Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies

Abstract

Purpose: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.

Methods: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

Results: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

Conclusion: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

Keywords: Atypical cohesinopathies; Clinical exome sequencing (CES); Cohesin pathway; STAG1; STAG2.

Figure 1.

Cohesin complex and its underlying genetic variants. A. Schematic diagram of the cohesin complex. The components are represented in different color shapes labeled with protein names. B. Comparison of genic distributions between our clinical exome cohort and two phenotype-driven cohorts of clinically diagnosed CdLS patients (from ref. and BHCMG, respectively) . Y-axis, proportion of molecular diagnosis provided by variants in each gene; x-axis, genes; black, patients without CdLS listed as differential diagnosis; dark grey, patients with CdLS as one of the differential diagnoses; grey, CdLS cohort from ref. ; light grey, CdLS cohort from BHCMG. C. Comparison of genic variant frequencies between COSMIC and ExAC cohorts. Filled circles represent comparison between frequencies of putative LoF variants between COSMIC and ExAC; open circles represent comparison between frequencies of missense variants between COSMIC and ExAC. Y-axis, ratio bewteen frequencies of genic variants (missense or putative LoF) in COSMIC and ExAC; x-axis, genes.

Figure 2.

The variants in STAG1 and STAG2. A. SNVs/indels in STAG1. B. SNVs/indels and one CNV deletion in STAG2. For panels A and B, the white segment represents the full-length protein, and the black segments represent protein domains; the missense variants are annotated above the segment, while the putative LoF variants (including the CNVs deletion in STAG2) are underneath; the variants colored in red are reported in the current study. The boxed variant (p.A638Vfs*10) in panel B is reported as a research variant. C. Diagram showing the CNV deletions overlapping STAG1 reported in the DECIPHER and current study. The red segments represent the deletions, which are divided in two groups of “DECIPHER” and “Current Study”. The bottom panel shows genes in the region. STAG1 is highlighted in red. D. Photographs showing the front and side facial profiles of Patients 8 and 9 with de novo variant in STAG2. The patient numbers and variants are listed under the photograph.