Eldomery-Sutton syndrome

Description of the human clinical phenotype of an autosomal recessive neuromuscular disorder caused by deficiency of the mitochondrial intermediate presequence protease (MIP), encoded by the gene MIPEP, was first reported by lead author Mohammad Eldomery and senior corresponding author V. Reid Sutton in 2016 in the journal Genome Medicine. The index subject was diagnosed with left ventricular non-compaction cardiomyopathy (LVNC) and Wolf-Parkinson-White syndrome at 5 1/2 months of age. In an attempt to identify the etiology of this cardiac phenotype, a series of tests were performed, including clinical whole exome sequencing. Because the clinical diagnostic laboratory did not identify pathogenic variants in known disease-associated genes, re-analysis of the exome data was performed by Dr. Mohammad Eldomery as part of the Baylor-Johns Hopkins Center for Mendelian Genomics. Biallelic variants were identified in the MIPEP gene, which was known in yeast and other organisms to be important in mitochondrial protein processing. Because LVNC is seen in other mitochondrial disorders, this was considered the best candidate gene. After interrogating the Baylor Genetic Laboratory clinical database and submitting the MIPEP gene to GeneMatcher, four other affected individuals from three families were identified with biallelic variants in MIPEP. In all cases, the phenotype is LVNC with severe hypotonia and developmental delay. All of the affected individuals, with the exception of the index case, died before 2 years of age from cardiac failure. Seizures and cataracts were also noted in some of the affected individuals. The MIPEP variants included missense variants, stop variants as well as a 1.4 Megabase deletion involving the MIPEP gene. Confirmation of the pathogenicity of these variants in MIPEP was performed in a yeast model system by Nora Vögtle and Chris Meisinger at the University of Freiburg, Germany.^[1]

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