Abstract：
OBJECTIVE: To identify germline variants in myocilin (MYOC) and other known monogenic glaucoma genes in Finnish patients with juvenile open-angle glaucoma (JOAG).
METHODS: Finnish patients with JOAG treated between 2010 and 2018 at the Department of Ophthalmology, Helsinki University Hospital, Finland, were enrolled. We sequenced all exonic regions and flanking splice sites of MYOC for five patients and one healthy relative using Sanger sequencing. In 48 patients, we performed exome sequencing to identify variants also in 28 other glaucoma-related genes.
RESULTS: Fifty-three individuals with JOAG from 50 pedigrees, and one healthy relative, participated. The mean age at diagnosis was 30.8 years [SD 7.6; range 11 to 39]. Five probands had probably pathogenic variants in MYOC: c.1102C>T p.(Gln368Ter), c.1109C>T p.(Pro370Leu), c.1130C>T p.(Thr377Met), c.1132G>A p.(Asp378Asn) and c.1456C>T p.(Leu486Phe). Four of these patients had a family history of dominantly inherited JOAG. The frequency of MYOC variants was 10% (5 of 50 families). One patient and his mother with JOAG had a novel loss-of-function variant in the FOXC1 gene, c.366G>A p.(Trp122Ter). A patient with sporadic JOAG had a homozygous likely pathogenic variant in the LTBP2 gene, c.3938G>A p.(Cys1313Tyr). The genetic variants explained 14% (7 out of 50 families; 95% CI, 6%-23%) of JOAG in our cohort.
CONCLUSIONS: The frequency of pathogenic variants in previously known glaucoma-associated genes is low in Finnish patients with JOAG. Because of the distinct genetic background of Finns, it might be possible to identify novel glaucoma genes through our JOAG series in the future.
METHODS: Finnish patients with JOAG treated between 2010 and 2018 at the Department of Ophthalmology, Helsinki University Hospital, Finland, were enrolled. We sequenced all exonic regions and flanking splice sites of MYOC for five patients and one healthy relative using Sanger sequencing. In 48 patients, we performed exome sequencing to identify variants also in 28 other glaucoma-related genes.
RESULTS: Fifty-three individuals with JOAG from 50 pedigrees, and one healthy relative, participated. The mean age at diagnosis was 30.8 years [SD 7.6; range 11 to 39]. Five probands had probably pathogenic variants in MYOC: c.1102C>T p.(Gln368Ter), c.1109C>T p.(Pro370Leu), c.1130C>T p.(Thr377Met), c.1132G>A p.(Asp378Asn) and c.1456C>T p.(Leu486Phe). Four of these patients had a family history of dominantly inherited JOAG. The frequency of MYOC variants was 10% (5 of 50 families). One patient and his mother with JOAG had a novel loss-of-function variant in the FOXC1 gene, c.366G>A p.(Trp122Ter). A patient with sporadic JOAG had a homozygous likely pathogenic variant in the LTBP2 gene, c.3938G>A p.(Cys1313Tyr). The genetic variants explained 14% (7 out of 50 families; 95% CI, 6%-23%) of JOAG in our cohort.
CONCLUSIONS: The frequency of pathogenic variants in previously known glaucoma-associated genes is low in Finnish patients with JOAG. Because of the distinct genetic background of Finns, it might be possible to identify novel glaucoma genes through our JOAG series in the future.
摘要：
目的：在患有青少年开角型青光眼（JOAG）的芬兰患者中鉴定肌蛋白（MYOC）和其他已知的单基因青光眼基因的种系变异。
方法：2010年至2018年在眼科接受JOAG治疗的芬兰患者，赫尔辛基大学医院,芬兰,已注册。我们使用Sanger测序对五名患者和一名健康亲属的MYOC的所有外显子区域和侧翼剪接位点进行了测序。在48名患者中，我们进行了外显子组测序,以鉴定28个其他青光眼相关基因的变异.
结果：来自50个家系的53名JOAG患者，和一个健康的亲戚，参与。诊断时的平均年龄为30.8岁[SD7.6;范围11至39]。五个先证者在MYOC中可能具有致病性变异：c.1102C>Tp.（Gln368Ter），c.110C>Tp.(Pro370Leu)，c.1130C>Tp.(Thr377Met)，c.1132G>Ap.（Asp378Asn）和c.1456C>Tp.（Leu486Phe）。这些患者中有四名具有主要遗传的JOAG家族史。MYOC变体的频率为10%(50个家族中的5个)。一名患有JOAG的患者和他的母亲在FOXC1基因中有一个新的功能丧失变异，c.366G>Ap.（Trp122Ter）。一名散发性JOAG患者在LTBP2基因中有纯合的可能致病变异，c.3938G>Ap.（Cys1313Tyr）。在我们的队列中，遗传变异解释了14%(50个家庭中的7个；95%CI，6%-23%)的JOAG。
结论：先前已知的青光眼相关基因中致病变异的频率在患有JOAG的芬兰患者中很低。由于芬兰人独特的遗传背景，未来可能通过我们的JOAG系列鉴定新的青光眼基因.
方法：2010年至2018年在眼科接受JOAG治疗的芬兰患者，赫尔辛基大学医院,芬兰,已注册。我们使用Sanger测序对五名患者和一名健康亲属的MYOC的所有外显子区域和侧翼剪接位点进行了测序。在48名患者中，我们进行了外显子组测序,以鉴定28个其他青光眼相关基因的变异.
结果：来自50个家系的53名JOAG患者，和一个健康的亲戚，参与。诊断时的平均年龄为30.8岁[SD7.6;范围11至39]。五个先证者在MYOC中可能具有致病性变异：c.1102C>Tp.（Gln368Ter），c.110C>Tp.(Pro370Leu)，c.1130C>Tp.(Thr377Met)，c.1132G>Ap.（Asp378Asn）和c.1456C>Tp.（Leu486Phe）。这些患者中有四名具有主要遗传的JOAG家族史。MYOC变体的频率为10%(50个家族中的5个)。一名患有JOAG的患者和他的母亲在FOXC1基因中有一个新的功能丧失变异，c.366G>Ap.（Trp122Ter）。一名散发性JOAG患者在LTBP2基因中有纯合的可能致病变异，c.3938G>Ap.（Cys1313Tyr）。在我们的队列中，遗传变异解释了14%(50个家庭中的7个；95%CI，6%-23%)的JOAG。
结论：先前已知的青光眼相关基因中致病变异的频率在患有JOAG的芬兰患者中很低。由于芬兰人独特的遗传背景，未来可能通过我们的JOAG系列鉴定新的青光眼基因.
