GNPAT and Rhizomelic Chondrodysplasia Punctata

GNPAT has been robustly associated with rhizomelic chondrodysplasia punctata through multiple independent studies. Case reports have identified loss‑of‑function mutations in GNPAT, including a homozygous deletion, c.1428delC (p.Met477CysfsTer18), which was uncovered in a patient with paternal isodisomy. This mutation is representative of the disruptive variants reported across independent families, supporting autosomal recessive inheritance (PMID:20583171).

Detailed genetic evidence is provided by at least three unrelated probands demonstrated in individual case reports and multi‑patient studies. These studies have identified additional variant types, including splice and frameshift mutations, that consistently segregate with the severe phenotype of RCDP. The genetic data are further bolstered by familial segregation analyses in consanguineous families, thereby strengthening the gene‑disease association (PMID:37323250, PMID:9843043).

Functional studies have contributed moderate evidence to the overall pathogenicity framework. In vitro assessments and cellular models indicate that mutations in GNPAT lead to diminished enzyme activity and impaired plasmalogen synthesis. These findings correlate strongly with the clinical and biochemical features observed in patients with RCDP, thereby providing experimental support for the disease mechanism (PMID:21990100).

The convergence of clinical, genetic, and functional data establishes a strong association between GNPAT dysfunction and rhizomelic chondrodysplasia punctata. In addition, multi‑patient genetic epidemiology studies further underline the significance of GNPAT variants in disease prevalence and expression. Although additional rare variants are reported across the literature, the loss‑of‑function allele c.1428delC (p.Met477CysfsTer18) remains representative of the disruption causing this disorder.

The integration of evidence from case studies with experimental validation offers clear diagnostic utility, aiding clinicians in establishing a definitive genetic diagnosis. Moreover, the precise delineation of variant types and their impact on enzyme function provides a valuable framework for both commercial assay development and future research publications.

Key Take‑home: The strong genetic and functional evidence linking GNPAT loss‑of‑function to rhizomelic chondrodysplasia punctata emphasizes its relevance for accurate diagnosis and underscores the clinical utility of including GNPAT in diagnostic gene panels.

References

• American journal of medical genetics. Part A • 2010 • Rhizomelic chondrodysplasia punctata type 2 resulting from paternal isodisomy of chromosome 1 PMID:20583171
• Clinical case reports • 2023 • Neonatal rhizomelic chondrodysplasia punctata type 2 caused by a novel homozygous variant in the GNPAT gene PMID:37323250
• American journal of medical genetics • 1998 • Developmental delay and growth failure caused by a peroxisomal disorder, dihydroxyacetonephosphate acyltransferase (DHAP-AT) deficiency PMID:9843043
• Human molecular genetics • 1998 • Acyl‑CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2 PMID:9536089
• Human mutation • 2012 • Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3 PMID:21990100

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