From syndrome families to functional genomics


There are more than 2,000 monogenic syndromes in man. Each syndrome has a specific combination of phenotypic features, and each differs from other syndromes by only one or a few of those features. Could the ordering of phenotypes into syndrome families tell us about the relationships of the underlying genes? If so, such phenotype relationships could be systematically exploited to find new disease genes and provide clues to gene interactions, pathways and functions.

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Figure 1: Integrating functional relationships and linkage analysis.
Figure 2: Phenotype clustering.


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The authors thank D. Donnai, B. Horsthemke, G. Vriend, A. Superti-Furga and H. van Bokhoven for ideas, hints, clues and fruitful discussions. H. Kääriäinen is thanked for providing the photograph of a patient with Stickler syndrome. This paper was presented in condensed form at the European Science Foundation meeting on functional genomics in Prague (May 2003).

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Correspondence to Han G. Brunner.

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Alzheimer disease


Fanconi anaemia

Fukuyama muscular dystrophy

Mohr syndrome


Opitz G syndrome


Pallister–Hall syndrome




Walker–Warburg syndrome


H.G.B. and M.D., unpublished observations

London Dysmorphology Database (LDDB)


Pictures of Standardized Syndromes and Undiagnosed Malformations (POSSUM)

Protien Families Database (Pfam)



A glycoprotein that binds to dystrophin, and helps to provide linkage between the sarcolemma and extracellular matrix in muscle.


The most common of the many types of short-limbed dwarfism. Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head and characteristic facial features.


Age, lifestyle, diet and gene-related degeneration of arteries owing to deposition of lipoid plaques (atheromas) on inner arterial walls; it is the main cause of coronary artery disease and a leading cause of death.


A genetic disorder that is linked to chromosomes 3, 15 and 16 that causes progressive blindness, obesity, extra fingers and toes, and mental retardation.


A disturbance in the development of cartilage, primarily the long bones. This can result in arrested growth and dwarfism.


The systematic examination and classification of abnormal external features.


A hereditary abnormality of red blood-cell shape.


A rare form of autosomal recessive muscular dystrophy, the symptoms of which begin before the age of 9 months and include mental retardation, loss of muscle tone or tension and weakness of the muscles.


(GO). A hierarchical organization of concepts (ontology) with three organizing principles: molecular functions (the tasks done by individual gene products), biological processes (for example, mitosis) and cellular components (examples include the nucleus and the telomere).


The first diagnosed case in a family.


A complete set of macromolecular interactions (physical and genetic). Current use of the word tends to refer to a comprehensive set of protein–protein interactions.


A weight factor that is defined as the logarithm of the number of documents divided by the number of documents that contain that term.


A numerical representation of the frequencies and weights of the different terms in a document.


A syndrome of multiple congenital dislocations and characteristic facies, notably with a prominent forehead, depressed nasal bridge and widely-spaced eyes.


A rare genetic disorder that is characterized by a flattened nasal bridge, nostrils that tilt upwards, widely-spaced eyes, myopia, cataracts and hearing loss.


A trait is considered to be oligogenic if two or more genes work together to produce the phenotype. An oligogenic trait, which implies that few genes are involved, should be contrasted with a polygenic trait, which implies that many genes are involved in phenotype expression.


A form of glycosylation of proteins that begins by adding a mannose at serine and threonine residues.


An X-linked condition with deafness, cleft palate, characteristic facies and a generalized bone dysplasia.


Part of a range of diseases that are characterized by a generalized increase in skeletal density.


An extremely rare genetic disorder that can be apparent at birth (congenital), the symptoms of which vary greatly in range and severity from case to case and can include a benign tumour of the hypothalamus, decreased pituitary function and the presence of extra fingers and/or toes.


Genetic disorders of the skeleton.


The overlap between these two inherited disorders of the skeletal system.


This group of hereditary syndromes involves a characteristic facial appearance, eye abnormalities, hearing loss and joint problems. Many individuals are born with cleft palates (an opening in the roof of the mouth).


The group or recognizable pattern of symptoms or abnormalities that indicate a particular trait or disease.


The recognition and classification of patterns of multiple congenital anomalies.


Recessively inherited deafness and retinitis pigmentosa.


Dominantly inherited white forelock, unequal or reduced pigmentation of the iris and deafness.


A rare autosomal recessive genetic disorder, the most consistent features of which are a lack of normal folds in the brain (lissencephaly), malformations of the back portion of the brain (cerebellum), abnormalities of the retina of the eye, and progressive degeneration and weakness of the voluntary muscles (congenital muscular dystrophy).


An inherited childhood skin eruption that is characterized by multiple pigmented spots (that resemble freckles) and larger atrophic lesions, eventually resulting in a glossy white thinning of the skin.

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Brunner, H., van Driel, M. From syndrome families to functional genomics. Nat Rev Genet 5, 545–551 (2004).

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