PDF(Pubmed)
Abstract：
UNASSIGNED: Familial hemophagocytic lymphohistiocytosis (FHLH) is an inherited life-threatening disease. Five types are identified, with the addition of congenital immunodeficiency syndromes in which HLH is a typical manifestation. The literature on this disease is very scarce in the Middle East, with only a few scattered reports.
UNASSIGNED: We report detailed demographic, clinical, and genomic data from 28 patients diagnosed with primary and familial HLH over the last decade in Qatar. An evaluation was performed of allele frequencies of deleterious variants from 12 primary and familial HLH causative genes on the Qatar Genome Programme (QGP) cohort of 14,669 Qatari individuals.
UNASSIGNED: The genetic diagnosis was obtained in 15 patients, and four novel mutations in Perforin 1 (PRF1), UNC13D, LYST, and RAB27A genes were found. We identified 22,945 low/high/moderate/modifier impact variants significantly enriched in the QGP in those 12 genes. The variants rs1271079313 in PRF1 and rs753966933 in RAB27A found in our patient cohort were significantly more prevalent in the QGP compared to the Genome Aggregation Database (gnomAD) database, with a high carrier frequency in the Qatari population.
UNASSIGNED: We established the first primary and familial HLH Registry in the Gulf Region and identified novel possibly pathogenic variants present at higher frequency in the Qatari population, which could be used for screening purposes. Raising awareness about primary and familial HLH and implementing screening activities in the Qatari highly inbred population could stem into more comprehensive premarital and prenatal evaluations and faster diagnosis.
UNASSIGNED: We report detailed demographic, clinical, and genomic data from 28 patients diagnosed with primary and familial HLH over the last decade in Qatar. An evaluation was performed of allele frequencies of deleterious variants from 12 primary and familial HLH causative genes on the Qatar Genome Programme (QGP) cohort of 14,669 Qatari individuals.
UNASSIGNED: The genetic diagnosis was obtained in 15 patients, and four novel mutations in Perforin 1 (PRF1), UNC13D, LYST, and RAB27A genes were found. We identified 22,945 low/high/moderate/modifier impact variants significantly enriched in the QGP in those 12 genes. The variants rs1271079313 in PRF1 and rs753966933 in RAB27A found in our patient cohort were significantly more prevalent in the QGP compared to the Genome Aggregation Database (gnomAD) database, with a high carrier frequency in the Qatari population.
UNASSIGNED: We established the first primary and familial HLH Registry in the Gulf Region and identified novel possibly pathogenic variants present at higher frequency in the Qatari population, which could be used for screening purposes. Raising awareness about primary and familial HLH and implementing screening activities in the Qatari highly inbred population could stem into more comprehensive premarital and prenatal evaluations and faster diagnosis.
摘要：
■家族性噬血细胞性淋巴组织细胞增生症（FHLH）是一种遗传性危及生命的疾病。确定了五种类型，加上先天性免疫缺陷综合征，其中HLH是典型的表现。关于这种疾病的文献在中东非常稀缺，只有一些分散的报告。
■我们报告了详细的人口统计信息，临床,和基因组数据从28名患者诊断为原发性和家族性HLH在过去十年在卡塔尔。在卡塔尔基因组计划（QGP）的14,669名卡塔尔个体中，对来自12个原发性和家族性HLH致病基因的有害变体的等位基因频率进行了评估。
■对15例患者进行了基因诊断，穿孔素1（PRF1）中的四个新突变，UNC13D,LYST,并发现了RAB27A基因。我们在这12个基因中鉴定了22,945个低/高/中等/修饰剂冲击变体在QGP中显著富集。与基因组聚集数据库（gnomAD）数据库相比，在我们的患者队列中发现的PRF1中的rs1271079313和RAB27A中的rs753966933变体在QGP中明显更普遍，在卡塔尔人口中具有很高的载波频率。
■我们在海湾地区建立了第一个原发性和家族性HLH登记处，并确定了在卡塔尔人群中以较高频率出现的新的可能致病变异，可用于筛查目的。提高对原发性和家族性HLH的认识，并在卡塔尔高度近交人群中开展筛查活动，可能会导致更全面的婚前和产前评估和更快的诊断。
■我们报告了详细的人口统计信息，临床,和基因组数据从28名患者诊断为原发性和家族性HLH在过去十年在卡塔尔。在卡塔尔基因组计划（QGP）的14,669名卡塔尔个体中，对来自12个原发性和家族性HLH致病基因的有害变体的等位基因频率进行了评估。
■对15例患者进行了基因诊断，穿孔素1（PRF1）中的四个新突变，UNC13D,LYST,并发现了RAB27A基因。我们在这12个基因中鉴定了22,945个低/高/中等/修饰剂冲击变体在QGP中显著富集。与基因组聚集数据库（gnomAD）数据库相比，在我们的患者队列中发现的PRF1中的rs1271079313和RAB27A中的rs753966933变体在QGP中明显更普遍，在卡塔尔人口中具有很高的载波频率。
■我们在海湾地区建立了第一个原发性和家族性HLH登记处，并确定了在卡塔尔人群中以较高频率出现的新的可能致病变异，可用于筛查目的。提高对原发性和家族性HLH的认识，并在卡塔尔高度近交人群中开展筛查活动，可能会导致更全面的婚前和产前评估和更快的诊断。
