French-Canadian type of Leigh syndrome via the LRPPRC Gene

The French-Canadian type of Leigh syndrome (LSFC; OMIM #220111), also called Saguenay-Lac-St-Jean cytochrome c oxidase deficiency (SLSJ-COX), is an infantile neurologic disorder characterized by acute severe lactic acidosis (Morin et al. Am J Hum Genet 53(2):488-496, 1993; Mootha et al. Proc Natl Acad Sci U S A 100(2):605-610, 2003; Debray et al. J Med Genet 48(3):183-189, 2011). Affected children have developmental delay of psychomotor skills, characteristic facial appearance, mental retardation, hypotonia, ataxia, and the development of lesions in the brainstem and basal ganglia. Approximately 90% of patients had metabolic and/or neurological acute crises and 82% of patients died at a median age of 1.6 years (Debray et al., 2011). This disease is clinically distinct from SURF1-caused Leigh syndrome and has been strictly found in patients from the Saguenay-Lac-St-Jean region, a genetic isolate in northern Québec, Canada.

The French-Canadian type of Leigh syndrome is an autosomal recessive disorder caused by defects in the LRPPRC gene (Mootha et al., 2003; Debray et al., 2011). LRPPRC has 38 exons that encode a leucine-rich protein, which localizes primarily to mitochondria and may play a role in mRNA processing in both the nucleus and mitochondrion. So far, only two LRPPRC mutations have been reported to cause the disease: c.1061C>T (p.A354V), which accounted for all but one of pathogenic alleles; and c.3830_3839delins10 (p.C1277Xdel8). 55 of 56 patients were homozygous for c.1061C>T and the remaining patient was compound heterozygous for both mutations (Debray et al., 2011). The carrier frequency in the population of Saguenay-Lac-St-Jean is about 1 in 25 (De Braekeleer et al. Hum Hered 41(3):141-146, 1991; Morin et al., 1993).

So far, only two LRPPRC mutations have been reported to cause the disease: c.1061C>T (p.A354V), which accounted for all but one of pathogenic alleles; and c.3830_3839delins10 (p.C1277Xdel8). 55 of 56 patients were homozygous for c.1061C>T and the remaining patient was compound heterozygous for both mutations (Debray et al. J Med Genet 48(3):183-189, 2011).

This test provides full coverage of all coding exons of the LRPPRC gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.