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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.

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