Abstract
Compound heterozygous (CH) variants occur when two recessive alleles are inherited and the variants are located at different loci within the same gene in a given individual. CH variants are important contributors to many different types of recessively inherited diseases. However, many studies overlook CH variants because identification of this type of variant requires knowing the parent of origin for each nucleotide. Using computational methods, haplotypes can be inferred using a process called “phasing,” which estimates the chromosomal origin of most nucleotides. In this paper, we used germline, phased, whole-genome sequencing (WGS) data to identify CH variants across seven pediatric diseases (adolescent idiopathic scoliosis: n = 16, congenital heart defects: n = 709, disorders of sex development: n = 79, ewing sarcoma: n = 287, neuroblastoma: n = 259, orofacial cleft: n = 107, and syndromic cranial dysinnervation: n = 172), available as parent-child trios in the Gabriella Miller Kids First Data Resource Center. Relatively little is understood about the genetic underpinnings of these diseases. We classified CH variants as “potentially damaging” based on minor allele frequencies (MAF), Combined Annotation Dependent Depletion scores, variant impact on transcription or translation, and gene-level frequencies in the disease group compared to a healthy population. For comparison, we also identified homozygous alternate (HA) variants, which affect both gene copies at a single locus; HA variants represent an alternative mechanism of recessive disease development and do not require phasing. Across all diseases, 2.6% of the samples had a potentially damaging CH variant and 16.2% had a potentially damaging HA variant. Of these samples with potentially damaging variants, the average number of genes per sample was 1 with a CH variant and 1.25 with a HA variant. Across all samples, 5.1 genes per disease had a CH variant, while 35.6 genes per disease had a HA variant; on average, only 4.3% of these variants affected common genes. Therefore, when seeking to identify potentially damaging variants of a putatively recessive disease, CH variants should be considered as potential contributors to disease development. If CH variants are excluded from analysis, important candidate genes may be overlooked.
Highlights
Each year in the United States, ∼3.0% of babies are born with a structural defect, and ∼11,050 children under the age of 15 are diagnosed with pediatric cancer (Lupo et al, 2019; American Cancer Society, 2020)
We focus on scenarios in which at least two alternate alleles occurred on different chromosomes in the same gene and/or locus; we assume the diseases follow an autosomal-recessive inheritance pattern in some cases and that these traits are subject to Mendelian inheritance
We included these variants in the analysis as a way to show how the number of samples and genes with potentially damaging homozygous alternate (HA) variants compares to the number of samples and genes with potentially damaging Compound heterozygous (CH) variants
Summary
Each year in the United States, ∼3.0% of babies are born with a structural defect, and ∼11,050 children under the age of 15 are diagnosed with pediatric cancer (Lupo et al, 2019; American Cancer Society, 2020). It has been shown that using a population-based, haplotype reference panel and/or trio-based samples can improve phasing as much as 10-fold (Choi et al, 2018); this process is computationally expensive, and current phasing algorithms require specific file formats or that reads be aligned to a specific reference genome and be free of multi-allelic positions. These requirements may deter some researchers from performing phasing—and identifying CH variants
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