PDF(Pubmed)
Abstract：
UNASSIGNED: A molecular diagnosis is only made in a subset of individuals with nonisolated microphthalmia, anophthalmia, and coloboma (MAC). This may be due to underutilization of clinical (whole) exome sequencing (cES) and an incomplete understanding of the genes that cause MAC. The purpose of this study is to determine the efficacy of cES in cases of nonisolated MAC and to identify new MAC phenotypic expansions.
UNASSIGNED: We determined the efficacy of cES in 189 individuals with nonisolated MAC. We then used cES data, a validated machine learning algorithm, and previously published expression data, case reports, and animal models to determine which candidate genes were most likely to contribute to the development of MAC.
UNASSIGNED: We found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189). Most genes affected in our cohort were not among genes currently screened in clinically available ophthalmologic gene panels. A subset of the genes implicated in our cohort had not been clearly associated with MAC. Our analyses revealed sufficient evidence to support low-penetrance MAC phenotypic expansions involving nine of these human disease genes.
UNASSIGNED: We conclude that cES is an effective means of identifying a molecular diagnosis in individuals with nonisolated MAC and may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained. Our data also suggest that deleterious variants in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, and TUBA1A can contribute to the development of MAC.
UNASSIGNED: We determined the efficacy of cES in 189 individuals with nonisolated MAC. We then used cES data, a validated machine learning algorithm, and previously published expression data, case reports, and animal models to determine which candidate genes were most likely to contribute to the development of MAC.
UNASSIGNED: We found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189). Most genes affected in our cohort were not among genes currently screened in clinically available ophthalmologic gene panels. A subset of the genes implicated in our cohort had not been clearly associated with MAC. Our analyses revealed sufficient evidence to support low-penetrance MAC phenotypic expansions involving nine of these human disease genes.
UNASSIGNED: We conclude that cES is an effective means of identifying a molecular diagnosis in individuals with nonisolated MAC and may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained. Our data also suggest that deleterious variants in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, and TUBA1A can contribute to the development of MAC.
摘要：
■分子诊断仅在非孤立性小眼病患者的一部分中进行，无眼炎,和结肠瘤（MAC）。这可能是由于临床（整个）外显子组测序（cES）的利用不足以及对导致MAC的基因的不完全理解。这项研究的目的是确定cES在非隔离MAC病例中的功效，并确定新的MAC表型扩展。
■我们确定了189名患有非隔离MAC的个体中cES的疗效。然后我们使用了cES数据，经过验证的机器学习算法，和以前发布的表达数据，病例报告,和动物模型，以确定哪些候选基因最有可能有助于MAC的发展。
■我们发现cES在非隔离MAC中的功效介于32.3％（61/189）和48.1％（91/189）之间。我们队列中受影响的大多数基因不在临床可用的眼科基因组中目前筛选的基因中。我们队列中涉及的基因子集与MAC没有明显关联。我们的分析显示，有足够的证据支持涉及9种人类疾病基因的低外显率MAC表型扩展。
■我们得出的结论是，cES是鉴定非分离MAC个体分子诊断的有效手段，并且可能鉴定出如果仅获得临床可用的眼科基因组就会被遗漏的推定破坏性变异。我们的数据还表明，BRCA2，BRIP1，KAT6A中的有害变体，KAT6B,NSF,RAC1,SMARCA4,SMC1A,TUBA1A可以为MAC的发展做出贡献。
■我们确定了189名患有非隔离MAC的个体中cES的疗效。然后我们使用了cES数据，经过验证的机器学习算法，和以前发布的表达数据，病例报告,和动物模型，以确定哪些候选基因最有可能有助于MAC的发展。
■我们发现cES在非隔离MAC中的功效介于32.3％（61/189）和48.1％（91/189）之间。我们队列中受影响的大多数基因不在临床可用的眼科基因组中目前筛选的基因中。我们队列中涉及的基因子集与MAC没有明显关联。我们的分析显示，有足够的证据支持涉及9种人类疾病基因的低外显率MAC表型扩展。
■我们得出的结论是，cES是鉴定非分离MAC个体分子诊断的有效手段，并且可能鉴定出如果仅获得临床可用的眼科基因组就会被遗漏的推定破坏性变异。我们的数据还表明，BRCA2，BRIP1，KAT6A中的有害变体，KAT6B,NSF,RAC1,SMARCA4,SMC1A,TUBA1A可以为MAC的发展做出贡献。
