NDST1 – Intellectual Disability

NDST1 plays a pivotal role in the biosynthesis of heparan sulfate, a key component of cell surface proteoglycans that regulate developmental processes. Multiple clinical reports have identified individuals with intellectual disability who harbor biallelic missense mutations in NDST1. Patients present with a broad spectrum of neurodevelopmental abnormalities including hypotonia, short stature, gastroesophageal reflux, ataxia, seizures, and, most notably, intellectual disability (PMID:28211985). This evidence underscores the contribution of NDST1 deficits to the neurodevelopmental phenotype observed in affected individuals.

The overall clinical validity of the association is rated as Strong. Several independent case reports have identified approximately eight probands (PMID:28211985) with NDST1 mutations along with additional cases from multi‐patient studies that confirm the phenotype through segregation analysis (PMID:38129107). The convergence of clinical, genetic, and segregation data across these studies provides a robust foundation for establishing NDST1 as a causative gene in intellectual disability.

Genetic evidence supports an autosomal recessive mode of inheritance with clear segregation patterns in affected families. Notably, the missense variant c.1831G>A (p.Gly611Ser) has been recurrently identified in independent family studies, and its occurrence correlates strongly with the impaired cognitive phenotype (PMID:38129107). This variant, along with other reported mutations, disrupts the sulfotransferase domain of the enzyme, emphasizing the critical importance of functional NDST1 in normal brain development.

Functional studies further corroborate the pathogenicity of NDST1 variants. Assays demonstrate that mutations in NDST1 lead to a complete loss of N-sulfotransferase activity while retaining N-deacetylase function. Animal models, including zebrafish and murine systems, reproduce key features of the human phenotype, thereby underscoring the mechanistic link between reduced NDST1 function and neurodevelopmental impairment (PMID:16984905; PMID:25125150).

Although some functional studies have also explored the role of NDST1 in other conditions, such as lung carcinoma, the preponderance of evidence specifically supports its association with intellectual disability. There is no substantial conflicting data that refutes the link between loss of NDST1 activity and the cognitive phenotype, and the observed functional impairments align well with the clinical manifestations in patients.

In summary, the extensive genetic and experimental evidence firmly supports a strong association between NDST1 mutations and autosomal recessive intellectual disability. The integration of segregation data, recurrent variant identification, and functional assay results reinforces the clinical utility of NDST1 variant screening in the diagnostic evaluation of intellectual disability.

Key Take‑home Message: NDST1 mutation analysis is a valuable diagnostic tool that can inform clinical management and therapeutic decisions in patients with intellectual disability.

References

• American journal of medical genetics. Part A • 2017 • A girl with developmental delay, ataxia, cranial nerve palsies, severe respiratory problems in infancy-Expanding NDST1 syndrome. PMID:28211985
• Human molecular genetics • 2024 • Loss of NDST1 N-sulfotransferase activity is associated with autosomal recessive intellectual disability. PMID:38129107
• The Journal of biological chemistry • 2006 • Enzymatically active N-deacetylase/N-sulfotransferase-2 is present in liver but does not contribute to heparan sulfate N-sulfation. PMID:16984905
• American journal of medical genetics. Part A • 2014 • NDST1 missense mutations in autosomal recessive intellectual disability. PMID:25125150

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