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High prevalence of deleterious mutations in concomitant nonsyndromic cleft and outflow tract heart defects.
Munabi, Naikhoba C O; Mikhail, Shady; Toubat, Omar; Webb, Michelle; Auslander, Allyn; Sanchez-Lara, Pedro A; Manojlovic, Zarko; Schmidt, Ryan J; Craig, David; Magee, William P; Kumar, Subramanyan Ram.
Affiliation
  • Munabi NCO; Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.
  • Mikhail S; Operation Smile Inc, Virginia Beach, Virginia, USA.
  • Toubat O; Division of Cardiac Surgery, Department of Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.
  • Webb M; Department of Translational Genomics, Keck School of Medicine of USC, Los Angeles, California, USA.
  • Auslander A; Operation Smile Inc, Virginia Beach, Virginia, USA.
  • Sanchez-Lara PA; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Manojlovic Z; Department of Translational Genomics, Keck School of Medicine of USC, Los Angeles, California, USA.
  • Schmidt RJ; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.
  • Craig D; Department of Pathology, Keck School of Medicine of USC, Los Angeles, California, USA.
  • Magee WP; Department of Translational Genomics, Keck School of Medicine of USC, Los Angeles, California, USA.
  • Kumar SR; Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.
Am J Med Genet A ; 188(7): 2082-2095, 2022 07.
Article in En | MEDLINE | ID: mdl-35385219
ABSTRACT
Our previous work demonstrating enrichment of outflow tract (OFT) congenital heart disease (CHD) in children with cleft lip and/or palate (CL/P) suggests derangements in common underlying developmental pathways. The current pilot study examines the underlying genetics of concomitant nonsyndromic CL/P and OFT CHD phenotype. Of 575 patients who underwent CL/P surgery at Children's Hospital Los Angeles, seven with OFT CHD, negative chromosomal microarray analysis, and no recognizable syndromic association were recruited with their parents (as available). Whole genome sequencing of blood samples paired with whole-blood-based RNA sequencing for probands was performed. A pathogenic or potentially pathogenic variant was identified in 6/7 (85.7%) probands. A total of seven candidate genes were mutated (CHD7, SMARCA4, MED12, APOB, RNF213, SETX, and JAG1). Gene ontology analysis of variants predicted involvement in binding (100%), regulation of transcription (42.9%), and helicase activity (42.9%). Four patients (57.1%) expressed gene variants (CHD7, SMARCA4, MED12, and RNF213) previously involved in the Wnt signaling pathway. Our pilot analysis of a small cohort of patients with combined CL/P and OFT CHD phenotype suggests a potentially significant prevalence of deleterious mutations. In our cohort, an overrepresentation of mutations in molecules associated with Wnt-signaling was found. These variants may represent an expanded phenotypic heterogeneity within known monogenic disease genes or provide novel evidence of shared developmental pathways. The mechanistic implications of these mutations and subsequent developmental derangements resulting in the CL/P and OFT CHD phenotype require further analysis in a larger cohort of patients.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cleft Lip / Cleft Palate / Heart Defects, Congenital Type of study: Prevalence_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Am J Med Genet A Journal subject: GENETICA MEDICA Year: 2022 Document type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cleft Lip / Cleft Palate / Heart Defects, Congenital Type of study: Prevalence_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Am J Med Genet A Journal subject: GENETICA MEDICA Year: 2022 Document type: Article Affiliation country: United States