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

Mesh : Eye Proteins / genetics Female Founder Effect Genes, X-Linked Humans Male Mutation Retinoschisis / diagnosis genetics pathology

来  源:   DOI:10.3390/genes13040675

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.
摘要:
对于X连锁遗传的疾病,在确定受影响的雄性之前,变异可能会通过多代携带者雌性传播。致病性RS1变异仅引起X连锁视网膜裂孔(XLRS)。虽然RS1受限于变化,在无关的先证者中经常观察到复发性变异。这里,我们研究了复发性致病变异,以确定突变热点和创始人等位基因事件对这一现象的相对负担.队列RS1变异分析和标准化分类,包括XLRS队列和RS1功能域中的变体富集,对332个无关的XLRS先证者进行了检查。鉴定了总共108个独特的RS1变体。通过单倍型分析在190个先证中评估了19个反复观察到的RS1变体的子集,使用微卫星和单核苷酸多态性。十四个变体具有至少两个先证者,其在〜1.95厘摩(cM)侧翼RS1上具有常见的变体特异性单倍型。总的来说,据报道,99/190的不相关先证者具有25种不同的共享单倍型。对该XLRS队列中常见RS1单倍型的检查表明,创始人效应在该疾病中起着重要作用。包括突变热点中的变体。这提高了临床变异分类的准确性,并且可以推广到其他X连锁疾病。
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