Identification of EXOSC9 Variants
SNP array testing in individual 1:II-1 revealed one isolated long contiguous stretch of homozygosity of approximately 14.0 Mb on chromosome 4 (117,649,360–131,644,865). Exome sequencing identified a rare homozygous variant, c.41T>C (p.Leu14Pro), in EXOSC9 (MIM: 606180; GenBank: NG_029848.1) within the region of homozygosity. This mutation is predicted to cause a disruption in the first alpha helix of EXOSC9.41 The parents of individual 1:II-1 were found to be heterozygous for the variant, consistent with autosomal-recessive inheritance (Figure 1B). The variant is a rare SNP (dbSNP: rs139632595) and has been reported six times in heterozygous state in the ExAC Browser in individuals from African descent with an allele frequency of 4.947 × 10−5. This variant was neither reported in individuals from Hispanic descent nor found in a homozygous state.
WES of individual 2:II-1 revealed the same c.41T>C variant as in individual 1:II-1 in compound heterozygosity with a EXOSC9 c.481C>T variant that leads to a premature stop of the protein (p.Arg161∗). The c.481C>T variant was listed three times in the ExAC Browser in the heterozygous state. To exclude variants in genes that are known to be associated with either SMA or with muscle diseases, we specifically screened the variant VCF files for variants therein but found none. Sanger sequencing confirmed compound heterozygosity (Figure 1).
Individuals 3:II-1 and 4:II-1 were subsequently identified to carry the same EXOSC9 c.41T>C in homozygosity.