PDF(Pubmed)
Abstract：
BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.
METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI.
RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2).
CONCLUSIONS: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.
METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI.
RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2).
CONCLUSIONS: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.
摘要：
背景：原发性先天性青光眼（PCG）在美国（U.S.）约影响10,000个活产婴儿中的1个。PCG具有常染色体隐性遗传模式，以及可变的表现力和降低的外显率已经被报道。最常见的突变基因可能是因果变异，CYP1B1在美国不太普遍，表明替代基因可能会导致这种情况。这项研究利用外显子组测序来研究美国PCG的遗传结构，并鉴定新的基因和变体。
方法：我们研究了37个家庭三重奏，其中婴儿患有PCG，并且是国家出生缺陷预防研究的一部分（出生1997-2011），美国出生缺陷多中心研究。样品经历外显子组测序,并将序列读数与人参考样品(NCBI构建37/hg19)进行比对。使用GEMINI在从头和孟德尔遗传模型下进行变体过滤。
结果：在候选变体中，CYP1B1代表最多(五个三重奏，13.5%）。12个先证者（32％）在其他基因中具有潜在的致病性变异，这些基因以前与PCG无关，但在眼睛发育和/或具有潜在表型重叠的孟德尔疾病的基础上很重要（例如，CRYBB2,RXRA,GLI2).
结论：这项基于人群的研究中发现的基因变异可能有助于进一步解释PCG的遗传学。
方法：我们研究了37个家庭三重奏，其中婴儿患有PCG，并且是国家出生缺陷预防研究的一部分（出生1997-2011），美国出生缺陷多中心研究。样品经历外显子组测序,并将序列读数与人参考样品(NCBI构建37/hg19)进行比对。使用GEMINI在从头和孟德尔遗传模型下进行变体过滤。
结果：在候选变体中，CYP1B1代表最多(五个三重奏，13.5%）。12个先证者（32％）在其他基因中具有潜在的致病性变异，这些基因以前与PCG无关，但在眼睛发育和/或具有潜在表型重叠的孟德尔疾病的基础上很重要（例如，CRYBB2,RXRA,GLI2).
结论：这项基于人群的研究中发现的基因变异可能有助于进一步解释PCG的遗传学。
