First characterization of a large deletion of the PDHA1 gene

Pyruvate dehydrogenase complex (PDC) deficiency is one of the major recognized causes of congenital lactic acidosis. The most common form is due to PDHA1 gene (Xp22.12) defects. Here, we report the case of a Polynesian girl presenting with delayed neurological development, cortical atrophy, and posterior corpus callosum agenesis. Elevated lactate and pyruvate levels in blood and cerebrospinal fluid suggested PDC deficiency. However, PDC activity was within the normal range in lymphocytes and the direct sequencing of the 11 exons and intron-exon junctions of the PDHA1 gene did not show any changes. Long-range PCR amplification of the whole gene (16 kb) from blood DNA revealed a heterozygous deletion of ≈4.2 kb. Fine mapping of the deletion breakpoint was achieved using purified long-range PCR products for restriction enzyme analysis and direct sequencing. The deletion removed a 4227 bp region covering part of intron 5 to part of intron 9 [g.10145_14371del4227]. The deletion breakpoint contained a short direct repeat (GTAG), which may be derived either from the upstream or the downstream homologous sequence. The presence of a GAG triplet and inverted repeats in the vicinity of the deletion suggest replication slippage at a polymerase α arrest site. This is the first time that a large intragenic deletion of the PDHA1 gene has been characterized.