Abstract：
OBJECTIVE: Microphthalmia is a severe congenital ocular disease featured by abnormal ocular development. The aim of this study was to detail the genetic and clinical characteristics of a large cohort of Chinese patients with microphthalmia related to MFRP variants, focusing on uncovering genotype-phenotype correlations.
METHODS: Fifty microphthalmia patients from 44 unrelated Chinese families were recruited. Whole-exome sequencing (WES) was conducted to analyze the coding regions and adjacent intronic regions of MFRP. Axial lengths (AL) were measured for all probands and available family members. Protein structures of mutations with high frequency in our cohort were predicted. The genotype-phenotype correlations were explored by statistical analysis.
RESULTS: Sixteen MFRP variants were detected in 17 families, accounting for 38.64 % of all microphthalmia families. There were 9 novel mutations (c.427+1G>C, c.428-2A>C, c.561_575del:p.A188_E192del, c.836G>A:p.C279Y, c.1010_1021del:p.H337_E340del:p.Y479*, c.1516_1517del:p.S506Pfs*66, c.1561T>G:p.C521G, c.1616G>A:p.R539H, and c.1735C>T:p.P579S) and six previously reported variants in MFRP, with p.E496K and p.H337_E340del being highly frequent, found in eight (47.06 %) and two families (11.76 %), respectively. Seven variants (43.75 %) were located in the C-terminal cysteine-rich frizzled-related domain (CRD) (7/16, 43.75 %). Protein prediction implicated p.E496K and p.H337_E340del mutations might lead to a destabilization of the MFRP protein. The average AL of all 42 eyes was 16.02 ± 1.05 mm, and 78.36 % of eyes with AL < 16 mm harbored p.E496K variant. Twenty-six eyes with variant variant had shorter AL than that of the other 16 eyes without this variant (p = 0.006), highlighting a novel genotype-phenotype correlation.
CONCLUSIONS: In this largest cohort of Chinese patients with microphthalmia, the 9 novel variants, high frequency of p.E496W, and mutation hotspots in CRD reveals unique insights into the MFRP mutation spectrum among Chinese patients, indicating ethnic variability. A new genotype-phenotype correlation that p.E496K variant associated with a shorter AL is unveiled. Our findings enhance the current knowledge of MFRP-associated microphthalmia and provide valuable information for prenatal diagnosis as well as future therapy.
METHODS: Fifty microphthalmia patients from 44 unrelated Chinese families were recruited. Whole-exome sequencing (WES) was conducted to analyze the coding regions and adjacent intronic regions of MFRP. Axial lengths (AL) were measured for all probands and available family members. Protein structures of mutations with high frequency in our cohort were predicted. The genotype-phenotype correlations were explored by statistical analysis.
RESULTS: Sixteen MFRP variants were detected in 17 families, accounting for 38.64 % of all microphthalmia families. There were 9 novel mutations (c.427+1G>C, c.428-2A>C, c.561_575del:p.A188_E192del, c.836G>A:p.C279Y, c.1010_1021del:p.H337_E340del:p.Y479*, c.1516_1517del:p.S506Pfs*66, c.1561T>G:p.C521G, c.1616G>A:p.R539H, and c.1735C>T:p.P579S) and six previously reported variants in MFRP, with p.E496K and p.H337_E340del being highly frequent, found in eight (47.06 %) and two families (11.76 %), respectively. Seven variants (43.75 %) were located in the C-terminal cysteine-rich frizzled-related domain (CRD) (7/16, 43.75 %). Protein prediction implicated p.E496K and p.H337_E340del mutations might lead to a destabilization of the MFRP protein. The average AL of all 42 eyes was 16.02 ± 1.05 mm, and 78.36 % of eyes with AL < 16 mm harbored p.E496K variant. Twenty-six eyes with variant variant had shorter AL than that of the other 16 eyes without this variant (p = 0.006), highlighting a novel genotype-phenotype correlation.
CONCLUSIONS: In this largest cohort of Chinese patients with microphthalmia, the 9 novel variants, high frequency of p.E496W, and mutation hotspots in CRD reveals unique insights into the MFRP mutation spectrum among Chinese patients, indicating ethnic variability. A new genotype-phenotype correlation that p.E496K variant associated with a shorter AL is unveiled. Our findings enhance the current knowledge of MFRP-associated microphthalmia and provide valuable information for prenatal diagnosis as well as future therapy.
摘要：
目的：小眼症是一种以眼部发育异常为特征的严重先天性眼病。这项研究的目的是详细介绍与MFRP突变相关的小眼症患者的遗传和临床特征。专注于揭示基因型-表型相关性。
方法：纳入来自44个无亲缘关系的中国家庭的50例小眼病患者。进行全外显子组测序(WES)以分析MFRP的编码区和邻近内含子区。测量所有先证者和可用家庭成员的轴向长度（AL）。预测了我们队列中高频率突变的蛋白质结构。通过统计分析探讨基因型与表型的相关性。
结果：在17个家族中检测到16个MFRP突变，占所有小眼症家庭的38.64%。有10个新的突变（c.427+1G>C，c.428-2A>C，c.561_575del：p。A188_E192del,c.836G>A：p。C279Y,c.1010_1021del：p。H337_E340del,c.1437C>A：p。Y479*,c.1516_1517del：p。S506Pfs*66，c.1561T>G：p。C521G,c.1616G>A：p。R539H,和c.1735C>T：p。P579S）和先前报道的MFRP突变，p.E496K和p.H337_E340del是非常频繁的，在八个家庭(47.06%)和两个家庭(11.76%)中发现，分别。七个突变（43.75％）位于C端富含半胱氨酸的卷曲相关域（CRD）（7/16，43.75％）。涉及p.E496K和p.H337_E340del突变的蛋白质预测可能导致MFRP蛋白质的不稳定。42只眼的平均AL为16.02±1.05mm,AL<16mm的眼睛中有78.36％具有p.E496K突变。有p.E496K突变的26只眼的AL比没有这种突变的16只眼的AL短（p=0.006），突出了一种新的基因型-表型相关性。
结论：在这个最大的中国小眼病患者队列中，11个新的突变，高频率的p.E496W，CRD中的突变热点揭示了中国患者对MFRP突变谱的独特见解，表明种族差异。揭示了一种新的基因型-表型相关性，即p.E496K突变与较短的AL相关。我们的发现增强了目前对MFRP相关小眼症的认识，并为产前诊断和未来治疗提供了有价值的信息。
方法：纳入来自44个无亲缘关系的中国家庭的50例小眼病患者。进行全外显子组测序(WES)以分析MFRP的编码区和邻近内含子区。测量所有先证者和可用家庭成员的轴向长度（AL）。预测了我们队列中高频率突变的蛋白质结构。通过统计分析探讨基因型与表型的相关性。
结果：在17个家族中检测到16个MFRP突变，占所有小眼症家庭的38.64%。有10个新的突变（c.427+1G>C，c.428-2A>C，c.561_575del：p。A188_E192del,c.836G>A：p。C279Y,c.1010_1021del：p。H337_E340del,c.1437C>A：p。Y479*,c.1516_1517del：p。S506Pfs*66，c.1561T>G：p。C521G,c.1616G>A：p。R539H,和c.1735C>T：p。P579S）和先前报道的MFRP突变，p.E496K和p.H337_E340del是非常频繁的，在八个家庭(47.06%)和两个家庭(11.76%)中发现，分别。七个突变（43.75％）位于C端富含半胱氨酸的卷曲相关域（CRD）（7/16，43.75％）。涉及p.E496K和p.H337_E340del突变的蛋白质预测可能导致MFRP蛋白质的不稳定。42只眼的平均AL为16.02±1.05mm,AL<16mm的眼睛中有78.36％具有p.E496K突变。有p.E496K突变的26只眼的AL比没有这种突变的16只眼的AL短（p=0.006），突出了一种新的基因型-表型相关性。
结论：在这个最大的中国小眼病患者队列中，11个新的突变，高频率的p.E496W，CRD中的突变热点揭示了中国患者对MFRP突变谱的独特见解，表明种族差异。揭示了一种新的基因型-表型相关性，即p.E496K突变与较短的AL相关。我们的发现增强了目前对MFRP相关小眼症的认识，并为产前诊断和未来治疗提供了有价值的信息。
