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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., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Objective: To evaluate characteristics of congenital heart disease (CHD) in patients with cleft lip and/or palate (CL/P) and assess potential associations with cleft outcomes., Design: Retrospective review of all patients with CL/P who underwent primary cleft treatment from 2009 to 2015., Setting: Children's Hospital Los Angeles, a tertiary hospital., Patients: Exclusion criteria included microform cleft lip diagnosis, international patients, and patients presenting for secondary repair or revision after primary repair at another institution., Main Outcomes Measured: Patient demographics, prenatal and birth characteristics, CL/P characteristics, syndromic status, postoperative complications, and other outcomes were analyzed relative to CHD diagnoses and management. Patients with CL/P with (+CHD) were compared to those without (-CHD) CHD using χ 2 tests and analysis of variance., Results: Among 575 patients with CL/P, 83 (14.4%) had CHD. Congenital heart disease rates were significantly higher in patients with cleft palate (CP) compared to other cleft types (χ 2 , P = .009). Eighty-one (97.6%) out of 83 +CHD patients were diagnosed prior to initial CL/P surgical assessment. Twenty-three (27.7%) +CHD patients required surgical repair of 10 cardiac anomalies prior to cleft care. Congenital heart disease was associated with delayed CP repair and increased rates of fistula in isolated patients with CP., Conclusions: Congenital heart disease is known to be more prevalent in patients with CL/P. These data suggest the condition is particularly increased in patients with CP. Severe forms of CHD are diagnosed and treated prior to cleft care however postoperative fistula may be more common in patients with CHD. Therefore, careful attention is required for patient optimization and palatal flap dissection in patients with coexisting CHD and CL/P.

We report four individuals from two unrelated consanguineous families with 3MC syndrome. In the first family, chromosome microarray data revealed that the two affected sisters, born to first-cousin parents, shared a unique homozygous C-terminal deletion in the COLEC11 gene. Two affected brothers from a second family, also born to first-cousin parents, shared a region of homozygosity that included the second gene known to cause the 3MC syndrome, MASP1. We discuss the diagnostic approach of craniofacial disorders born to consanguineous parents and highlight a literature search and reference a helpful dysmorphology solution powered by FDNA (Facial Dysmorphology Novel Analysis) technology.

Background: Life-threatening anomalies, such as congenital heart disease (CHD) must be identified in patients with cleft lip and/or palate (CL/P) to minimize perioperative risk. Nevertheless, screening practices vary highly among cleft teams and programs, and little is known about the prevalence and clinical significance of CHD in nonsyndromic CL/P patients. Through a systematic literature review, this study examines the demographics and severity of CHD in the nonsyndromic CL/P population. The implications of concomitant CHD in providing safe and comprehensive cleft care both in the United States and abroad are discussed., Methods: A systematic review of PubMed literature from 1980 to September 2015 was performed following PRISMA guidelines. Studies describing rates of CHD and severity of lesions specifically in nonsyndromic and all CL/P patients were included. Analysis of cumulative data was performed according to nonsyndromic status and cleft type., Results: Twelve studies were found to meet inclusion criteria. Of the 4055 nonsyndromic CL/P patients who met inclusion criteria, 7.42% (n=301) had CHD, which was significantly greater than the general population (~1%; odds ratio [OR], 7.94; P<0.0001). Congenital heart disease was significantly more common in cleft palate (CP) (OR, 15.1), combined CL and palate (CL+P) (OR, 13.5), and CL (OR, 4.23) compared with the general population. Palatal clefts (CP and CL+P) had significantly increased odds of CHD compared with CL (OR, 3.58 and 3.19, respectively, both P<0.0001). The most common forms of CHD were atrial or ventricular septal defects (n=210, 74.2%), which typically do not require surgical intervention in the general population. Clinical significance of these CHD lesions in CL/P patients is not fully known., Conclusions: Cleft management programs aim to maximize the number of patients receiving care while maintaining patient safety. Appropriate evaluation of perioperative risk necessitates understanding the prevalence of CHD in CL/P patients and the severity of those lesions. Patients with CL/P, particularly patients with palatal clefts, have significantly higher odds of having CHD than the general population. Congenital heart disease is most likely to present as atrial or ventricular septal defects, which are lesions that are unlikely to impact safety during cleft repair surgery.

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/MAPK) pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor-stimulated fibroblasts revealed that P-MEK1/2 was ∼50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)