A Case Report of Suspected Achondrogenesis Type 1A with Novel TRIP11 Variant: Parental Carrier Detection and Targeted Prenatal Exclusion in a Subsequent Pregnancy

Abstract

Background: Achondrogenesis type 1A (ACG1A) is a rare perinatally lethal skeletal dysplasia that results from biallelic loss-of-function variants in TRIP11, which encodes the Golgi microtubule-associated protein GMAP-210. A case of clinically suspected ACG1A in an unrelated couple is described after termination at 19 weeks of gestation of a severely micromorphic fetus with cloverleaf skull, sacral agenesis, vertebral flattening, and thoracic hypoplasia. Genetic testing was not done on the affected fetus.

Case Presentation: A heterozygous 13-base-pair deletion in exon 13 of TRIP11 (Chr14:g.91999349_91999361del) was discovered in the mother during a subsequent preconception genetic evaluation using whole exome sequencing (WES). In the father, Sanger sequencing confirmed the same heterozygous variant consistent with an autosomal recessive inheritance. According to the American College of Medical Genetics and Genomics (ACMG) criteria, the frameshift deletion, which is expected to cause premature termination, was deemed likely pathogenic (PVS1, PM2, PP3) and was not present in public variant databases. Although molecular confirmation in the affected fetus was unavailable, the phenotype was highly suggestive of TRIP11-related ACG1A. While molecular confirmation in the affected fetus was not pos-sible, the phenotype strongly suggested TRIP11-related ACG1A. In the subsequent pregnancy, targeted prenatal testing with amniocentesis showed absence of the familial variant in the fetus and the pregnancy was continued.

Conclusion: This case expands the mutational spectrum of TRIP11 and underscores the clinical utility of exome sequencing for carrier detection and recurrence preven-tion in lethal skeletal dysplasias. It also emphasizes the importance of clinical pheno-typing integration with molecular diagnostics while recognizing the limitations that arise in the absence of fetal genotyping.