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.