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


ABSTRACT:

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.

SUBMITTER: Xiao B 

PROVIDER: S-EPMC6785455 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Xiao Bing B   Wang Lili L   Liu Huili H   Fan Yanjie Y   Xu Yan Y   Sun Yu Y   Qiu Wenjuan W  

Molecular genetics & genomic medicine 20190827 10


<h4>Background</h4>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.<h4>Methods</h4>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 proband  ...[more]

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