Uniparental isodisomy caused autosomal recessive diseases: NGS-based analysis allows the concurrent detection of homogenous variants and copy-neutral loss of heterozygosity.

Background Uniparental disomy (UPD) leading to autosomal recessive (AR) diseases is rare. We found an unusual homozygous state in two nonconsanguineous families, and only one parent in each family was a heterozygote. Methods Two patients with homozygosity for pathogenic variants were revealed by whole-exome sequencing (WES), further Sanger sequencing found that only one of the parents was a heterozygote. Initial genotype and copy number variations analysis from WES data of probands involving whole chromosomes 1 and 9 containing these two pathogenic variants were performed, genome-wide single-nucleotide polymorphism (SNP) array analysis was used to confirm these results. Results Whole-exome sequencing identified a homozygous c.3423_3424delTG mutation in AGL in patient 1 and a homozygous c.241-1G>C mutation in SURF1 in patient 2. Further parental testing found that only the two patients' healthy fathers were heterozygous. WES-based copy number and genotype analysis found a copy-neutral loss of heterozygosity (LOH) of whole chromosome 1 in patient 1 and of whole chromosomes 9 and 10 in patient 2. Further genome-wide SNP array and family haplotype analyses confirmed whole paternal uniparental isodisomy (UPiD) 1 in patient 1 and paternal UPiD 9 and maternal UPiD 10 in patient 2. Therefore, UPiD caused AR monogenic glycogen storage disease type-III (GSDIII) in patient 1 and Leigh syndrome in patient 2 through non-Mendelian inheritance of two mutant copies of a gene from each patient's father. Conclusion Our report highlights that a single NGS-based analysis could allow us to find homozygous sequence variants and copy-neutral LOH in such cases. Our report also describes the first case of GSDIII caused by UPiD 1 and Leigh syndrome caused by UPiD 9.