Genetic Approaches to Rare and Undiagnosed Diseases

Rare and novel disorders often present in childhood and represent a diagnostic challenge that can be addressed using advanced genetic techniques. In the United States, rare disorders are defined as those affecting <200,000 people (about 1 in 1,500 persons), but no single definition has been agreed on internationally.

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

NIH Undiagnosed Diseases Program

One approach toward investigating undiagnosed diseases was taken by the National Institutes of Health (NIH) Undiagnosed Diseases Program ( UDP ), which was expanded to a nationwide Undiagnosed Diseases Network (UDN). For the >4,000 patient applications to the UDP, prior investigations are recounted in a summary letter from the referring clinician and documented with medical records that include photos, videos, imaging, and histologic slides of biopsy material. Specialty consultants review the records, and the UDP directors determine the next steps. Accepted patients come to the NIH Clinical Center for a week-long inpatient admission. Approximately half the patients with undiagnosed diseases have neurologic disease; cardiovascular, rheumatology, immunology, and pulmonary problems are also common. Approximately 40% of accepted patients are children, who often have congenital anomalies and neurologic disorders.

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 ).

Table 101.1

Initial Studies to Generate New Diagnostic Hypotheses

TEST	RELATED DISORDERS/DISORDER GROUPS
Electrolytes, lactate, pyruvate	Energy metabolism defects, including mitochondrial disorders
Plasma amino acids	Renal disorders, amino acid disorders
Urine organic acids	Renal disorders, organic acid disorders, energy metabolism disorders, vitamin deficiencies
Aldolase, creatine phosphokinase	Muscle disorders
Carnitine (free, total, acyl, panel)	Fatty acid oxidation disorders, carnitine metabolism disorders
Cerebrospinal fluid (CSF) analysis	Neurotransmitter disorders, inborn errors of metabolism, select disorders that may present only in the CSF
Brain MRI/magnetic resonance spectroscopy	Structural and morphologic clues to disorders affecting central nervous system
Mass spectrometry to detect N - and O -linked proteoglycan abnormalities	Congenital disorders of glycosylation
Lysosomal enzyme testing	Lysosomal storage diseases
White cell and skin electron microscopy	Lysosomal storage diseases; neuronal lipofuscinoses
Pathologic evaluation of affected tissues with special stains, DNA hybridization	Any
Echocardiogram, electrocardiogram	Structural and functional abnormalities of the heart
Nerve conduction velocity, electromyogram	Dysfunction of anterior horn cells, nerves, neuromuscular junction, or muscle
Fibroblast cell line	Any
Single nucleotide polymorphism, exome/genome/karyotype	Any
Erythrocyte sedimentation rate, C-reactive protein	Inflammatory disorders

Table 101.2

Diagnostic Evaluation of the Neurologically Impaired Child

Consultations

Genetics/genetic counseling
Neurology
Ophthalmology
Endocrinology
Immunology
Rheumatology
Dermatology
Cardiology
Neuropsychology
Nutrition
Rehabilitative medicine
- Physical therapy
- Occupational therapy
- Speech therapy

Procedures

Swallow study for aspiration
Abdominal ultrasound (hepatosplenomegaly)
Skeletal survey (dysostosis)
Bone density scan (nonambulatory or growth failure patients)
Bone age
Electroencephalogram, evoked responses, electroretinogram (ERG)
Muscle biopsy for electron transport chain function, histology, immunohistochemistry
Neuropsychometric testing
Nerve biopsy

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