Cartilage-hair Hypoplasia (CHH) and Related Disorders via the RMRP Gene

Cartilage-hair hypoplasia (OMIM#250250, aka McKusick-type metaphyseal chondrodysplasia) is a pleiotropic disease, characterized by disproportionate short stature, hypoplastic hair, and metaphseal abnormalities. Other common features include defective immunity manifested by unusual susceptibility to chickenpox, risk for malignancies, Hirschsprung disease, hypoplastic anemia, and impaired spermatogenesis (Ridanpaa et al. Eur J Hum Genet 10:439-447, 2002). Metaphyseal dysplasia without hypotrichosis (MDWH; OMIM#250460), manifesting only as short stature and metaphyseal dysplasia, is thought to be a variant of CHH (Bonafe et al. Clin Genet 61:146-151, 2002). Anauxetic dysplasia (AD; OMIM#607095) is the severe form in the spectrum, characterized by extreme disproportionate short stature, hypodontia, and mild mental retardation (Thiel et al. Am J Hum Genet 81:519-529, 2007).

Cartilate-hair hypoplasia (CHH) and its related disorders (MDWH and AD) are inherited in an autosomal recessive manner. All three disorders are caused by variants in RMRP gene. RMRP encodes the RNA component of the mitochondrial RNA-processing endonuclease (MRP), which is a ubiquitously expressed eukaryotic endoribonuclease that cleaves various RNAs, including ribosomal, messenger, and mitochondrial RNAs (Ridanpaa et al. Am J Med Genet 121C:81-83, 2003). The gene product is an untranslated RNA, which is essential for RNase activity. Variants found in RMRP can be classified into two categories: insertions, duplications, or triplications in the promoter between TATA box and the transcription initiation site and variants in the transcribed region. The promoter variants can result in inefficient transcription initiation, while the ones in the transcribed region usually disrupt base-pairing required for conserved secondary structure and interaction with protein subunits. No clear genotype-phenotype correlation has been established. CHH is especially frequent among the Amish and Finnish populations; the carrier frequencies are 1:19 and 1:76, respectively. The most prevalent CHH-associated RMRP variant is g.70A>G, which is found in >90% Amish and Finnish patients and 48% of non-Finnish patients (Ridanpaa et al. Eur J Hum Genet 10:439-447, 2002).

This test is predicted to detect disease variants in >90% patients with CHH (Hermanns et al. Am J Med Genet 140A:2121-2130, 2006; Ridanpaa et al. Eur J Hum Genet 10:439-447, 2002). The sensitivity for patients with MDWH or AD is unknown.

This test provides full coverage of the transcribed region of the RMRP gene, plus ~100 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.