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

<div><p>Context</p><p>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).</p><p>Objective</p><p>Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12.</p><p>Materials and Methods</p><p>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 <i>VDR</i> was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>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.</p></div

Genome-wide SNP Array Indicating Complete Maternal Isodisomy of Chromosome 12.

<p>B allele frequencies of chromosome 12 in the proband, the mother, and the father are shown. Allele segregation in the proband comprised AA (4,154 SNPs) and BB (4,742 SNPs) homozygotes only, and loss of heterozygosity (AB; 0 SNP). The parental allele segregation of chromosome 12 showed a heterozygous pattern. All other chromosomes had normal homo/heterozygous patterns. In the diagram for the proband, the pink spots (1,514 SNPs) represent SNPs identified as maternal, with no evidence of paternal SNPs (which would be blue).</p

After Treatment with High-dose Oral Calcium Supplementation.

<p>(A) Treatment course and laboratory data are shown. (B) Bone roentgenogram at 3 years and 8 months of age, showing markedly improved signs of rickets.</p

Sequence Analysis of the Common Target SNPs that Could Identify Parental Origin.

<p>Sequence Analysis of the Common Target SNPs that Could Identify Parental Origin.</p

<i>VDR</i> Analysis of the Proband and her Parents, with the Position of the Target SNPs on Chromosome 12.

<p>(A) Proband pedigree with chromatograms of the <i>VDR</i> mutation. The <i>VDR</i> 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.</p

Additional file 1: of Development of waist circumference percentiles for Japanese children and an examination of their screening utility for childhood metabolic syndrome: a population-based cross-sectional study

Table S1. Box–Cox values for power (L), adjusted mean (M), and coefficient of variation (S) of WC for the Japanese children of boys and girls from 4.50 to 12.75 years of age. Table S2. Box–Cox values for power (L), adjusted mean (M), and coefficient of variation (S) of WC/Ht for the Japanese children of boys and girls from 4.50 to 12.75 years of age. (DOCX 179 kb