Abstract：
OBJECTIVE: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs).
METHODS: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations.
RESULTS: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses.
CONCLUSIONS: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.
METHODS: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations.
RESULTS: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses.
CONCLUSIONS: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.
摘要：
目的：确定未解决的眼先天性颅骨神经支配障碍（oCCDs）的遗传病因和基因型/表型关联。
方法：我们对467个先证者（550个受影响的个体和1108个个体）与遗传未解决的oCCDD进行了表型分析和外显子组或基因组测序，整合家系分析，人类和动物模型表型，和从头变体来识别罕见的候选单核苷酸变体，插入/删除，和结构变异破坏蛋白质编码区。对优先的变体进行致病性分类并评估基因型/表型相关性。
结果：分析阐明了表型亚组，在43/467先证者(9.2%)中发现致病性/可能致病性变异，以及70/467个额外先证者(15.0%)中不确定意义的优先变体。这些包括已建立的oCCDD基因中的已知和新变体，与有时包括oCCDDs的综合征相关的基因(例如，MYH10,KIF21B,TGFBR2,TUBB6),符合表型的综合征组分但没有先前的oCCDD关联的基因(例如，CDK13,TGFB2),与oCCDDs或综合征表型无关联的基因(例如，TUBA4A,KIF5C,CTNNA1,KLB,FGF21),以及与导致误诊的oCCDD表型相关的基因。
结论：这项研究表明，未解决的oCCDs是临床和遗传异质性疾病，通常与其他孟德尔疾病重叠，并为未来的复制和功能研究提名了许多候选人。
方法：我们对467个先证者（550个受影响的个体和1108个个体）与遗传未解决的oCCDD进行了表型分析和外显子组或基因组测序，整合家系分析，人类和动物模型表型，和从头变体来识别罕见的候选单核苷酸变体，插入/删除，和结构变异破坏蛋白质编码区。对优先的变体进行致病性分类并评估基因型/表型相关性。
结果：分析阐明了表型亚组，在43/467先证者(9.2%)中发现致病性/可能致病性变异，以及70/467个额外先证者(15.0%)中不确定意义的优先变体。这些包括已建立的oCCDD基因中的已知和新变体，与有时包括oCCDDs的综合征相关的基因(例如，MYH10,KIF21B,TGFBR2,TUBB6),符合表型的综合征组分但没有先前的oCCDD关联的基因(例如，CDK13,TGFB2),与oCCDDs或综合征表型无关联的基因(例如，TUBA4A,KIF5C,CTNNA1,KLB,FGF21),以及与导致误诊的oCCDD表型相关的基因。
结论：这项研究表明，未解决的oCCDs是临床和遗传异质性疾病，通常与其他孟德尔疾病重叠，并为未来的复制和功能研究提名了许多候选人。
