Prenatal Presentation of RMRP ‐Related Skeletal Dysplasia: Clinical and Genomic Expansion

The RNA subunit of the mitochondrial RNA processing endoribonuclease complex is encoded by RMRP. Biallelic variants in RMRP are known for anauxetic dysplasia 1 (AD), cartilage-hair hypoplasia (CHH), and metaphyseal dysplasia without hypotrichosis. More than 140 variants in RMRP have been reported in patients with RMRP-related disorders. Genotype-phenotype correlation is poorly understood. Patients documented are predominantly children and young adults, and prenatal onset of clinical symptoms has been reported in only a limited number of cases. We identified biallelic variants in RMRP in a family with two affected fetuses with lethal skeletal dysplasia. We collected eight more patients who developed prenatal symptoms of RMRP-related disorders. We describe extensive clinical phenotyping, an atlas of radiological images, and genetic results of 10 novel fetal cases presenting with CHH and compare our findings with seven further previously reported fetuses. Despite the variability of clinical signs in CHH, a severe fetal presentation may be suspected as early as 16 weeks of gestation based on skeletal findings. We observed that variants clustering at the paired domains of the RMRP transcript and/or promoter regions preferably lead to early severe phenotypes. The molecular diagnosis may be missed, as current exome captures do not always include RNA genes.