Figure 1.
Figure 1. Heterozygous RTEL1 variants. (A) Linear representation of RTEL1 isoform 3 (1300 amino acids; NM_001283009.1). Colored boxes indicate the conserved RTEL1 domains, and lines indicate the positions of individual variants in the gene. Twenty-one novel (black) and 2 previously described (red) heterozygous variants were identified in 8 patients from the NIH cohort (n = 59) and in 19 patients from the KCH cohort (n = 457). Variants are represented by triangles, circles, and squares, which also represent the type of the variant (missense variants, stop-gained variants, or splicing variants, respectively). Blue triangles represent 2 compound heterozygous patients. Splicing variants are indicated by dashed lines. *Eleven variants had a CADD phred score of >15 (this score was selected to predicted RTEL1 deleteriousness; supplemental Table 2). (B-G) Ribbon representation of the 3D structure models of the RTEL1 domains. Amino acid changes observed in patients are colored in red and displayed in an atomic representation in the figure within their close neighborhood. Panel B focuses on variants located on the ARCH and HD2 domains and panel C on the first harmonin-N-like domain. Panels D-G focus on variants located on the C4C4-RING domain, helicase domain 1, the FeS cluster, and helicase domain 2, respectively. The RTEL1 3D structure information obtained by comparative modeling predicted 14 of 23 RTEL1 variants as substitutions that may destabilize the domain 3D structure in which they are located or affect the protein partner interactions of RTEL1 (supplemental data). (H) The frequency of potential deleterious RTEL1 missense and LoF in the ExAC database (n = 60 706), KCH (n = 457), and NIH (n = 59) cohorts. Missense variants are enriched in the NIH cohort but not in the KCH cohort when compared with the ExAC database. However, the KCH cohort had a very significant enrichment in LoF variants when compared with ExAC. (I) Frequency of missense RTEL1 variants stratified by CADD phred score in the ExAC database, and the KCH and NIH cohorts. The CADD predicts deleteriousness of a given variant. All variants with CADD over 15 from KCH and NIH had CADD over 20 as well. The CADD of 15 was selected as a cutoff to predict a variant as deleterious on the basis of the frequency identified in the ExAC database. HD1, helicase domain 1; HD2, helicase domain 2; HNL-1, first harmonin-N-like domain.

Heterozygous RTEL1 variants. (A) Linear representation of RTEL1 isoform 3 (1300 amino acids; NM_001283009.1). Colored boxes indicate the conserved RTEL1 domains, and lines indicate the positions of individual variants in the gene. Twenty-one novel (black) and 2 previously described (red) heterozygous variants were identified in 8 patients from the NIH cohort (n = 59) and in 19 patients from the KCH cohort (n = 457). Variants are represented by triangles, circles, and squares, which also represent the type of the variant (missense variants, stop-gained variants, or splicing variants, respectively). Blue triangles represent 2 compound heterozygous patients. Splicing variants are indicated by dashed lines. *Eleven variants had a CADD phred score of >15 (this score was selected to predicted RTEL1 deleteriousness; supplemental Table 2). (B-G) Ribbon representation of the 3D structure models of the RTEL1 domains. Amino acid changes observed in patients are colored in red and displayed in an atomic representation in the figure within their close neighborhood. Panel B focuses on variants located on the ARCH and HD2 domains and panel C on the first harmonin-N-like domain. Panels D-G focus on variants located on the C4C4-RING domain, helicase domain 1, the FeS cluster, and helicase domain 2, respectively. The RTEL1 3D structure information obtained by comparative modeling predicted 14 of 23 RTEL1 variants as substitutions that may destabilize the domain 3D structure in which they are located or affect the protein partner interactions of RTEL1 (supplemental data). (H) The frequency of potential deleterious RTEL1 missense and LoF in the ExAC database (n = 60 706), KCH (n = 457), and NIH (n = 59) cohorts. Missense variants are enriched in the NIH cohort but not in the KCH cohort when compared with the ExAC database. However, the KCH cohort had a very significant enrichment in LoF variants when compared with ExAC. (I) Frequency of missense RTEL1 variants stratified by CADD phred score in the ExAC database, and the KCH and NIH cohorts. The CADD predicts deleteriousness of a given variant. All variants with CADD over 15 from KCH and NIH had CADD over 20 as well. The CADD of 15 was selected as a cutoff to predict a variant as deleterious on the basis of the frequency identified in the ExAC database. HD1, helicase domain 1; HD2, helicase domain 2; HNL-1, first harmonin-N-like domain.

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