The phenotype combining Treacher Collins Syndrome features with Diamond-Blackfan Anemia is a heterogeneous ribosomopathy. K. Sol-Church1, D. Stabley1, A. Haskins Olney2, C. Curry3, J. Fisher3, L. Pilchman1, C. Schanen1, J. X. Chong4, D. E. Ward1, K. W. Gripp5, UW Center for Mendelian Genomics, Seattle WA 1) Biomedical Research, Alfred I duPont Hospital for Children, Wilmington, DE; 2) Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE; 3) Genetic Medicine Central California, Fresno/UCSF, CA; 4) University of Washington Center for Mendelian Genomics, Seattle, WA; 5) Medical Genetics, A. I. duPont Hospital for Children, Wilmington, DE.

   Diamond-Blackfan anemia (DBA) and Treacher Collins syndrome (TCS) are two distinct congenital disorders caused by defective ribosome biogenesis. DBA is a bone marrow failure syndrome, which typically present with macrocytic anemia in early infancy, short stature with craniofacial anomalies and a risk for cancer. DBA is caused by heterozygous mutations in ribosomal proteins, most commonly RPS19. TCS is characterized by severe craniofacial dystosis resulting in conductive hearing loss and typically results from heterozygous TCOF1 mutations affecting RNA polymerase. A combination of facial features resembling DBA and TCS was reported as a distinctive phenotype (Gripp, AJMG 2001; Handler, J Craniofac Surg 2009). Patients with the combined DBA/TCS phenotype were negative for mutations in these candidate genes. Material and Methods: Whole exome sequencing was performed on DNA isolated from the members of five unrelated families including seven individuals with a DBA/TCS phenotype. Data analysis generated candidate variants that were validated using Sanger sequencing and segregation analysis. Results: A heterozygous germline RPS26 mutation c.259C>T, predicting p.Arg87Ter, is present in the affected family members reported in Handler 2009, but not in the unaffected mother. This variant identified by rs148942765 is not seen in the 1,000 genome or UW-CMG databases. In two families, a novel c.1A>G transition in exon 1 of RPS28 (p.Met1Val), is heterozygous in one proband; and apparently mosaic in another unrelated proband. This mutation is not reported in the publicly available databases. In a fourth family, two cousins inherited an X-linked c.191A>G mutation in the TSR2 gene from their mothers. The resulting p.Glu64Gly change affects a conserved residue of a pre-rRNA-processing protein. Data analysis is ongoing for the last family. Discussion: We identified novel pathogenic mutations in genes involved in RNA processing in 4 families with a complex DBA/TCS phenotype. Though the RPS26 mutation is novel, this gene is known to be involved in DBA. In contrast, this is the first evidence that a mutation in RPS28 causes this phenotype. It is noteworthy that a similar p.Met1Val variant in RPS26 causes DBA10. Most strikingly, we identified an X-linked form of this syndrome in cousins harboring a mutation in yet another ribosomal gene TSR2. These data suggest that the DBA/TCS phenotype is a rare expression of the DBA spectrum, rather than an independent phenotype.

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