Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome

Anju Shukla, Malavika Hebbar, Anshika Srivastava, Rajagopal Kadavigere, Priyanka Upadhyai, Anil Kanthi, Oliver Brandau, Stephanie Bielas, Katta M Girisha

The iron-sulfur (Fe-S) cluster (ISC) biogenesis pathway is indispensable for many fundamental biological processes and pathogenic variations in genes encoding several components of the Fe-S biogenesis machinery, such as NFU1, BOLA3, IBA57 and ISCA2 are already implicated in causing four types of multiple mitochondrial dysfunctions syndromes (MMDS). We report on two unrelated families, with two affected children each with early onset neurological deterioration, seizures, extensive white matter abnormalities, cortical migrational abnormalities, lactic acidosis and early demise. Exome sequencing of two affected individuals, one from each family, revealed a homozygous c.259G>A [p.(Glu87Lys)] variant in ISCA1 and Mendelian segregation was confirmed in both families. The ISCA1 variant lies in the only shared region of homozygosity between the two families suggesting the possibility of a founder effect. In silico functional analyses and structural modeling of the protein predict the identified ISCA1 variant to be detrimental to protein stability and function. Notably the phenotype observed in all affected subjects with the ISCA1 pathogenic variant is similar to that previously described in all four types of MMDS. Our findings suggest association of a pathogenic variant in ISCA1 with another MMDS.Journal of Human Genetics advance online publication, 30 March 2017; doi:10.1038/jhg.2017.35.