Molecular Biology and Forensic Laboratory, Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, Lahore, 54000, Pakistan.
Department of Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, Pakistan.
Genes Genomics. 2021 May;43(5):503-512. doi: 10.1007/s13258-021-01070-7. Epub 2021 Mar 12.
Intellectual disability (ID) is a heterogeneous disorder affecting 1-3% of the population. Elucidation of monogenic variants for ID is a current challenge. These variants can be better demonstrated in consanguineous affected families.
The study was designed to find the genetic variants of ID in consanguineous families.
We analyzed five unrelated consanguineous Pakistani families affected with ID using whole exome sequencing (WES). Data was analyzed using different bioinformatics tools and software.
We mapped four variants including three novels in four different ID known genes. Each variant is found in a different family, co-segregating with a recessive pattern of inheritance. The novel variants found are; c. 2_4del (p.?) mapped in ROS1 and c. 718G>A (p.Gly240Arg) in GRM1. Another novel causative variant, c.2673del (p.Gly892Aspfs17) identified in COL18A1 in a recessive form, a gene reported for Knobloch syndrome that manifests ID along with typical retinal abnormalities, and this phenotype was confirmed on reverse phenotyping. A mutation c.2134C>T (p.Arg712) in TRAPPC9 has been found first time in the homozygous recessive form in our enrolled three affected siblings while it was previously reported in compound heterozygous form in a Caucasian descent. While fifth family remained unsolved.
These mutations in four different genes with a recessive inheritance would be a contribution to the disease variant database of this devastating disorder.
智力障碍（ID）是一种影响 1-3%人群的异质性疾病。阐明 ID 的单基因变异是当前的挑战。这些变异在近亲受累家庭中表现得更好。
本研究旨在寻找近亲受累家庭中 ID 的遗传变异。
我们使用全外显子组测序（WES）分析了 5 个无亲缘关系的巴基斯坦近亲受累 ID 家庭。使用不同的生物信息学工具和软件对数据进行分析。
我们在四个不同的 ID 已知基因中定位了四个变体，包括三个新变体。每个变体都存在于不同的家庭中，与隐性遗传模式共分离。发现的新变体包括：c.2_4del（p.）在 ROS1 中，c.718G>A（p.Gly240Arg）在 GRM1 中。另一个新的致病变体 c.2673del（p.Gly892Aspfs17）在 COL18A1 中以隐性形式发现，该基因被报道与 Knobloch 综合征有关，表现为 ID 以及典型的视网膜异常，并且这种表型在反向表型确认。c.2134C>T（p.Arg712）在 TRAPPC9 中的突变在我们纳入的 3 个受影响的兄弟姐妹中首次以纯合隐性形式发现，而之前在高加索血统的复合杂合形式中报道过。而第五个家庭仍然没有解决。
这四个具有隐性遗传的不同基因中的突变将为这种毁灭性疾病的疾病变异数据库做出贡献。
