Center for Medical Genetics, Gansu Provincial Maternity and Child Care Hospital, Gansu Provincial Clinical Research Center for Birth Defects and Rare Diseases, Lanzhou, China.
School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China.
Mol Genet Genomic Med. 2024 Jan;12(1):e2308. doi: 10.1002/mgg3.2308. Epub 2023 Nov 27.
Immune skeletal dysplasia with neurodevelopmental abnormalities (ISDNA) is an extremely rare, autosomal recessive genetic disorder characterized by various skeletal abnormalities, neurodevelopmental deficits, and abnormal immune system function. ISDNA is caused by variation in the exostosin-like 3 (EXTL3) gene, located on chromosome 8p21.2, whose primary function is the biosynthesis of heparan sulfate (HS) skeleton structure. Only a few variations in the EXTL3 gene have been discovered so far. In these years of development, many pathogenic variants in genetic diseases with genetic and phenotypic heterogeneity have been investigated using whole-exome sequencing (WES) technology.
In this research, a novel EXTL3 variant was first detected in a patient using WES, which was validated from Sanger sequencing in this family. Family history and clinical information were then collected through comprehensive medical examinations and genetic counseling. In silico prediction was then utilized to confirm the pathogenicity of the variant.
A novel homozygous variant, NM_001440: c.2015G>A (p.Arg672Gln) in the EXTL3 gene, was identified using WES, which has never been reported before. Sanger sequencing was performed to confirm that the variant segregated with the disease within the family.
This research identified a novel pathogenic variant in the EXTL3 gene responsible for ISDNA in a Chinese family. It showed the potential diagnostic role of WES in ISDNA, expanded the EXTL3 gene variation spectrum, and demonstrated that the diagnosis of ISDNA using WES is feasible and effective. More comprehensive genetic counseling and precise prenatal diagnosis for the next pregnancy can also be provided to families with genetic disorders.
免疫骨骼发育不良伴神经发育异常（ISDNA）是一种极其罕见的常染色体隐性遗传疾病，其特征为多种骨骼异常、神经发育缺陷和免疫系统功能异常。ISDNA 是由位于 8p21.2 染色体上的外切体样 3（EXTL3）基因突变引起的，其主要功能是合成肝素硫酸（HS）骨架结构。到目前为止，只发现了 EXT3 基因的少数几种变异。在这些年的发展中，使用全外显子组测序（WES）技术研究了遗传和表型异质性的遗传疾病中的许多致病变体。
在这项研究中，首先使用 WES 在患者中检测到一种新型 EXTL3 变体，该变体在该家族中通过 Sanger 测序得到验证。然后通过全面的医学检查和遗传咨询收集家族史和临床信息。然后利用计算机预测来确认变体的致病性。
使用 WES 鉴定出 EXT3 基因中的一种新型纯合变体 NM_001440：c.2015G>A（p.Arg672Gln），该变体以前从未报道过。进行 Sanger 测序以确认该变体在家族内与疾病共分离。
本研究在中国一个家族中发现了 EXTL3 基因导致 ISDNA 的一种新型致病变体。它表明 WES 在 ISDNA 中的潜在诊断作用，扩展了 EXTL3 基因变异谱，并证明使用 WES 诊断 ISDNA 是可行且有效的。还可以为遗传疾病的家庭提供更全面的遗传咨询和精确的产前诊断。
