Abstract：
BACKGROUND: GJA8 gene is known to cause autosomal dominant congenital cataract. Here we report a novel compound heterozygous variant of GJA8 gene in two siblings that mimics an autosomal recessive trait.
METHODS: Two siblings from a non-consanguineous Chinese family suffered from isolated congenital cataract. Whole exome sequencing was performed to identify disease-causing variants followed by a confirmatory Sanger sequencing.
RESULTS: Whole exome sequencing revealed a novel compound heterozygous variant of GJA8 gene, c.855delG(p.Met286Trpfs*71)/c.1125delC(p.Gly376Glufs*33), in the proband. Sanger sequencing confirmed that the proband and his sister harboured this compound heterozygous variant, while the parents were heterozygous carriers, suggesting an autosomal recessive inheritance pattern. Both parents showed mildly impaired vision, but only the father had mild nuclear opacities, suggesting an autosomal dominant trait with reduced penetrance in one of the pathogenic alleles.
CONCLUSIONS: Our report shows compound heterozygous variant of GJA8 gene may mimic autosomal recessive inheritance pattern, and reminds clinicians to perform needful examination. The two novel pathogenic GJA8 variants expand the mutational spectrum of congenital cataract. This study also provides accurate genetic diagnosis for the family.
METHODS: Two siblings from a non-consanguineous Chinese family suffered from isolated congenital cataract. Whole exome sequencing was performed to identify disease-causing variants followed by a confirmatory Sanger sequencing.
RESULTS: Whole exome sequencing revealed a novel compound heterozygous variant of GJA8 gene, c.855delG(p.Met286Trpfs*71)/c.1125delC(p.Gly376Glufs*33), in the proband. Sanger sequencing confirmed that the proband and his sister harboured this compound heterozygous variant, while the parents were heterozygous carriers, suggesting an autosomal recessive inheritance pattern. Both parents showed mildly impaired vision, but only the father had mild nuclear opacities, suggesting an autosomal dominant trait with reduced penetrance in one of the pathogenic alleles.
CONCLUSIONS: Our report shows compound heterozygous variant of GJA8 gene may mimic autosomal recessive inheritance pattern, and reminds clinicians to perform needful examination. The two novel pathogenic GJA8 variants expand the mutational spectrum of congenital cataract. This study also provides accurate genetic diagnosis for the family.
摘要：
背景：已知GJA8基因可引起常染色体显性遗传先天性白内障。在这里，我们报告了两个兄弟姐妹中GJA8基因的新型复合杂合变体，该变体模拟了常染色体隐性性状。
方法：来自一个非血缘关系的中国家庭的两个兄弟姐妹患有孤立的先天性白内障。进行全外显子组测序以鉴定致病变体,随后进行确认性Sanger测序。
结果：全外显子组测序揭示了GJA8基因的一种新的复合杂合变体，c.855delG（p。Met286Trpfs*71）/c.1125delC（p。Gly376Glufs*33），在先证者中。桑格测序证实先证者和他的妹妹有这种复合杂合变体，而父母是杂合携带者，提示一种常染色体隐性遗传模式.父母双方都表现出轻度视力受损，但只有父亲有轻微的核混浊，提示在一个致病等位基因中具有降低的外显率的常染色体显性性状。
结论：我们的报告显示GJA8基因的复合杂合变体可能模拟常染色体隐性遗传模式，并提醒临床医生进行必要的检查。两种新的致病性GJA8变体扩展了先天性白内障的突变谱。本研究也为该家族提供了准确的基因诊断。
方法：来自一个非血缘关系的中国家庭的两个兄弟姐妹患有孤立的先天性白内障。进行全外显子组测序以鉴定致病变体,随后进行确认性Sanger测序。
结果：全外显子组测序揭示了GJA8基因的一种新的复合杂合变体，c.855delG（p。Met286Trpfs*71）/c.1125delC（p。Gly376Glufs*33），在先证者中。桑格测序证实先证者和他的妹妹有这种复合杂合变体，而父母是杂合携带者，提示一种常染色体隐性遗传模式.父母双方都表现出轻度视力受损，但只有父亲有轻微的核混浊，提示在一个致病等位基因中具有降低的外显率的常染色体显性性状。
结论：我们的报告显示GJA8基因的复合杂合变体可能模拟常染色体隐性遗传模式，并提醒临床医生进行必要的检查。两种新的致病性GJA8变体扩展了先天性白内障的突变谱。本研究也为该家族提供了准确的基因诊断。
