Genetic Approaches to Rare and Undiagnosed Diseases

Scope of Genetic Disease

An estimated 8000 rare disorders are recognized, and the existence of approximately 23,000 human genes suggests that many more genetic diseases will be discovered in the future. Potential reasons patients may remain undiagnosed despite extensive prior investigation include:

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  The genetic variant had not previously been associated with the disease phenotype.

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  There is genetic pleiotropy (same gene but different variant producing a different phenotype).

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  There is genetic heterogeneity (different genes producing similar phenotype).

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  Presentation is known but atypical features for a known disease.

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  Multiple diseases are contributing to the presenting set of disease features.

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  Somatic mosaicism

Clinical Evaluation

Patients remain without a definitive diagnosis after an extensive workup in part because every individual has a unique genetic and environmental background, and diseases have variable expression. Undiagnosed conditions include those never before seen, unusual presentations of otherwise recognizable conditions, and combinations of conditions that obfuscate each other's identities. A thorough clinical investigation allows the clinician to broaden the differential diagnosis through research, consultation, and clinical testing. Extensive phenotyping, imaging, and other tests provide better documentation of the presentation and allow for association with diseases not yet discovered, genetic variants, and patient cohorts.

A complete history anchors the data and includes prenatal and neonatal findings, developmental milestones, growth pattern, onset and progression of symptoms and signs, precipitating influences, response to medications, and a pedigree to determine which family members are possibly affected. Pertinent physical findings include dysmorphisms, organomegaly, neurologic impairment, bone involvement, and dermatologic findings. Because many rare and novel disorders are multisystemic, consultants play a critical role in every diagnostic evaluation. Typical studies performed to address possible diagnoses are listed in Table 101.1 ; neurodevelopmental or neurodegenerative phenotypes require even more extensive studies ( Table 101.2 ).