Premature termination codon variants in CHD1 and SF3B2 in a complex pedigree with phenotypic variability
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction
We report on the identification of premature termination codon variants in genes CHD1 and SF3B2 in a pedigree with variable phenotypes. The pedigree proband was initially reviewed for intellectual disability and behavioral concerns. Pedigree review indicated a positive family history for intellectual disability, and a possible secondary phenotype in the proband’s maternal half-sister. Our findings highlight the genetic complexity that can underly phenotypic variability within pedigrees, and expand the mutational spectrum for disease-associated variants in CHD1 and SF3B2.
Case Presentation
The proband is a 15-year-old female with intellectual disability, depression, anxiety, tremors, migraine headaches, and mineralization of the bilateral globi pallidi. The proband’s 35-year-old mother has a history of learning deficiency, bipolar 1 disorder, anxiety, neuropathy, cholecystectomy, hyperemesis, hypokalemia, and hypomagnesemia. She has a 12-year-old maternal half-sister with coloboma, micrognathia, bilateral epibulbar dermoids, bilateral renal hypodysplasia, and ear bullocks. She also has a 2-year-old maternal half-sister with dental abnormalities and normal development.
Diagnostic Workup
Previous genetic testing including exome and microarray were nondiagnostic for the proband. Genome sequencing was performed for the proband, her mother and two maternal half-sisters. We identified a frameshift variant c.4804_4807del;pGlul1602Asnfs* 21 in the gene CHD1, present in the proband, her mother and both maternal half-sisters. CDH1 is associated with autosomal dominant Pilarowski-Bjornsson syndrome (PILBOS; OMIM:617682), a neurodevelopmental disorder characterized by a variable phenotype that includes developmental delay and impairment, autism spectrum disorder, speech apraxia, seizures and mild dysmorphic features. The identified variant is curated as a VUS under current ACMG guidelines. However, considering the family history and the phenotypic overlap with PILBOS, the variant in CHD1 likely explains the intellectual disability observed in the proband and the learning deficiency observed in her mother.
In the 12-year-old half-sister, a nonsense variant c.574C>T;p.Arg192* was identified in the gene SF3B2. This variant was absent from her mother. Pathogenic variants in SF3B2 are associated with autosomal dominant craniofacial microsomia-1 (OMIM: 164210). The identified variant is curated as likely pathogenic according to ACMG guidelines, and may explain the microagnathia, epibulbar dermoids, and ear bullocks observed for this participant. Additional findings in the pedigree include a variant m.908A>G in gene MT-RNR1, at heteroplasmy levels above 50% for all tested participants.
Discussion
Genome sequencing identified premature termination codon variants in the genes CHD1 and SF3B2 in a pedigree with variable phenotypes. The variant in CHD1 was identified in the proband, her mother and two maternal half-sisters. Most patients currently reported with CHD1 variants harbor pathogenic missense variants, resulting in disruption of CHD1-mediated chromatin opening. We identified a frameshift variant in the last exon of CHD1, predicted to escape nonsense-mediated decay resulting in a truncated product. The presence of the identified variant in the proband’s half-sisters potentially relates to intrafamilial phenotypic variability of premature termination codon variants in this gene. Follow-up studies to test the impact of the identified variant on chromatin opening could further validate its relevance for disease.
Conclusion
We report on the identification of premature termination codon variants in the genes CHD1 and SF3B2 in a pedigree with variable phenotypes. Our findings highlight the genetic complexity that can underly phenotypic variability within pedigrees, and expand the mutational spectrum for disease-associated variants in CHD1 and SF3B2.
We report on the identification of premature termination codon variants in genes CHD1 and SF3B2 in a pedigree with variable phenotypes. The pedigree proband was initially reviewed for intellectual disability and behavioral concerns. Pedigree review indicated a positive family history for intellectual disability, and a possible secondary phenotype in the proband’s maternal half-sister. Our findings highlight the genetic complexity that can underly phenotypic variability within pedigrees, and expand the mutational spectrum for disease-associated variants in CHD1 and SF3B2.
Case Presentation
The proband is a 15-year-old female with intellectual disability, depression, anxiety, tremors, migraine headaches, and mineralization of the bilateral globi pallidi. The proband’s 35-year-old mother has a history of learning deficiency, bipolar 1 disorder, anxiety, neuropathy, cholecystectomy, hyperemesis, hypokalemia, and hypomagnesemia. She has a 12-year-old maternal half-sister with coloboma, micrognathia, bilateral epibulbar dermoids, bilateral renal hypodysplasia, and ear bullocks. She also has a 2-year-old maternal half-sister with dental abnormalities and normal development.
Diagnostic Workup
Previous genetic testing including exome and microarray were nondiagnostic for the proband. Genome sequencing was performed for the proband, her mother and two maternal half-sisters. We identified a frameshift variant c.4804_4807del;pGlul1602Asnfs* 21 in the gene CHD1, present in the proband, her mother and both maternal half-sisters. CDH1 is associated with autosomal dominant Pilarowski-Bjornsson syndrome (PILBOS; OMIM:617682), a neurodevelopmental disorder characterized by a variable phenotype that includes developmental delay and impairment, autism spectrum disorder, speech apraxia, seizures and mild dysmorphic features. The identified variant is curated as a VUS under current ACMG guidelines. However, considering the family history and the phenotypic overlap with PILBOS, the variant in CHD1 likely explains the intellectual disability observed in the proband and the learning deficiency observed in her mother.
In the 12-year-old half-sister, a nonsense variant c.574C>T;p.Arg192* was identified in the gene SF3B2. This variant was absent from her mother. Pathogenic variants in SF3B2 are associated with autosomal dominant craniofacial microsomia-1 (OMIM: 164210). The identified variant is curated as likely pathogenic according to ACMG guidelines, and may explain the microagnathia, epibulbar dermoids, and ear bullocks observed for this participant. Additional findings in the pedigree include a variant m.908A>G in gene MT-RNR1, at heteroplasmy levels above 50% for all tested participants.
Discussion
Genome sequencing identified premature termination codon variants in the genes CHD1 and SF3B2 in a pedigree with variable phenotypes. The variant in CHD1 was identified in the proband, her mother and two maternal half-sisters. Most patients currently reported with CHD1 variants harbor pathogenic missense variants, resulting in disruption of CHD1-mediated chromatin opening. We identified a frameshift variant in the last exon of CHD1, predicted to escape nonsense-mediated decay resulting in a truncated product. The presence of the identified variant in the proband’s half-sisters potentially relates to intrafamilial phenotypic variability of premature termination codon variants in this gene. Follow-up studies to test the impact of the identified variant on chromatin opening could further validate its relevance for disease.
Conclusion
We report on the identification of premature termination codon variants in the genes CHD1 and SF3B2 in a pedigree with variable phenotypes. Our findings highlight the genetic complexity that can underly phenotypic variability within pedigrees, and expand the mutational spectrum for disease-associated variants in CHD1 and SF3B2.