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EXTL3 – Immunoskeletal Dysplasia with Neurodevelopmental Abnormalities

Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA) is an ultra-rare autosomal recessive disorder caused by biallelic variants in EXTL3. To date, 17 cases have been described in unrelated families, including the 15th case reported in an Indian patient homozygous for c.953C>T (p.Pro318Leu) ([PMID:35114981]), the 16th lethal phenotype case ([PMID:38010729]), and the 17th novel Chinese family harboring c.2015G>A (p.Arg672Gln) ([PMID:38010033]). Affected individuals present with short stature (HP:0004322), coarse facial features (HP:0000280), global developmental delay (HP:0001263), hypotonia (HP:0001252), neurodevelopmental delay (HP:0012758), skeletal dysplasia (HP:0002652), immunodeficiency (HP:0002721), and hepatic cysts (HP:0001407).

Genetic evidence is limited: all reported probands carry homozygous missense variants with no additional segregation data. Functional studies of EXTL3 demonstrate its role in heparan sulfate chain elongation—siRNA knockdown alters chain length in HEK293 cells, consistent with a loss-of-function mechanism—but variant-specific assays are lacking (The Journal of Biological Chemistry, 2007 [PMID:17761672]). No conflicting evidence has been reported. Further functional characterization and larger cohorts are needed to advance clinical validity. Key Take-home: Biallelic EXTL3 missense variants cause ISDNA; early molecular diagnosis via WES enables precise genetic counseling and management.

References

  • BMC Pediatrics • 2022 • An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C>T variant in EXTL3 gene: a case report PMID:35114981
  • Pediatric allergy, immunology, and pulmonology • 2023 • EXTL3-Associated Immunoskeletal Dysplasia with Neurodevelopmental Abnormalities: A Lethal Phenotype. PMID:38010729
  • Molecular genetics & genomic medicine • 2024 • Immune skeletal dysplasia with neurodevelopmental abnormalities caused by a novel variant of EXTL3 gene in a Chinese family. PMID:38010033
  • The Journal of Biological Chemistry • 2007 • Contribution of EXT1, EXT2, and EXTL3 to heparan sulfate chain elongation. PMID:17761672

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

17 probands in unrelated families with biallelic EXTL3 missense variants; no segregation data; limited cohort size

Genetic Evidence

Limited

Homozygous pathogenic variants identified in three unrelated families (total 17 cases); no additional affected relatives segregating

Functional Evidence

Limited

EXTL3 knockdown alters heparan sulfate chain elongation in vitro, consistent with LoF, but lacks variant-specific functional assays