Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Details

• Alternative Title:
  Am J Med Genet A
• Personal Author:
  Diaz Perez, Kimberly K. ; Chung, Sydney ; Taylor Head, S. ; Epstein, Michael P. ; Hecht, Jacqueline T. ; Wehby, George L. ; Weinberg, Seth M. ; Murray, Jeffrey C. ; Marazita, Mary L. ; Leslie, Elizabeth J.
• Description:
  Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.
• Subjects:
  Cleft Lip Cleft Palate Exome Sequencing Humans Interferon Regulatory Factors Phenotype
• Keywords:
  Exome Sequencing Multiplex Families Orofacial Clefts Variant Segregation
• Source:
  Am J Med Genet A. 191(10):2558-2570
• Pubmed ID:
  37350193
• Pubmed Central ID:
  PMC10528230
• Document Type:
  Journal Article
• Funding:
  R03 DE027103/DE/NIDCR NIH HHSUnited States/ ; R01 DE014667/DE/NIDCR NIH HHSUnited States/ ; R01 DE030342/DE/NIDCR NIH HHSUnited States/ ; P50 DE016215/DE/NIDCR NIH HHSUnited States/ ; HHSN268201700006C/HL/NHLBI NIH HHSUnited States/ ; R01 DD000295/DD/NCBDD CDC HHSUnited States/ ; R37 DE008559/DE/NIDCR NIH HHSUnited States/ ; R01 DE011931/DE/NIDCR NIH HHSUnited States/ ; HHMI/Howard Hughes Medical InstituteUnited States/ ; R01 DE016148/DE/NIDCR NIH HHSUnited States/ ; R00 DE025060/DE/NIDCR NIH HHSUnited States/ ; T32 GM008490/GM/NIGMS NIH HHSUnited States/ ; R01 DE009886/DE/NIDCR NIH HHSUnited States/ ; R01 DE028342/DE/NIDCR NIH HHSUnited States/
• Volume:
  191
• Issue:
  10
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:4b128dee92ef6f81b14af08912f5a45a68212973c81981f85936da8a96acee8c642532293299406a6b8faca22b11ff8b32c3bf7121605253204eb2c39fb4578e
• Download URL:
  https://stacks.cdc.gov/view/cdc/133514/cdc_133514_DS1.pdf
• File Type:
  [PDF - 668.86 KB ]