Predominant Founder Effect among Recurrent Pathogenic Variants for an X-Linked Disorder

Abstract

For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.

Trial registration: ClinicalTrials.gov NCT02471287 NCT00378742.

Keywords: ACMG/AMP variant interpretation guideline; RS1; X-linked disorder; X-linked retinoschisis (XLRS); founder effect; haplotype analysis; variant classification.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

RS1 variant types and localizations in the XLRS cohort and gnomAD. (a) Variant type distribution in the XLRS cohort. (b) RS1 protein domains (Top) and variant allele frequencies (AF) along the cDNA position in the XLRS cohort (middle) and gnomAD (bottom). The splice region variants in the XLRS cohort include intronic variants reported in clinical reports. The splice region variants in the gnomAD dataset include intronic variants in ±3–8 nucleotides from the exon–intron junctions. The gnomAD v2.1.1 dataset does not contain any variants in the ±2 canonical splicing sites. Variants denoted are those with AF > 0.03 in XLRS or >0.001 in gnomAD. (c) Allele frequencies for variants present in both XLRS cohort and gnomAD. Shaded: the XLRS prevalence of 1 in 5000 to 1 in 25,000 males.

Figure 2

Variant analysis using the ACMG/AMP classification system, including 104 SNVs and small Indels. (a) Variant interpretation in the current study as compared to ClinVar interpretations. (b) Variant interpretation with and without application of PM1 and PS4.

Figure 3

Distribution of distinct shared haplotypes (multi-colored) among 19 recurrently observed RS1 variants, including probands with no variant-specific shared haplotypes (gray).

Figure 4

Geographical distribution of three recurrent variants by proband ZIP code. (a) Three probands with variant-specific haplotypes (Hap15) tightly cluster (blue inset); one proband with the same RS1 variant shared 2/7 haplotype markers (gray). (b) Twelve probands with variant-specific haplotypes are in blue (Hap4); one proband with the same RS1 variant shared 6/7 haplotype markers (gray). (c) Six probands with variant specific haplotypes are in blue (Hap5), and one proband shared 6/7 haplotype markers (gray).