A Novel BRF1 Mutation in Two Middle-Aged Siblings with Cerebellofaciodental Syndrome
Cerebellofaciodental syndrome (CFDS) is a rare autosomal recessive neurodevelopmental disorder characterized by a distinct set of clinical features, including cerebellar hypoplasia, intellectual disability, facial dysmorphisms, short stature, microcephaly, and dental anomalies. Since its initial description in 2015 by Borck et al., only six families with CFDS have been reported in the medical literature. The age of the affected individuals in these cases ranged from infancy to early adulthood, leaving a gap in understanding the natural history and clinical progression of the disease in older patients. This article presents a detailed account of a novel homozygous BRF1 gene mutation identified in two middle-aged siblings with CFDS, providing valuable insights into the genetic and clinical characteristics of this rare syndrome.
The study involved a consanguineous family of five members, including two affected siblings, their parents, and one unaffected sibling. All family members underwent comprehensive neurological evaluations conducted by qualified neurologists. Genomic DNA was extracted from peripheral blood leukocytes of all individuals, and whole exome sequencing was performed using the Agilent SureSelect Human All ExonV6 kit. Sequencing was carried out on an Illumina HiSeq 4000 Sequencer, and the resulting high-quality reads were aligned to the human reference genome (GRCh37/hg19) using the BWA tool. Variant calling was performed using SAMtools, and variant annotation and interpretation were conducted using ANNOVAR.
The researchers applied strict filtering criteria to identify potential pathogenic variants. These criteria included: (1) homozygous or compound heterozygous variants; (2) variants with a frequency of less than 1% in the 1000 Genomes Project, esp6500, and gnomAD databases; (3) variants located in exonic or splicing regions (±2 base pairs); (4) nonsynonymous variants; and (5) variants predicted to be harmful by at least two predictive software tools, including SIFT, PolyPhen-2, MutationTaster, and CADD, or predicted to affect splicing by dbscSNV. Cosegregation analysis was performed using polymerase chain reaction and Sanger sequencing, and candidate variants were further sequenced in 200 normal chromosomes. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines.
Whole exome sequencing of the proband revealed a homozygous missense variant c.874C>A (p.P292T) in the BRF1 gene (NM_001519) that met all the filtering criteria. This novel variant was located at the same residue as the previously reported pathogenic variant c.875C>A (p.P292H). The c.874C>A variant was absent in the 1000 Genomes Project, esp6500, and gnomAD databases and was highly conserved across species. It was predicted to be disease-causing by SIFT, PolyPhen-2, and MutationTaster. Cosegregation analysis confirmed that the two affected siblings carried the homozygous variant, while their parents were heterozygous carriers, and the unaffected sibling was wildtype. The variant was absent in 200 normal chromosomes and was classified as likely pathogenic according to ACMG guidelines (PM1, PM2, PM5, PP2, PP3).
The proband, a 41-year-old woman, was referred to the hospital for acute cerebral infarction. She presented with acute-onset right limb numbness and weakness, headache, dizziness, and nausea. Her medical history included intellectual disability and speech delay noted in preschool, muscle atrophy of the distal lower limbs at age ten, hypertension, and recurrent upper respiratory infections. Physical examination revealed positive neurological signs, including intellectual disability, slurred speech, slender extremities with truncal obesity, limb weakness, sensory disturbance of the right limbs, and right positive pyramidal signs (increased muscle tone, tendon hyperreflexia, and positive pathological signs). Craniofacial dysmorphisms included sparse hair and eyebrows, wave-shaped eyelids, a flat nose, low-set ears, an open-mouthed appearance, and micrognathia. Dental anomalies included prominent upper central incisors and early tooth loss. Skeletal anomalies included short stature, long slender fingers, camptodactyly of the fifth finger, and pes planus. Microcephaly and scoliosis were not observed. Her Mini-Mental State Examination (MMSE) score was five. Laboratory tests revealed severe hyperhomocysteinemia, hypokalemia, and hyperthyroidism. Imaging studies confirmed thyroid carcinoma, and brain computed tomography (CT) showed brain atrophy, particularly cerebellar vermis atrophy, bilateral periventricular leukomalacia, ventricular enlargement, and multiple scattered low-density lacunes.
The proband’s older brother, a 43-year-old male, exhibited similar clinical features. He was born prematurely and showed significant psychomotor impairment, including motor and speech delay. He learned to walk by age two and to speak by age three. He developed muscle atrophy of the distal lower limbs at age ten. Physical examination revealed intellectual disability, slender extremities with truncal obesity, craniofacial dysmorphisms (sparse hair and eyebrows, wave-shaped eyelids, low-set ears, flat nose, and micrognathia), dental anomalies (early tooth loss), and skeletal anomalies (short stature, long slender fingers, camptodactyly of the distal interphalangeal joint of the index finger, and pes planus). Microcephaly and scoliosis were not observed. His MMSE score was 12.
The clinical manifestations of both patients align with the essential features of CFDS, including cerebellar hypoplasia, intellectual disability, craniofacial dysmorphisms, dental anomalies, and skeletal anomalies. However, the study also identified previously undescribed features in these middle-aged patients, such as distal limb muscle atrophy, truncal obesity, long slender fingers, finger joint contractures, early tooth loss, and pes planus. These findings suggest that CFDS may manifest differently at different ages and highlight the clinical heterogeneity of the syndrome. The absence of microcephaly and scoliosis in these patients, which were common in previously reported cases, further underscores this variability.
The BRF1 gene, located on chromosome 14q32.33, encodes the BRF1 protein, which contains a conserved zinc ribbon domain and two cyclin domains. BRF1 is ubiquitously expressed in brain tissues, including the cerebellum, cerebellar hemisphere, anterior cingulate cortex, cortex, hippocampus, and basal ganglia. Previous studies have demonstrated that BRF1 plays a critical role in RNA polymerase III-dependent transcription, and its suppression in zebrafish resulted in a significant reduction in brain size. Additionally, loss of BRF1 has been shown to decrease tRNA levels and translation activity, increase apoptosis and necrosis, and reduce the size of multiple organs. BRF1 is also highly expressed in various human cancer cells, and elevated levels of BRF1 have been associated with poor prognosis in cancers such as prostate and breast cancer.
The identification of the novel BRF1 variant c.874C>A (p.P292T) in these middle-aged siblings expands the genetic and clinical spectrum of CFDS. The variant’s location at the same residue as the previously reported pathogenic variant c.875C>A (p.P292H) suggests that this amino acid position is a hotspot for mutations in the BRF1 gene. The study’s findings reinforce the pathogenicity of BRF1 mutations and provide further evidence of the gene’s role in CFDS.
In conclusion, this study reports a novel homozygous BRF1 mutation in two middle-aged siblings with CFDS, contributing to the understanding of the syndrome’s natural history and clinical heterogeneity. The identification of previously unrecognized features in these patients, such as distal limb muscle atrophy, truncal obesity, and finger joint contractures, suggests that CFDS may present differently at various stages of life. These findings are essential for the accurate diagnosis and management of CFDS and highlight the need for further research to elucidate the underlying mechanisms of the disease.
doi.org/10.1097/CM9.0000000000001901
Was this helpful?
0 / 0