Identification of a Novel IQCE Large Deletion through Copy Number Variant Analysis from Whole-Exome Sequencing Data of a Patient with Postaxial Polydactyly Type A7

Abstract

<b><i>Introduction:</i></b> Non-syndromic polydactyly has been associated with pathogenic variants in 11 genes until today, including <i>IQCE</i> gene. More precisely, loss-of-function of <i>IQCE</i> is associated with the autosomal recessive disorder postaxial polydactyly type A7 (PAPA7, MIM #617642). <b><i>Case Presentation:</i></b> A 3-year-old female patient was referred to our genetics department with postaxial polydactyly, syndactyly, brachydactyly, and hypoplastic teeth. Through whole-exome sequencing (WES), a pathogenic <i>IQCE</i> variant was identified (c.895_904del) in the homozygous state, which adequately explained the disease phenotype of our patient. However, copy number variant (CNV) analysis from WES data, using ExomeDepth, revealed a novel, likely pathogenic large deletion involving <i>IQCE</i> genomic regions (DEL:chr7:2606751_2641098) encompassing exons 2–18 of the gene. <b><i>Conclusion:</i></b> <i>IQCE</i> gene codes for a 695-amino acid protein located at the base of the primary cilia that positively regulates the Hedgehog signaling pathway. This case report represents the first description of a large deletion in <i>IQCE</i> and indicates that implementation of ExomeDepth in routine WES analysis can contribute valuable information toward elucidating the correct etiology of rare genetic diseases, increasing the diagnostic yield, and minimizing the need for additional tests.

Identification of a novel IQCE variant in a Korean patient with nonsyndromic postaxial polydactyly

“…Previously, a total of seven pathogenic and likely pathogenic variations of IQCE have been reported, all of which were truncating or loss-of-function mutations (Fig. 1c) (Tilemis et al ., 2023). According to the American College of Medical Genetics and Genomics guidelines, the novel variant (p.Cys514Alafs*50) identified in our patient is a truncating null variant caused by a short indel mutation (PVS1).…”

“…PAP type A7 can present with polydactyly, 2-3 toe syndactyly, which correlates well with the phenotype of the patient. Other reported clinical features include brachydactyly, hypoplastic teeth, overweight and learning disabilities (Estrada-Cuzcano et al ., 2020; Tilemis et al ., 2023). The patient has shown normal growth and development, but regular follow-up is needed to monitor these statuses.…”

Germline CNV Detection through Whole-Exome Sequencing (WES) Data Analysis Enhances Resolution of Rare Genetic Diseases

“…Among the advantages of calling CNVs from WES data, characterization of complex genotypes comprising both CNVs and SNVs or small insertions/deletions minimizes costs and time to final diagnosis [38][39][40], while also allowing differentiation between true or false homozygosity, as well as compound heterozygosity of variants in AR genes. In point of fact, 11 patients with pathogenic SNVs in AR genes were falsely characterized as either homozygous for an SNV (patients 14, 25, 30, and 40), when they actually carried a large deletion in-trans configuration with the SNV (Table 3; Supplementary Materials, Table S3), or as carriers (patients 8, 10, 20, 21, 23, 29, and 32), while they really were compound heterozygotes for the SNV and a CNV in the same AR gene (Table 3; Supplementary Materials, Table S3).…”

“…In patient 25, a 3-year-old girl presenting with polydactyly, brachydactyly, and hypoplastic teeth, WES revealed compound heterozygosity of IQCE variants; a small deletion and a novel large deletion, encompassing exons 2-18 [39].…”