Should an isolated cleft palate be referred to clinical genetics?

Isolated Cleft Palate and Genetics Referral

Yes, isolated cleft palate is an indication for referral to clinical genetics, as approximately 50% of cleft palate cases occur as part of known genetic syndromes, and even seemingly isolated cases may have underlying monogenic causes that significantly alter recurrence risk counseling. 1, 2

Why Genetics Referral is Essential

High Rate of Syndromic Association

• Approximately 50% of cleft palate cases are syndromic, meaning they occur as part of a broader genetic condition that requires specific medical surveillance and management 1
• Even when cleft palate appears isolated at birth, underlying genetic syndromes may not be immediately apparent, as some features develop later in childhood 3
• Genetic variants in known cleft palate genes (TBX22, COL2A1, FBN1, PCGF2, KMT2D) are identified in approximately 17% of patients with apparently isolated cleft palate 2

Critical Syndromes to Exclude

The genetics evaluation specifically screens for conditions that dramatically change medical management:

• 22q11.2 deletion syndrome: Requires cardiac evaluation, immunologic assessment, calcium monitoring, and has distinct surgical considerations including risk of hypernasality after adenoidectomy 4
• Van der Woude syndrome (IRF6 mutations): The most common syndromic form of cleft palate (2% of all cases), distinguished only by subtle lower lip pits that may be easily missed, but changes recurrence risk from 4-6% to 50% 5, 6
• Hereditary diffuse gastric cancer (CDH1 mutations): Personal or family history of cleft lip/palate with diffuse gastric cancer warrants CDH1 genetic testing, as this identifies individuals requiring gastric cancer surveillance 4
• Kabuki syndrome (KMT2D mutations): Found in 60% of Kabuki syndrome cases presenting with cleft palate, characteristic facies, developmental delay, and hypogammaglobulinemia 4
• Nevoid basal cell carcinoma syndrome (Gorlin syndrome): Cleft palate is a minor diagnostic criterion; identification is critical to avoid radiation therapy which triggers aggressive basal cell carcinomas 7

Impact on Recurrence Risk Counseling

• Distinguishing monogenic from multifactorial inheritance fundamentally changes family counseling: Identifying a pathogenic variant shifts recurrence risk from the multifactorial 4-6% to 25% (autosomal recessive) or 50% (autosomal dominant) 2, 5
• Without genetic testing, families with recessive conditions may be given falsely reassuring recurrence risks 2
• Parental testing is essential even when parents appear unaffected, as parents may be mildly affected, have somatic mosaicism, or carry recessive variants 4, 3

What the Genetics Evaluation Includes

Comprehensive Clinical Assessment

The genetics evaluation should specifically evaluate for: 4

• Three-generation pedigree with attention to consanguinity and hearing status (as some cleft palate syndromes include hearing loss) 4
• Facial/cervical dysmorphology: Synophrys, dystopia canthorum, preauricular pits, branchial cysts, dental anomalies 4
• Cardiac evaluation: Syncope, arrhythmia, congenital heart defects (22q11.2 deletion, other syndromes) 4
• Ophthalmologic features: Heterochromia irides, retinitis pigmentosa, myopia (Stickler syndrome, other collagenopathies) 4
• Renal abnormalities: Hematuria, structural defects (branchio-oto-renal syndrome) 4
• Integumentary changes: Abnormal pigmentation, white forelock (Waardenburg syndrome) 4

Genetic Testing Strategy

• Chromosomal microarray (CMA) is the first-line test, identifying 22q11.2 deletions and other clinically relevant copy number variants 4
• Targeted gene panel or exome sequencing should be considered when CMA is negative, particularly if additional clinical features are present 2, 3
• All newborns with orofacial clefts should be offered genetic testing, at least for a panel of known cleft palate genes, with multifactorial risk counseling reserved only for cases where testing is negative and there is no suggestive family history 2

Integration with Multidisciplinary Cleft Team

• Geneticists are essential members of the comprehensive cleft palate team alongside plastic surgeons, otolaryngologists, speech-language pathologists, audiologists, and orthodontists 8, 3
• Genetic diagnosis informs surgical planning (e.g., 22q11.2 deletion patients require special perioperative considerations including irradiated blood products if T cells are low) 4
• Identification of specific syndromes triggers additional medical surveillance (e.g., echocardiography for 22q11.2 deletion, gastric cancer screening for CDH1 carriers, dermatologic surveillance for Gorlin syndrome) 4, 7

Common Pitfalls to Avoid

• Assuming isolated cleft palate is non-syndromic without formal genetics evaluation leads to missed diagnoses and inadequate medical surveillance 3
• Failing to test parents misses inherited conditions and prevents accurate recurrence risk counseling 4
• Applying multifactorial recurrence risks without excluding monogenic causes provides inaccurate family planning information 2
• Not recognizing subtle syndromic features (e.g., small lip pits in Van der Woude syndrome) that distinguish monogenic from multifactorial inheritance 5, 6