Abstract：
Acquired early-onset bilateral cataracts can result from systemic etiologies or genetic disorders.
In this observational study, we analyzed individuals 18 months to 35 years of age with acquired bilateral cataracts via a next-generation sequencing panel of 66 genes to identify disease-causing genetic variants.
Of 347 patients enrolled, 313 (90.2%) were <19 years (median, 8 years). We identified 74 pathogenic or likely pathogenic variants in 69 patients. Of the variants, we observed 64 single nucleotide variants (SNV) in 24 genes and 10 copy number variants (CNV) of varying size and genomic location. SNVs in crystallin genes were most common, accounting for 27.0% of all variants (20 of 74). Of those, recurrent variants included known cataract-causing variants CRYBA1 c.215+1G>A, observed in 3 patients, and CRYBA1 c.272_274delGAG, CRYBB2 c.463C>T and c.562C>T, and CRYAA c.62G>A, each observed in 2 patients. In 5 patients, we identified CNV deletions ranging from 1.32-2.41 Mb in size associated with 1q21.1 microdeletion syndrome. Biallelic variants in CYP27A1 were identified in two siblings, one as part of targeted follow-up family testing, who were subsequently diagnosed with cerebrotendinous xanthomatosis, a rare but treatable autosomal recessive disease that often presents with acquired early-onset bilateral cataracts.
This study demonstrates the utility of genetic testing in individuals with acquired early-onset bilateral cataracts to help clarify etiology. Identification of causative genetic variants can inform patient management and facilitate genetic counseling by identifying genetic conditions with risk of recurrence in families.
In this observational study, we analyzed individuals 18 months to 35 years of age with acquired bilateral cataracts via a next-generation sequencing panel of 66 genes to identify disease-causing genetic variants.
Of 347 patients enrolled, 313 (90.2%) were <19 years (median, 8 years). We identified 74 pathogenic or likely pathogenic variants in 69 patients. Of the variants, we observed 64 single nucleotide variants (SNV) in 24 genes and 10 copy number variants (CNV) of varying size and genomic location. SNVs in crystallin genes were most common, accounting for 27.0% of all variants (20 of 74). Of those, recurrent variants included known cataract-causing variants CRYBA1 c.215+1G>A, observed in 3 patients, and CRYBA1 c.272_274delGAG, CRYBB2 c.463C>T and c.562C>T, and CRYAA c.62G>A, each observed in 2 patients. In 5 patients, we identified CNV deletions ranging from 1.32-2.41 Mb in size associated with 1q21.1 microdeletion syndrome. Biallelic variants in CYP27A1 were identified in two siblings, one as part of targeted follow-up family testing, who were subsequently diagnosed with cerebrotendinous xanthomatosis, a rare but treatable autosomal recessive disease that often presents with acquired early-onset bilateral cataracts.
This study demonstrates the utility of genetic testing in individuals with acquired early-onset bilateral cataracts to help clarify etiology. Identification of causative genetic variants can inform patient management and facilitate genetic counseling by identifying genetic conditions with risk of recurrence in families.
摘要：
背景：获得性早发性双侧白内障可由全身性病因或遗传性疾病引起。
方法：在这项观察性研究中，我们通过66个基因的下一代测序小组分析了18个月至35岁的获得性双侧白内障患者,以鉴定致病遗传变异.
结果：在347名患者中，313（90.2%）为19岁或更年轻（中位数，8年）。我们在69例患者中确定了74例致病或可能的致病变异。在变体中，我们在24个基因中观察到64个单核苷酸变异(SNV)和10个不同大小和基因组位置的拷贝数变异(CNV).晶状体蛋白基因中的SNV是最常见的，占所有变体的27.0%（74个中的20个）。其中,复发性变异包括已知的引起白内障的变异CRYBA1c.215+1G>A，在3名患者中观察到，和CRYBA1c.272_274delGAG，CRYBB2c.463C>T和c.562C>T，和CRYAAc.62G>A，各观察2例。在5名患者中，我们发现与1q21.1微缺失综合征相关的CNV缺失大小为1.32-2.41Mb.在两个兄弟姐妹中鉴定了CYP27A1中的双等位基因变体，一个作为有针对性的后续家庭测试的一部分，他们随后被诊断出患有脑性黄瘤病，一种罕见但可治疗的常染色体隐性疾病，常伴有获得性早发性双侧白内障。
结论：这项研究证明了基因检测在获得性早发性双侧白内障患者中的应用，有助于明确病因。致病性遗传变异的识别可以通过识别具有家庭复发风险的遗传状况来告知患者管理并促进遗传咨询。
方法：在这项观察性研究中，我们通过66个基因的下一代测序小组分析了18个月至35岁的获得性双侧白内障患者,以鉴定致病遗传变异.
结果：在347名患者中，313（90.2%）为19岁或更年轻（中位数，8年）。我们在69例患者中确定了74例致病或可能的致病变异。在变体中，我们在24个基因中观察到64个单核苷酸变异(SNV)和10个不同大小和基因组位置的拷贝数变异(CNV).晶状体蛋白基因中的SNV是最常见的，占所有变体的27.0%（74个中的20个）。其中,复发性变异包括已知的引起白内障的变异CRYBA1c.215+1G>A，在3名患者中观察到，和CRYBA1c.272_274delGAG，CRYBB2c.463C>T和c.562C>T，和CRYAAc.62G>A，各观察2例。在5名患者中，我们发现与1q21.1微缺失综合征相关的CNV缺失大小为1.32-2.41Mb.在两个兄弟姐妹中鉴定了CYP27A1中的双等位基因变体，一个作为有针对性的后续家庭测试的一部分，他们随后被诊断出患有脑性黄瘤病，一种罕见但可治疗的常染色体隐性疾病，常伴有获得性早发性双侧白内障。
结论：这项研究证明了基因检测在获得性早发性双侧白内障患者中的应用，有助于明确病因。致病性遗传变异的识别可以通过识别具有家庭复发风险的遗传状况来告知患者管理并促进遗传咨询。
