Devadoss Gandhi Geethanjali, Aliyev Elbay, Syed Najeeb, Vempalli Fazulur Rehaman, Saad Chadi, Mbarek Hamdi, Al-Saei Omayma, Al-Maraghi Aljazi, Abdi Mona, Krishnamoorthy Navaneethakrishnan, Badii Ramin, Akil Ammira A, Ben-Omran Tawfeg, Fakhro Khalid A
Human Genetics Department, Sidra Medicine, Doha, Qatar.
Bioinformatics, Genomic Data Science Core Sec, Sidra Medicine, Doha, Qatar.
Genet Med. 2024 Dec;26(12):101268. doi: 10.1016/j.gim.2024.101268. Epub 2024 Sep 14.
To date, approximately 1400 inherited metabolic disorders (IMDs) have been described, some of which are treatable. It is estimated that 2% to 3% of live births worldwide are affected by treatable IMDs. Roughly 80% of IMDs are autosomal recessive, leading to a potentially higher incidence in regions with high consanguinity.
The study utilized genome sequencing data from 14,060 adult Qatari participants who were recruited by the Qatar Biobank and sequenced by the Qatar Genome Program. The genome sequencing data were analyzed for 125 nuclear genes known to be associated with 115 treatable IMDs.
Our study identified 253 pathogenic/likely pathogenic single-nucleotide variations associated with 69 treatable IMDs, including 211 known and 42 novel predicted loss-of-function variants. We estimated that approximately 1 in 13 unrelated individuals (8%) carry a heterozygous pathogenic variant for at least 1 of 46 treatable IMDs. Notably, phenylketonuria/hyperphenylalaninemia and homocystinuria had among the highest carrier frequencies (1 in 68 and 1 in 85, respectively).
Population-based studies of treatable IMDs, particularly in globally under-studied populations, can identify high-frequency alleles segregating in the community and inform public health policies, including carrier and newborn screening.
迄今为止，已描述了约1400种遗传性代谢疾病（IMD），其中一些是可治疗的。据估计，全球2%至3%的活产儿受可治疗的IMD影响。大约80%的IMD是常染色体隐性遗传，这导致在近亲结婚率高的地区发病率可能更高。
该研究利用了由卡塔尔生物样本库招募并由卡塔尔基因组计划进行测序的14060名成年卡塔尔参与者的基因组测序数据。对已知与115种可治疗的IMD相关的125个核基因的基因组测序数据进行了分析。
我们的研究确定了与69种可治疗的IMD相关的253个致病/可能致病的单核苷酸变异，包括211个已知的和42个新预测的功能丧失变异。我们估计，大约每13个无亲缘关系的个体中就有1个（8%）携带至少46种可治疗的IMD中1种的杂合致病变异。值得注意的是，苯丙酮尿症/高苯丙氨酸血症和同型胱氨酸尿症的携带频率最高（分别为1/68和1/85）。
对可治疗的IMD进行基于人群的研究，特别是在全球研究不足的人群中，可以识别在社区中分离的高频等位基因，并为公共卫生政策提供信息，包括携带者和新生儿筛查。
