Immune skeletal dysplasia with neurodevelopmental abnormalities caused by a novel variant of EXTL3 gene in a Chinese family.

Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 101603758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2324-9269 (Electronic) Linking ISSN: 23249269 NLM ISO Abbreviation: Mol Genet Genomic Med Subsets: MEDLINE

Original Publication: [Hoboken, NJ] : John Wiley & Sons, [2013]-

Musculoskeletal Abnormalities*/genetics ; N-Acetylglucosaminyltransferases*/genetics ; Osteochondrodysplasias*/genetics; Female ; Humans ; Pregnancy ; China ; Heparitin Sulfate

Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
(© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

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2021-1-182 the Lanzhou Science and Technology Plan Project; 2022-5-81 the Lanzhou Science and Technology Plan Project; 2018-RC-95 the Lanzhou Talent Innovation and Entrepreneurship Project; 2016YFC1000307 the National Key Research and Development Program of China; 2005DKA32408 the National Population and Reproductive Health Science Data Center; 21JR7RA680 the Science and Technology Program of Gansu Province

Keywords: EXTL3 gene; immune skeletal dysplasia with neurodevelopmental abnormalities; immune system function abnormalities; neurodevelopmental deficits; skeletal abnormalities

0 (EXTL3 protein, human)
9050-30-0 (Heparitin Sulfate)
EC 2.4.1.- (N-Acetylglucosaminyltransferases)

Date Created: 20231127 Date Completed: 20240205 Latest Revision: 20240205

20250114

PMC10767689

10.1002/mgg3.2308

38010033