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Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array.

Tamura M, Isojima T, Kawashima M, Yoshida H, Yamamoto K, Kitaoka T, Namba N, Oka A, Ozono K, Tokunaga K, Kitanaka S - PLoS ONE (2015)

Bottom Line: She was successfully treated with high-dose oral calcium.Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders.Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

ABSTRACT

Context: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD).

Objective: Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12.

Materials and methods: A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.

Results: The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium.

Conclusions: This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

No MeSH data available.


Related in: MedlinePlus

VDR Analysis of the Proband and her Parents, with the Position of the Target SNPs on Chromosome 12.(A) Proband pedigree with chromatograms of the VDR mutation. The VDR analysis showed a homozygous Arg73Ter mutation in the proband, a heterozygous mutation in the mother, and no mutation in the father. Mutations were checked by bidirectional sequencing. A black symbol indicates the proband, a dot symbol indicates a carrier, a square indicates a male, and a circle indicates a female. (B) Diagram of the VDR protein and gene, and chromosome 12 with positions of the mutation and the sequence-analyzed SNPs. The nonsense mutation, Arg73Ter, is located in the DNA binding domain of the VDR protein in exon 4. The indicated common SNPs were analyzed in the family; vWA indicates the position of a marker included in the STR analysis.
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pone.0131157.g002: VDR Analysis of the Proband and her Parents, with the Position of the Target SNPs on Chromosome 12.(A) Proband pedigree with chromatograms of the VDR mutation. The VDR analysis showed a homozygous Arg73Ter mutation in the proband, a heterozygous mutation in the mother, and no mutation in the father. Mutations were checked by bidirectional sequencing. A black symbol indicates the proband, a dot symbol indicates a carrier, a square indicates a male, and a circle indicates a female. (B) Diagram of the VDR protein and gene, and chromosome 12 with positions of the mutation and the sequence-analyzed SNPs. The nonsense mutation, Arg73Ter, is located in the DNA binding domain of the VDR protein in exon 4. The indicated common SNPs were analyzed in the family; vWA indicates the position of a marker included in the STR analysis.

Mentions: Sequencing the VDR in the patient revealed a single homozygous base pair substitution, c.217C>A (Fig 2A). This substitution was predicted to result in a nonsense mutation p.Arg73Ter, which is a premature stop codon in the DBD (Fig 2B). This mutation has been reported in 5 other patients with HVDRR and is functionally inactive [15–18]. From these findings, we considered that HVDRR in this patient was caused by a homozygous nonsense mutation in the VDR.


Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array.

Tamura M, Isojima T, Kawashima M, Yoshida H, Yamamoto K, Kitaoka T, Namba N, Oka A, Ozono K, Tokunaga K, Kitanaka S - PLoS ONE (2015)

VDR Analysis of the Proband and her Parents, with the Position of the Target SNPs on Chromosome 12.(A) Proband pedigree with chromatograms of the VDR mutation. The VDR analysis showed a homozygous Arg73Ter mutation in the proband, a heterozygous mutation in the mother, and no mutation in the father. Mutations were checked by bidirectional sequencing. A black symbol indicates the proband, a dot symbol indicates a carrier, a square indicates a male, and a circle indicates a female. (B) Diagram of the VDR protein and gene, and chromosome 12 with positions of the mutation and the sequence-analyzed SNPs. The nonsense mutation, Arg73Ter, is located in the DNA binding domain of the VDR protein in exon 4. The indicated common SNPs were analyzed in the family; vWA indicates the position of a marker included in the STR analysis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496068&req=5

pone.0131157.g002: VDR Analysis of the Proband and her Parents, with the Position of the Target SNPs on Chromosome 12.(A) Proband pedigree with chromatograms of the VDR mutation. The VDR analysis showed a homozygous Arg73Ter mutation in the proband, a heterozygous mutation in the mother, and no mutation in the father. Mutations were checked by bidirectional sequencing. A black symbol indicates the proband, a dot symbol indicates a carrier, a square indicates a male, and a circle indicates a female. (B) Diagram of the VDR protein and gene, and chromosome 12 with positions of the mutation and the sequence-analyzed SNPs. The nonsense mutation, Arg73Ter, is located in the DNA binding domain of the VDR protein in exon 4. The indicated common SNPs were analyzed in the family; vWA indicates the position of a marker included in the STR analysis.
Mentions: Sequencing the VDR in the patient revealed a single homozygous base pair substitution, c.217C>A (Fig 2A). This substitution was predicted to result in a nonsense mutation p.Arg73Ter, which is a premature stop codon in the DBD (Fig 2B). This mutation has been reported in 5 other patients with HVDRR and is functionally inactive [15–18]. From these findings, we considered that HVDRR in this patient was caused by a homozygous nonsense mutation in the VDR.

Bottom Line: She was successfully treated with high-dose oral calcium.Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders.Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

ABSTRACT

Context: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD).

Objective: Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12.

Materials and methods: A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.

Results: The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium.

Conclusions: This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

No MeSH data available.


Related in: MedlinePlus