TRIP11 – Achondrogenesis type IA

Achondrogenesis type IA (ACG1A) is a rare, lethal autosomal recessive chondrodysplasia caused by biallelic loss-of-function variants in TRIP11, encoding the Golgi microtubule-associated protein GMAP-210. Affected fetuses present with severe intrauterine growth restriction, a narrow thorax, and pronounced limb hypoplasia, resulting in perinatal lethality (PMID:29872333).

To date, six unrelated fetuses from four independent families have been reported with ACG1A and biallelic TRIP11 variants: two compound heterozygous frameshifts c.2128_2129del (p.Ile710CysfsTer19) and c.2304_2307del (p.Asn768LysfsTer7) (PMID:29872333), one homozygous frameshift c.1938_1941del (p.Arg647fs) (PMID:31903676), and four fetuses homozygous for the deep intronic splice-altering variant c.5457+81T>A (PMID:34057271).

All pathogenic alleles result in GMAP-210 loss of function: frameshifts introduce premature stop codons, and the intronic c.5457+81T>A variant causes aberrant splicing with intron retention and transcript decay. No missense or hypomorphic variants have been associated with the lethal ACG1A phenotype. Segregation in two sibships further supports autosomal recessive inheritance (PMID:34057271).

Functional studies in patient-derived fibroblasts reveal drastically reduced TRIP11 mRNA and protein levels, disrupted Golgi architecture, and impaired ciliogenesis (PMID:34057271). Complementary zebrafish trip11 morphant models reproduce Golgi fragmentation and skeletal defects analogous to human ACG1A (PMID:30518689).

No conflicting evidence has challenged the causative role of TRIP11 in ACG1A; genotype–phenotype correlations consistently distinguish lethal ACG1A from milder TRIP11-related dysplasias. Collectively, the genetic and experimental data support a Strong ClinGen gene–disease association.

Key Take-home: Biallelic TRIP11 loss-of-function variants are a robust molecular marker for prenatal diagnosis and genetic counseling of lethal achondrogenesis type IA.

References

• The application of clinical genetics • 2018 • Achondrogenesis type 1A: clinical, histologic, molecular, and prenatal ultrasound diagnosis. PMID:29872333
• American journal of medical genetics. Part A • 2020 • Pathogenic variants in the TRIP11 gene cause a skeletal dysplasia spectrum from odontochondrodysplasia to achondrogenesis 1A. PMID:31903676
• Human Mutation • 2021 • Biallelic deep intronic variant c.5457+81T>A in TRIP11 causes loss of function and results in achondrogenesis 1A. PMID:34057271
• JCI Insight • 2018 • A common pathomechanism in GMAP-210- and LBR-related diseases. PMID:30518689

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