result was confirmed by array-based comparative genomic hybridization analysis, revealing a duplication of the 29-kb region encompassing putative regulatory elements and exon 2 of PAFAH1B1 . The region was characterized as an intragenic tandem duplication by sequencing, revealing a 28-bp microhomology sequence at the breakpoint junctions. Parental genetic testing confirmed that the tandem duplication occurred de novo . Reverse transcription-PCR on RNA extracted from peripheral blood leukocytes revealed that the expression level of PAFAH1B1 decreased to that in a patient with Miller-Dieker syndrome, a contiguous gene-deletion disorder characterized by classical lissencephaly and a facial dysmorphism. Conclusions This study expanded the spectrum of PAFAH1B1 variants and identified a unique genomic architecture including microhomology sequences in PAFAH1B1 underlying an intragenic tandem duplication leading to ILS.