下一代测序检测北印度FXIII缺乏症患者中F13A1的基因谱

Genetic Spectrum in F13A1 Detected by Next-Generation Sequencing Among North Indian Patients with FXIII Deficiency.

作者信息

Sharma Ritika, Jamwal Manu, Singh Namrata, Sharma Prashant, Bansal Deepak, Trehan Amita, Malhotra Pankaj, Jain Arihant, Ahluwalia Jasmina, Das Reena, Kumar Narender

机构信息

Department of Hematology, Postgraduate Institute of Medical Education and Research, 160012 Chandigarh, India.

Department of Pediatrics (Hematology-Oncology Unit), Postgraduate Institute of Medical Education and Research, 160012 Chandigarh, India.

出版信息

Indian J Hematol Blood Transfus. 2023 Apr;39(2):276-283. doi: 10.1007/s12288-022-01579-1. Epub 2022 Nov 1.

DOI:10.1007/s12288-022-01579-1

PMID:37006978

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10064406/

Abstract

PURPOSE

The study aimed to explore the molecular defects underlying FXIII deficiency.

MATERIALS AND METHODS

Sixteen unrelated cases were enrolled based on the indication of the urea clot solubility test and Factor XIII-A antigen levels. Cases were further subjected to targeted next-generation sequencing (custom gene panel: , , , , The pathogenic/likely pathogenic variants were validated by Sanger sequencing in the patients and family members.

RESULTS

Mean age of referral to our center was 27.2 years (8 week-67 years). Consanguinity was found in only one of the 16 cases and 9 cases presented in infancy. The most common symptoms were skin bleeds (69%) and umbilical cord bleed (50%). The clot solubility test was positive in 12, inconclusive in 1, and normal in 3. Mean FXIII-A levels were 15.7 IU/dL (range 0.6 to 49.5 IU/dL). Pathogenic/likely pathogenic variants in were found in 11 (69%). Nine cases (82%) were homozygous, and two were compound heterozygous. Total eleven variants were found of which four were missense (c.1226G>A; c.998C>T; c.631G>C; c.2134A>C); three deletion (c.521delG; c.742delA; c.1405_1408delCAAA); two nonsense (c.1112G>A; c.1127G>A) and two splice site (c.1909-1G>C; c.2045G>A). No probably pathogenic variant was found in the .

CONCLUSION

Inherited FXIII deficiency with bleeding is associated with genetic defects in predominantly the gene. A variety of variants were seen in this cohort. A nonsense variant c.1127G>A found in three of our cases seems to be recurrent. This data will contribute to designing functional studies and antenatal testing in affected families.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s12288-022-01579-1.

摘要

目的

本研究旨在探究凝血因子 XIII 缺乏症潜在的分子缺陷。

材料与方法

根据尿素凝块溶解度试验结果及凝血因子 XIII - A 抗原水平，纳入 16 例无亲缘关系的病例。对病例进一步进行靶向二代测序（定制基因 panel：……）。通过 Sanger 测序在患者及其家庭成员中验证致病/可能致病的变异。

结果

转诊至我们中心的患者平均年龄为 27.2 岁（8 周 - 67 岁）。16 例中仅 1 例有近亲结婚情况，9 例在婴儿期发病。最常见的症状为皮肤出血（69%）和脐带出血（50%）。凝块溶解度试验 12 例呈阳性，1 例结果不确定，3 例正常。凝血因子 XIII - A 平均水平为 15.7 IU/dL（范围 0.6 至 49.5 IU/dL）。11 例（69%）发现基因存在致病/可能致病的变异。9 例（82%）为纯合子，2 例为复合杂合子。共发现 11 种变异，其中 4 种为错义变异（c.1226G>A；c.998C>T；c.631G>C；c.2134A>C）；3 种为缺失变异（c.521delG；c.742delA；c.1405_1408delCAAA）；2 种为无义变异（c.1112G>A；c.1127G>A）；2 种为剪接位点变异（c.1909 - 1G>C；c.2045G>A）。基因未发现可能致病的变异。