Heterozygous structural variation mimicking homozygous missense mutations in NEU1 associated with presenting clinical signs in eyes alone

ABSTRACT Introduction Biallelic mutations in neuraminidase 1 (NEU1) are associated with cherry-red spots. Whole genome sequencing contributes to eliminating pseudo-homozygous mutations when large-scale deletion of one allele in NEU1 and other genes occurs. Patients and methods Bilateral cherry-red spots in the macula were the only detectable sign in an 11-year-old girl with reduced visual acuity over the last two years. Targeted exome sequencing of genes for inherited eye diseases identified a homozygous c.544A>G (p.Ser182Gly) variation in the NEU1 gene. This variant was also present in her mother in the heterozygous state but not in her father. Whole genome sequencing identified a heterozygous 27.5 kb deletion involving the whole coding exons of NEU1 in her father. Sanger sequencing disclosed the breakpoint of the deletion. This heterozygous deletion was also detected in the patient, so the c.544A>G mutation should be heterozygous in the patient. Conclusion The results of this case remind us of the limitations of routine exome sequencing and the need to perform segregation studies and deletion/duplication analysis or WGS if parental studies do not support exome findings. In addition, patients with sialidosis may present with ocular manifestations without systemic signs early in the disease course.