Disease Expression and Familial Transmission of Fuchs Endothelial Corneal Dystrophy With and Without CTG18.1 Expansion.
Disease Expression and Familial Transmission of Fuchs Endothelial Corneal Dystrophy With and Without CTG18.1 Expansion.
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DOI：
10.1167/iovs.62.1.17
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发表时间：
2021-01-04
影响因子：
4.4
通讯作者：
Baratz KH
中科院分区：
文献类型：
--
作者：
Xu TT;Li YJ;Afshari NA;Aleff RA;Rinkoski TA;Patel SV;Maguire LJ;Edwards AO;Brown WL;Fautsch MP;Wieben ED;Baratz KH
描述Fuchs角膜内皮营养不良（FECD）的遗传、突变和三核苷酸重复扩增稳定性。前瞻性招募了1000名无FECD和无FECD的无关和相关受试者。CTG18.1重复序列长度（CTG18.1L）通过短串联重复序列分析和白细胞DNA的Southern印迹测定。采用多变量Logistic回归和广义估计方程模型。有546例不相关的FECD病例（67.6%女性; 70 ± 10岁）和235例对照（63.8%女性; 73 ± 8岁;均≥ 50岁）。CTG18.1exp+在424例（77.7%）和18例（7.7%）对照组中观察到（P = 2.48 × 10-44）。CTG18.1扩增与FECD严重程度相关（P = 5.62 × 10-7）。该研究的家庭分支包括来自112个FECD受影响家庭的331名成员; 87个家庭为CTG18.1exp+。无论扩增状态如何，均观察到常染色体显性遗传，FECD表达可变。CTG18.1扩增的FECD检出率随年龄增加而增加，从最年轻（19-46岁）的44.4%到最年长（64-91岁）的86.2%。在62例CTG18.1exp+的亲子传递中，48例（77.4%）CTG18.1L发生了≤ 10次重复的变化，8例（12.9%）CTG18.1L发生了≥50次重复的变化，其中5例出现了较大的扩增（≥ 1000-2000次重复），并发生了收缩。在44个没有遗传CTG18.1exp+等位基因的后代中，8个（18.2%）表现出FECD。CTG18.1扩增与FECD高度相关，但表现出不完全扩增。CTG18.1L的不稳定性发生在少数的亲子传播，与大的扩张表现出收缩。在CTG18.1exp+家族中的家族成员中观察到的没有CTG18.1扩增的FECD突出了FECD表型与CTG18.1扩增之间的关系的复杂性。
To characterize inheritance, penetrance, and trinucleotide repeat expansion stability in Fuchs endothelial corneal dystrophy (FECD). One thousand unrelated and related subjects with and without FECD were prospectively recruited. CTG18.1 repeat length (CTG18.1L) was determined via short tandem repeat assay and Southern blotting of leukocyte DNA. Multivariable logistic regression and generalized estimating equation models were employed. There were 546 unrelated FECD cases (67.6% female; 70 ± 10 years) and 235 controls (63.8% female; 73 ± 8 years; all ≥ 50 years). CTG18.1 expansion (CTG18.1exp+) was observed in 424 (77.7%) cases and 18 (7.7%) controls (P = 2.48 × 10–44). CTG18.1 expansion was associated with FECD severity (P = 5.62 × 10–7). The family arm of the study included 331 members from 112 FECD-affected families; 87 families were CTG18.1exp+. Autosomal dominant inheritance with variable expression of FECD was observed, regardless of expansion status. FECD penetrance of CTG18.1 expansion increased with age, ranging from 44.4% in the youngest (19–46 years) to 86.2% in the oldest (64–91 years) age quartiles. Among 62 parent–offspring transmissions of CTG18.1exp+, 48 (77.4%) had a change in CTG18.1L ≤ 10 repeats, and eight (12.9%) were ≥50 repeats, including five large expansions (∼1000–2000 repeats) that contracted. Among 44 offspring who did not inherit the CTG18.1exp+ allele, eight (18.2%) exhibited FECD. CTG18.1 expansion was highly associated with FECD but demonstrated incomplete penetrance. CTG18.1L instability occurred in a minority of parent–offspring transmissions, with large expansions exhibiting contraction. The observation of FECD without CTG18.1 expansion among family members in CTG18.1exp+ families highlights the complexity of the relationship between the FECD phenotype and CTG18.1 expansion.
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作者：
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通讯作者：
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影响因子：
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作者：
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