465 - Evaluating Genetic Testing Practices for Neonates with Cleft Lip and/or Palate in the Neonatal Intensive Care Unit

Publication Number: 2453.465

Lily J. Buckner, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, United States; Brittany Bunag, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, United States; Sepideh Saroukhani, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, United States; Vershanna Morris, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, United States

Background: Cleft lip and/or palate (CL/P) arises from a disruption in craniofacial development. CL/P may be classified as syndromic when additional congenital anomalies are present, or as non-syndromic when the cleft occurs in isolation. Pathogenic genetic variants associated with syndromic CL/P have been detected among patients initially classified as non-syndromic, highlighting the value of genetic testing. However, testing often yields variants of unknown significance (VUS), providing limited clinical insight.

Objective: This study aims to determine genetic testing practices in syndromic versus non-syndromic CL/P and to assess whether previously reported VUS have since been reclassified as pathogenic or likely pathogenic.

Design/Methods: A retrospective chart review was performed to assess neonates with CL/P admitted to the Neonatal Intensive Care Unit at Children’s Memorial Hermann Hospital (January 2012 - January 2022). Maternal medical history and patient characteristics were collected in REDCap, including demographic, clinical, and genetic testing data. Genetic testing results that yielded VUS were compared with ClinVar and Decipher Genomics databases to determine if these variants were reclassified as pathogenic or likely pathogenic.

Results: Of the 144 patients analyzed, 121 had syndromic CL/P, of whom 93% received genetic testing, compared to 23 with non-syndromic CL/P, of whom 29% received genetic testing (p < 0.01). In the syndromic CL/P group, genetic testing identified 58 VUS and 52 pathogenic or likely pathogenic variants, whereas in non-syndromic CL/P group, genetic testing identified 5 VUS and no pathogenic or likely pathogenic variants. Of the 63 VUS identified overall, 54 had sufficient clinical data for comparison in ClinVar/Decipher, revealing 34 matching variants associated with craniofacial anomalies. Notably, 17 were reclassified as pathogenic or likely pathogenic.

Conclusion(s): Patients with non-syndromic CL/P received significantly lower rates of genetic testing, yet some had VUS that were reclassified as pathogenic or likely pathogenic. This highlights the potential role of genetic testing in isolated clefts to reveal underlying genetic factors. Identifying genetic variants can help inform families on recurrence risk for future pregnancies.