title: BRF1 mutations in a family with growth failure, markedly delayed bone age, and central nervous system anomalies.
abstract: Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature but also other organs/tissues causing additional clinical abnormalities. A 10-year old boy was evaluated for impaired postnatal linear growth (height 113.3 cm, -4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age. Exome sequencing identified compound heterozygous variants in the gene encoding RNA polymerase III transcription initiation factor 90 kDa subunit (BRF1) in both affected siblings: a missense mutation (c.875 C > G:p.P292R) and a frameshift mutation (c.551delG:p.C184Sfs). The frameshift mutation is expected to lead to nonsense-mediated mRNA decay (NMD) and/or to protein truncation. Expression of BRF1 with the P292R missense mutation failed to rescue yeast lacking BRF1. The findings confirm a previous report showing that biallelic mutations in BRF1 cause cerebellar-facial-dental syndrome. Our findings also help define the growth phenotype, indicating that the linear growth failure can become clinically evident before the neurological abnormalities and that a severely delayed bone age may serve as a diagnostic clue.
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Y H
authors.initials: YH
authors.lastname: Jee
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Sowada
authors.affiliation: Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Markello
authors.affiliation: Section of Pediatric Endocrinology and Diabetes, Department of Pediatrics, St. Christopher's Hospital of Children, Philadelphia, PA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Rezvani
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Borck
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Baron
mesh_terms: D002648:Child; D060825:Cognitive Dysfunction / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics; D059472:Exome; D005145:Face / Q000002:abnormalities; D005190:Family; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics*; D015003:Yeasts / Q000235:genetics
chemical_list: C441028:BRF1 protein, human; D035381:TATA-Binding Protein Associated Factors
keywords: BRF1; delayed bone age; exome sequencing; neurologic syndrome; severe short stature