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Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT-ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations.

To the Editor: We read with interest and much concern the recent recommendation of the College regarding carrier screening in individuals of Ashkenazi Jewish (AJ) descent (Genet Med 2008;10: 54 –56). Specifically, we felt that Recommendation 4, “if only one member of a couple is of AJ background, testing should still be offered,” is quite problematic. As stated in the Guidelines, the cumulative probability of being a carrier for one of the conditions in the panel is between 20 and 25%. One in 4 or 1 in 5 couples where only one member is of AJ descent will be identified as at increased risk to have an affected child and offered testing for that specific condition for the non-AJ partner. The screening of the non-AJ partner for the mutations that occur in the AJ population is an exercise in unknown probabilities (Table 1). Since the frequency of those mutations that occur more often in the AJ population is unknown in non-AJ populations, there is no way to revise a couple’s risk after screening the non-AJ member for the AJ mutations. Counseling a couple that the non-AJ member does not carry any of the AJ mutations does not provide much solace (or information) regarding their risk for a child with one of the AJ genetic conditions. In the case of cystic fibrosis (where gene frequencies are known in various populations) and in the case of Tay-Sachs disease (where enzyme analysis is informative regardless of ethnicity) the Practice Guidelines do provide useful information that would aid a family in their decision-making process. Even without testing the non-AJ member, counselors can be reassuring to those couples where the AJ member is a carrier for Dysautonomia, Bloom syndrome, or Mucolipidosis IV, as these conditions are either extremely rare or unreported in non-AJ populations. So the question remaining (with the exception of cystic fibrosis and Tay-Sachs screening) is what do we accomplish by the implementation of these Guidelines in couples where only one member is of AJ descent? Michael L. Begleiter, MS, CGC Janda L. Buchholz, MS, CGC Andrea M. Atherton, MS, CGC Lee Z. Mays, MS, CGC Molly M. Lund, MS, CGC Meghan E. Strenk, MS Genetics, Dysmorphology and Metabolism, The Children’s Mercy Hospitals & Clinics, Kansas City, Missouri, The University of Missouri-Kansas City, School of Medicine, Kansas City, Missouri