RMRP was first reported in relation to autosomal recessive cartilage-hair hypoplasia in 2001 (Ridanpaa et al, PMID: 11207361). The phenotype of CHH patients can be variable but may include: shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-colored hair, hematologic abnormalities and a spectrum of combined immunodeficiency. RMRP encodes an untranslated RNA component of mitochondrial RNA processing endoribonuclease that is critical for DNA replication; defective RMRP functioning ultimately impairs cell proliferation and differentiation. Over 130 variants (insertions, duplications and missense variations) have been reported in numerous publications (PMIDs: 11207361, 14569125, 16254002, 17015150, 18978468, 19150606, 21063072, 21570718, 25663137, 28094436, 28126377) and many are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be loss of function. Heterozygous carriers have not been shown to have a clinical phenotype. This gene-disease association is also supported by experimental evidence, PMIDs 20133615, 24889605, 10911993, 18804272). In summary, RMRP is definitively associated with autosomal recessive cartilage-hair hypoplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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