Identification of Novel and Recurrent RMRP Variants in a Series of Brazilian Patients with Cartilage-Hair Hypoplasia: McKusick Syndrome.

Cartilage-hair hypoplasia syndrome (CHH) is an autosomal recessive disorder caused by pathogenic variants of the RMRP gene and characterized by metaphyseal bone dysplasia associated with hypotrichosis, immunodeficiency, and predisposition to malignancy. However, the genotype-phenotype correlation in CHH is not well understood. Here, we report a single country cohort of 23 Brazilian patients with clinical and radiological features consistent with CHH. We found 23 different pathogenic variants in the RMRP gene - 12 novel and 11 previously described in the literature. Interestingly, the most frequent Finnish pathogenic variant related to CHH (g.71A>G) was not found in our cohort. In contrast, more than 50% of the patients carried the rare g.196C>T variant suggesting a possible founder effect in the Brazilian population. In silico analysis showed that pathogenic variants occurred either in the regions conserved in mammalian species or within essential domains for the ribonucleoprotein complex. Pathogenicity prediction studies can improve the understanding of how these variants affect RNA.

The Liberfarb syndrome, a multisystem disorder affecting eye, ear, bone, and brain development, is caused by a founder pathogenic variant in thePISD gene.

PURPOSE: We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers. METHODS: Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing. RESULTS: Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts. CONCLUSION: We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.