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Copy number variations in a population with prune belly syndrome.

ABSTRACT: Prune Belly Syndrome (PBS) is a congenital multisystem myopathy with mild to lethal severity. While of uncertain etiology, 95% male predominance and familial occurrence suggest a genetic basis. As copy number variations (CNVs) can cause unexplained genetic disorders, we tested for novel CNVs in a large PBS population. We genotyped 21 unrelated PBS patients by high-resolution array comparative genomic hybridization (aCGH) and phenotyped using a novel PBS severity scoring system. Available parents were screened for detected CNV via quantitative PCR (qPCR). We additionally screened for recurrence of identified novel candidate CNVs on 106 PBS probands by qPCR. We identified 10 CNVs in 8 of 21 PBS patients tested (38%). Testing confirmed inheritance from an unaffected biological parent in six patients; parental samples were unavailable in two probands. One candidate CNV includes duplication of the X-chromosome AGTR2 gene, known to function in urinary tract development. Subsequent screening of the larger PBS cohort did not identify any recurrent CNVs. Presence of CNV did not correlate with PBS severity scoring. CNVs were uncommon in this large PBS population, but analysis of identified variants may inform disease pathogenesis and reveal targets for therapeutic intervention for this rare, severe disorder.

SUBMITTER: Iqbal NS

PROVIDER: S-EPMC6289753 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Copy number variations in a population with prune belly syndrome.

Iqbal Nida S NS Jascur Thomas A TA Harrison Steven S Chen Catherine C Arevalo Michelle K MK Wong Daniel D Sanchez Emma E Grimsby Gwen G Wilson Kathleen K Baker Linda A LA

American journal of medical genetics. Part A 20181004 11

Prune Belly Syndrome (PBS) is a congenital multisystem myopathy with mild to lethal severity. While of uncertain etiology, 95% male predominance and familial occurrence suggest a genetic basis. As copy number variations (CNVs) can cause unexplained genetic disorders, we tested for novel CNVs in a large PBS population. We genotyped 21 unrelated PBS patients by high-resolution array comparative genomic hybridization (aCGH) and phenotyped using a novel PBS severity scoring system. Available parents ...[more]

PMID: 30285310

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Project description:BackgroundThe populations of the Arabian Peninsula remain the least represented in public genetic databases, both in terms of single nucleotide variants and of larger genomic mutations. We present the first high-resolution copy number variation (CNV) map for a Gulf Arab population, using a hybrid approach that integrates array genotyping intensity data and next-generation sequencing reads to call CNVs in the Qatari population.MethodsCNVs were detected in 97 unrelated Qatari individuals by running two calling algorithms on each of two primary datasets: high-resolution genotyping (Illumina Omni 2.5M) and high depth whole-genome sequencing (Illumina PE 100bp). The four call-sets were integrated to identify high confidence CNV regions, which were subsequently annotated for putative functional effect and compared to public databases of CNVs in other populations. The availability of genome sequence was leveraged to identify tagging SNPs in high LD with common deletions in this population, enabling their imputation from genotyping experiments in the future.ResultsGenotyping intensities and genome sequencing data from 97 Qataris were analyzed with four different algorithms and integrated to discover 16,660 high confidence CNV regions (CNVRs) in the total population, affecting ~28 Mb in the median Qatari genome. Up to 40% of all CNVs affected genes, including novel CNVs affecting Mendelian disease genes, segregating at different frequencies in the 3 major Qatari subpopulations, including those with Bedouin, Persian/South Asian, and African ancestry. Consistent with high consanguinity levels in the Bedouin subpopulation, we found an increased burden for homozygous deletions in this group. In comparison to known CNVs in the comprehensive Database of Genomic Variants, we found that 5% of all CNVRs in Qataris were completely novel, with an enrichment of CNVs affecting several known chromosomal disorder loci and genes known to regulate sugar metabolism and type 2 diabetes in the Qatari cohort. Finally, we leveraged the availability of genome sequence to find suitable tagging SNPs for common deletions in this population.ConclusionWe combine four independently generated datasets from 97 individuals to study CNVs for the first time at high-resolution in a Gulf Arab population.

Dataset Information

Copy number variations in a population with prune belly syndrome.

Publications

Copy number variations in a population with prune belly syndrome.

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