PMC6070557_01
PMC6070557_02
Patient 1 exome analysis.. a The 4-bp INDEL variant of the ZEB2 gene was identified in patient 1 from WES analysis. b Schematic representation of the ZEB2 protein and its domains, indicating the location of the frameshift mutation that results in premature protein termination. c Screen capture of the BAM files analysis using the Integrative Genomics Viewer (http://software.broadinstitute.org/software/igv/bam) for the ZEB2 INDEL p.Ser726TyrfsTer7 variant that was found in patient 1 and both of their parents. The blue arrow indicates the exact location of the 4-bp INDEL leading to a frameshift that results in premature protein termination
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Fig1
After obtaining the WES data for both patients as well as the parents of patient 1, the subsequent analysis identified a novel truncation variant (NM_014795.3:c.2177_2180delCTTT, NP_055610.1:p.Ser726TyrfsTer7) in patient 1 that was determined to be a deleterious mutation according to the variant interpretation guidelines of the ACMG (Fig. 1). The novel 4-bp INDEL that leads to the frameshift p.Ser726TyrfsTer7 (Fig. 1) was confirmed as de novo using Sanger sequencing. Subsequent analyses revealed the presence of a novel pathogenic truncation variant (NP_055610.1: p.Ser726TyrfsTer7) of the ZEB2 gene in patient 1, which led to the loss of the CID and Zinc-finger 2 protein domains and resulted in haploinsufficiency (Fig. 1).
Patient 2 exome analysis.. a Summary of the annotated SNVs in the ZEB2 gene that were found to be either benign or pathogenic (8ZEB2 and VUS (GTDC1)) in the patient. b A detailed diagram of the deleted region (chr2:144704611-145277958) encompassing ZEB2 as well as the neighboring GTDC1 and TEX41 genes as detected using the XHMM algorithm, which encompasses 25 target regions that are highlighted in red and are equivalent to 0.573 Mb. c The ZEB2 pathogenic deletion (1.08 Mb), as confirmed by a CGH assay (arr[GRCh37] 2q22.3(144569168_145648045)x1), which includes the 0.573 Mb deletion detected via WGS. The CGH array extended the deleted region to include a partial deletion of the downstream TEX41 gene, which is a non-protein coding gene of unknown function
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Fig2
The screening analysis of CNVs in patient 2 identified a novel deletion of at least 0.573 Mb (GRCh37/hg19 chr2:g.144704611-145277958) that was predicted to lead to the complete loss of the ZEB2 gene, resulting in haploinsufficiency (Fig. 2a, b). This mutation was confirmed by a CGH array to be a novel 1.08 Mb heterozygous deletion (arr[GRCh37] 2q22.3(144569168_145648045)x1) that encompasses the 0.568 Mb deletion that was detected during the WES data analysis (Fig. 2c).