Diagnostic Testing for Polygenic Obesity
For suspected polygenic obesity, begin with comprehensive clinical assessment including detailed history, physical examination with BMI and waist circumference, and standard laboratory tests (fasting glucose, lipid profile, liver enzymes, thyroid function), but genetic testing is generally not indicated unless there are features suggesting monogenic or syndromic obesity. 1
Initial Clinical Assessment
History and Physical Examination
The diagnostic workup should focus on identifying contributing factors and excluding secondary causes:
- Weight history: Document highest and lowest adult body weight, previous weight loss attempts, age of onset and duration of obesity, and family history of obesity 1
- Dietary and activity patterns: Assess types and timing of meals, physical activity levels, and potential triggers for excessive energy intake 1
- Medication review: Identify medications associated with weight gain that could be contributing factors 1
- Family history: Three-generation pedigree analysis is essential if syndromic or monogenic obesity is suspected 1
- Physical examination: Measure BMI and waist circumference (≥88 cm in women, ≥102 cm in men indicates increased metabolic risk) 1
- Signs of secondary causes: Look for acanthosis nigricans (insulin resistance), hirsutism (PCOS), thin atrophic skin (Cushing's), large neck circumference (sleep apnea) 1
Standard Laboratory Testing
All patients with obesity require baseline metabolic screening 1:
- Comprehensive metabolic panel (kidney function, liver enzymes) 1
- Fasting lipid profile 1
- Fasting glucose or HbA1c (screen for prediabetes/diabetes) 1
- Thyroid function tests (TSH) 1
- ECG for cardiovascular risk assessment 1
When to Consider Genetic Testing
Genetic testing is NOT routinely indicated for polygenic obesity, which represents the vast majority of obesity cases 2, 3. However, specific clinical features warrant genetic evaluation:
Indications for Genetic Testing
Consider genetic testing when:
- Early-onset severe obesity (childhood onset with BMI >95th percentile) with hyperphagia and food-seeking behavior 4
- Syndromic features: Developmental delay, intellectual disability, dysmorphic features, or congenital anomalies 1, 2
- Family history suggestive of dominant inheritance pattern with multiple affected family members 4
- Specific clinical syndromes: Features of Prader-Willi, Bardet-Biedl, Fragile X, Cohen, or Albright Hereditary Osteodystrophy 2
Genetic Testing Approach
If genetic testing is indicated, whole-exome sequencing is superior to targeted gene panels 5:
- Whole-exome sequencing detects monogenic obesity in 5.8% of patients overall, with higher yield (6.3%) in children and syndromic cases (7.0%) 5
- 40% of patients with monogenic obesity carry variants in genes not included in current obesity panels 5
- Diagnostic yield is paradoxically lower in extreme obesity cases 5
Key genes for monogenic obesity include: LEP, LEPR, POMC, PCSK1, MC4R, SIM1, BDNF, NTRK2 2
Important Clinical Pitfalls
Do not order genetic testing for typical polygenic obesity: The genetic predisposition involves multiple common variants (polygenes) that are also found in normal-weight individuals and can only be identified through statistical analyses, not clinical genetic testing 3, 6
Polygenic variants have minimal individual effect: For example, the MC4R Val103Ile polymorphism—the first confirmed polygenic variant—only affects BMI by approximately -0.5 kg/m² 3
Genetic testing should not be limited to extreme obesity: Diagnostic yield does not correlate with severity of obesity, and important cases may be missed if testing is restricted to only the most severe cases 5
Secondary Testing Based on Clinical Findings
Order additional tests only when history or physical examination suggests specific complications 1:
- Sleep studies (polysomnography) if symptoms of obstructive sleep apnea or obesity-hypoventilation syndrome 1
- Screening for Cushing's syndrome if clinical features present 1
- PCOS evaluation in women with hirsutism or menstrual irregularities 1
- Liver imaging or elastography if elevated liver enzymes suggest metabolic-associated fatty liver disease 1
- Cardiovascular stress testing only in symptomatic patients or those at high Framingham risk 1