Objective: To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale, multicenter carrier screening.
Methods: This study was conducted among a total of 33 104 participants (16 610 females) from 12 clinical centers across China.Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods.
Results: The overall combined carrier frequency was 55.58% for 197 autosomal genes and 1.84% for 26 X-linked genes in these participants.Among the 16 669 families, 874 at-risk couples (5.24%) were identified.Specifically, 584 couples (3.50%) were at risk for autosomal genes, 306(1.84%) for X-linked genes, and 16 for both autosomal and X-linked genes.The most frequently detected autosomal at-risk genes included GJB2(autosomal recessive deafness type 1A, 393 couples), HBA1/HBA2(α-thalassemia, 36 couples), PAH (phenylketonuria, 14 couples), and SMN1(spinal muscular atrophy, 14 couples).The most frequently detected X-linked at-risk genes were G6PD (G6PD deficiency, 236 couples), DMD (Duchenne muscular dystrophy, 23 couples), and FMR1(fragile X syndrome, 17 couples).After excluding GJB2 c.109G>A, the detection rate of at-risk couples was 3.91%(651/16 669), which was lowered to 1.72%(287/16 669) after further excluding G6PD.The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰(72.5/16 669).Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95% of at-risk couples, while screening for the top 54 genes further increased the detection rate to over 99%.
Conclusion: This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population.In carrier testing, genetic counseling for specific genes or gene variants can be challenging, and the couples need to be informed of these difficulties before testing and provided with options for not screening these genes or gene variants.
目的: 通过大规模多中心的多种遗传病携带者筛查，调查中国人群单基因病的流行病学特征以及突变谱，为制定适合中国人群的遗传病预防策略提供依据。
方法: 本研究在中国的12个临床中心共招募33 104例受检者（16 610例女性），基于高通量测序和多种PCR对223个基因的携带者状态进行检测。
结果: 197个常染色体基因的合并携带者频率为55.58%，26个X连锁基因的合并携带者频率为1.84%。在16 669例家系中，共检出874对（5.24%）高危夫妇。其中常染色体基因高危夫妇584对（3.50%），X连锁基因高危夫妇306对（1.84%），16对夫妇同时为常染色体基因和X连锁基因高危夫妇。最常检出的常染色体高危基因包括GJB2（常染色体隐性耳聋1A，393对），HBA1/HBA2（α-地中海贫血，36对）和PAH（苯丙酮尿症，14对），SMN1（脊髓性肌萎缩症，14对）。最常检出的X连锁高危基因包括G6PD（G6PD缺乏症，236对），DMD（进行性假肥大性肌营养不良，23对）和FMR1（脆性X综合征，17对）。除外G6PD后的高危夫妇率为3.91%（651/16 669），进一步除外GJB2 c.109G>A位点后，高危夫妇率为1.72%（287/16 669）。理论上严重的单基因病出生缺陷的发病率约为4.35‰（72.5/16 669）。对导致高危夫妇最多的22个基因进行筛查可检出95%以上的高危夫妇，对导致高危夫妇最多的54个基因进行筛查可检出99%以上的高危夫妇。
结论: 本研究揭示了我国人群中223种单基因病的携带者频率，为中国人群的携带者筛查策略制定和panel设计提供依据。在携带者筛查实践中，针对某些特殊基因或变异位点的遗传咨询可能会面临困难。这些特殊基因或变异需要在检测前告知受检夫妇，并在可能的情况下提供不筛查这些基因或变异的选择。
Keywords: genetic carrier screening; genetic counseling; monogenic disorders.