BRF1 – Cerebellar-Facial-Dental Syndrome

Cerebellar-facial-dental syndrome is an autosomal recessive neurodevelopmental disorder characterized by intellectual disability, microcephaly, cerebellar hypoplasia, dental anomalies, growth retardation, and dysmorphic features. Initial reports identified biallelic missense alterations in BRF1 in three unrelated families presenting with microcephaly, short stature, cerebellar hypoplasia, and dental anomalies (PMID:25561519).

Subsequent case series expanded the spectrum: compound heterozygous BRF1 variants including a frameshift and a missense (c.551delG [p.Cys184SerfsTer22], c.875C>A [p.Pro292His]) were reported in two affected siblings with growth failure, delayed bone age, CNS anomalies, and dysmorphic facies (PMID:27748960).

Two siblings homozygous for a novel missense variant (c.654G>C, p.Trp218Cys) exhibited primary microcephaly, corpus callosum hypoplasia, congenital heart defects, severe developmental delay, and sensorineural hearing impairment; expression studies demonstrated drastically reduced BRF1 protein levels (PMID:32896090).

An adult patient was diagnosed with compound heterozygosity for c.1649delG (p.Gly550AlafsTer36) and c.42T>C (p.Arg141Cys), presenting with intellectual disability, cerebellar hypoplasia, dental anomalies, and novel skeletal findings (PMID:33645901).

A 14-month-old boy with global developmental delay, hearing impairment, cerebellar vermis hypoplasia, enlarged cisterna magna, and fourth ventricle prominence carried compound heterozygous variants including a novel missense (p.Trp218Gly) identified by WES (PMID:39005000).

Overall, nine patients from seven unrelated families have been reported, including three families ([PMID:25561519]), two sibships ([PMID:27748960]; [PMID:32896090]), one adult ([PMID:33645901]), and one infant ([PMID:39005000]). Segregation in two sibships confirms autosomal recessive inheritance. The variant spectrum includes at least five missense and two loss-of-function alleles, with no founder variants described.

Functional studies in zebrafish brf1 knockdown models recapitulated key neurodevelopmental anomalies and decreased survival, while in vivo complementation assays and patient cell expression analyses confirmed loss-of-function of disease-associated alleles (PMID:25561519; PMID:27748960). These data support a haploinsufficiency mechanism leading to impaired RNA polymerase III transcription.

Integration of genetic and experimental findings establishes a strong clinical validity for BRF1 in cerebellar-facial-dental syndrome. Molecular diagnosis enables accurate genetic counseling, carrier testing, and tailored surveillance for cardiac, auditory, and neurodevelopmental complications.

Key Take-home: Biallelic BRF1 mutations cause autosomal recessive cerebellar-facial-dental syndrome through loss of Pol III transcription activity, guiding precise diagnosis and management.

References

• Genome research • 2015 • BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies PMID:25561519
• Clinical genetics • 2017 • BRF1 mutations in a family with growth failure, markedly delayed bone age, and central nervous system anomalies PMID:27748960
• American Journal of Medical Genetics Part A • 2020 • Expanding the phenotype of cerebellar-facial-dental syndrome: Two siblings with a novel variant in BRF1 PMID:32896090
• American Journal of Medical Genetics Part A • 2021 • Cerebellofaciodental syndrome in an adult patient: Expanding the phenotypic and natural history characteristics PMID:33645901
• International Journal of Developmental Neuroscience • 2024 • Identification of novel variants in BRF1 gene from patient with developmental delay, hearing abnormality, and nervous system anomalies PMID:39005000

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