Ethylmalonic Encephalopathy via the ETHE1 Gene

Ethylmalonic encephalopathy (OMIM #602473) is an infantile metabolic disorder affecting brain, gastrointestinal tract, and peripheral vessels (Tiranti et al. Am J Hum Genet 74(2):239-252, 2004; Tiranti et al. J Med Genet 43(4):340-346, 2006). Affected children have neurodevelopmental delay and regression, recurrent petechiae, orthostatic acrocyanosis, prominent pyramidal and extrapyramidal signs, and chronic diarrhea. The main neuropathological features of the disease are symmetrical necrotic lesions in the deep gray matter structures. Ethylmalonic acid levels are increased in body fluids and cytochrome c oxidase activity is decreased in skeletal muscle. Death occurs in the first decade of life. This disease has been mainly found in children of Mediterranean or Arab descent.

Ethylmalonic encephalopathy is an autosomal recessive disorder caused by defects in the ETHE1 gene (Tiranti et al., 2004; Tiranti et al., 2006). ETHE1 has 7 exons that encode a sulfur dioxygenase, which is a member of the sulphide detoxification pathway and is important in mitochondrial homeostasis and energy metabolism. Genetic defects located throughout the ETHE1 gene include missense, nonsense, splicing mutations and small deletion/insertions (Tiranti et al., 2004; Tiranti et al., 2006). Gross deletions within the ETHE1 gene are common, accounting for approximately 20% of pathogenic alleles. In particular, deletion of exon 4 has been most frequently reported (Tiranti et al., 2004; Tiranti et al., 2006; Drousiotou et al. Clin Genet 79(4):385-390, 2011).

Approximately 75-80% of ETHE1 mutations have been identified via Sanger sequencing of coding exons and flanking sequences (Tiranti et al. J Med Genet 43(4):340-346, 2006; Mineri et al. J Med Genet 45(7):473-478, 2008).

This test provides full coverage of all coding exons of the ETHE1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.