Opinion | Published:

From syndrome families to functional genomics

Nature Reviews Geneticsvolume 5pages545551 (2004) | Download Citation



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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Donnai, D. & Read, A. P. How clinicians add to knowledge of development. Lancet 362, 477–484 (2003).

  2. 2

    Hamosh, A. et al. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 30, 52–55 (2002).

  3. 3

    Evans, C. D. Computer systems in dysmorphology. Clin. Dysmorphol. 4, 185–201 (1995).

  4. 4

    Tao, Y. C. & Leibel, R. L. Identifying functional relationships among human genes by systematic analysis of biological literature. BMC Bioinformatics 3, 16 (2002).

  5. 5

    Perez-Iratxeta, C., Bork, P. & Andrade, M. A. Association of genes to genetically inherited diseases using data mining. Nature Genet. 31, 316–319 (2002).

  6. 6

    van Driel, M. A., Cuelenaere, K., Kemmeren, P. P., Leunissen, J. A. & Brunner, H. G. A new web-based data mining tool for the identification of candidate genes for human genetic disorders. Eur. J. Hum. Genet. 11, 57–63 (2003).

  7. 7

    Freudenberg, J. & Propping, P. A similarity-based method for genome-wide prediction of disease-relevant human genes. Bioinformatics 18 (Suppl. 2), S110–S115 (2002).

  8. 8

    Freimer, N. & Sabatti, C. The human phenome project. Nature Genet. 34, 15–21 (2003).

  9. 9

    Cohen, M. M. Syndromology: an updated conceptual overview. III. Syndrome delineation. Int. J. Oral. Maxillofac. Surg. 18, 281–285 (1989).

  10. 10

    Fraser, F. C. & Lytwyn, A. Spectrum of anomalies in the Meckel syndrome, or: 'Maybe there is a malformation syndrome with at least one constant anomaly'. Am. J. Med. Genet. 9, 67–73 (1981).

  11. 11

    McKusick, V. A. On lumpers and splitters, or the nosology of genetic disease. Perspect. Biol. Med. 12, 298–312 (1969).

  12. 12

    Verloes, A. Numerical syndromology: a mathematical approach to the nosology of complex phenotypes. Am. J. Med. Genet. 55, 433–443 (1995).

  13. 13

    Preus, M. Numerical classification of syndromes. Hosp. Pract. 20, 111–118, 127–129 (1985).

  14. 14

    Romeo, G. & McKusick, V. A. Phenotypic diversity, allelic series and modifier genes. Nature Genet. 7, 451–453 (1994).

  15. 15

    Biesecker, L. G. Lumping and splitting: molecular biology in the genetics clinic. Clin. Genet. 53, 3–7 (1998).

  16. 16

    Pinsky, L. The polythetic (phenotypic community) system of classifying human malformation syndromes. Birth Defects Orig. Artic. Ser. 13, 13–30 (1977).

  17. 17

    Lindeman-Kusse, M. C., Van Haeringen, A., Hoorweg-Nijman, J. J. & Brunner, H. G. Cytogenetic abnormalities in two new patients with Pitt–Rogers–Danks phenotype. Am. J. Med. Genet. 66, 104–112 (1996).

  18. 18

    Morton, N. E. The detection and estimation of linkage between the genes for elliptocytosis and the Rh blood type. Am. J. Hum. Genet. 8, 80–96 (1956).

  19. 19

    D'Andrea, A. D. & Grompe, M. The Fanconi anaemia/BRCA pathway. Nature Rev. Cancer. 3, 23–34 (2003).

  20. 20

    Roberts, E. et al. Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J. Med. Genet. 39, 718–721 (2002).

  21. 21

    Beales, P. L. et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet–Biedl syndrome. Am. J. Hum. Genet. 72, 1187–1199 (2003).

  22. 22

    Chiurazzi, P., Hamel, B. C. & Neri, G. XLMR genes: update 2000. Eur. J. Hum. Genet. 9, 71–81 (2001).

  23. 23

    Weil, D. et al. Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin. Hum. Mol. Genet. 12, 463–471 (2003).

  24. 24

    Zakrzewski, S. & Sperling, K. Genetic heterogeneity of Fanconi's anemia demonstrated by somatic cell hybrids. Hum. Genet. 56, 81–84 (1980).

  25. 25

    Meetei, A. R. et al. A novel ubiquitin ligase is deficient in Fanconi anemia. Nature Genet. 35, 165–170 (2003).

  26. 26

    van der Knaap, M. S. et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann. Neurol. 51, 264–270 (2002).

  27. 27

    Paloneva, J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71, 656–662 (2002).

  28. 28

    Cormand, B. et al. Clinical and genetic distinction between Walker–Warburg syndrome and muscle–eye–brain disease. Neurology 56, 1059–1069 (2001).

  29. 29

    Beltran-Valero de Bernabe, D. et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome. Am. J. Hum. Genet. 71, 1033–1043 (2002).

  30. 30

    Potterf, S. B., Furumura, M., Dunn, K. J., Arnheiter, H. & Pavan, W. J. Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3. Hum. Genet. 107, 1–6 (2000).

  31. 31

    Bondurand, N. et al. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum. Mol. Genet. 9, 1907–1917 (2000).

  32. 32

    Ming, J. E. & Muenke, M. Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am. J. Hum. Genet. 71, 1017–1032 (2002).

  33. 33

    Badano, J. L. et al. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet–Biedl patients with two mutations at a second BBS locus. Hum. Mol. Genet. 12, 1651–1659 (2003).

  34. 34

    Ansley, S. J. et al. Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature. 425, 628–633 (2003).

  35. 35

    Bootsma, D. & Hoeijmakers, J. H. DNA repair. Engagement with transcription. Nature, 363, 114–115 (1993).

  36. 36

    Lehmann, A. R. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev. 15, 15–23 (2001).

  37. 37

    Brunner, H. G., Hamel, B. C. & Van Bokhoven, H. The p63 gene in EEC and other syndromes. J. Med. Genet. 39, 377–381 (2002).

  38. 38

    Kennedy, J. L., Farrer, L. A., Andreasen, N. C., Mayeux, R. & St George-Hyslop, P. The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science 302, 822–826 (2003).

  39. 39

    Giot, L. et al. A protein interaction map of Drosophila melanogaster. Science 302, 1727–1736 (2003).

  40. 40

    Stuart, J. M., Segal, E., Koller, D. & Kim, S. K. A gene-co-expression network for global discovery of conserved genetic modules. Science 302, 249–255 (2003).

  41. 41

    Turner, F. S., Clutterbuck, D. R. & Semple, C. A. POCUS: mining genomic sequence annotation to predict disease genes. Genome Biol. 4, R75 (2003).

  42. 42

    Wilbur, W. J. & Yang, Y. An analysis of statistical term strength and its use in the indexing and retrieval of molecular biology texts. Comput. Biol. Med. 26, 209–222 (1996).

  43. 43

    Duijf, P. H., van Bokhoven, H. & Brunner, H. G. Pathogenesis of split-hand/split-foot malformation. Hum. Mol. Genet. 12, R51–R60 (2003).

  44. 44

    Kornak, U. et al. Mutations in the a3 subunit of the vacuolar H+-ATPase cause infantile malignant osteopetrosis. Hum. Mol. Genet. 9, 2059–2063 (2000).

  45. 45

    Kornak, U. et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104, 205–215 (2001).

  46. 46

    Chalhoub, N. et al. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nature Med. 9, 399–406 (2003).

  47. 47

    Bowe, A. E. et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem. Biophys. Res. Commun. 284, 977–981 (2001).

  48. 48

    Shimada, T. et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc. Natl Acad. Sci. USA. 98, 6500–6505 (2001).

  49. 49

    Superti-Furga, A., Bonafe, L. & Rimoin, D. L. Molecular-pathogenetic classification of genetic disorders of the skeleton. Am. J. Med. Genet. 106, 282–293 (2001).

  50. 50

    Spranger, J. Pattern recognition in bone dysplasias. Prog. Clin. Biol. Res. 200, 315–342 (1985).

  51. 51

    Krakow, D. et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nature Genet. 36, 405–410 (2004).

  52. 52

    Ayme, S. & Preus, M. The Marshall and Stickler syndromes: objective rejection of lumping. J. Med. Genet. 21, 34–38 (1984).

  53. 53

    Annunen, S. et al. Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. Am. J. Hum. Genet. 65, 974–983 (1999).

  54. 54

    van Steensel, M. A., Buma, P., de Waal Malefijt, M. C., van den Hoogen, F. H. & Brunner, H. G. Oto-spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am. J. Med. Genet. 70, 315–323 (1997).

  55. 55

    Donnai, D., Burn, J. & Hughes, H. Smith–Lemli–Opitz syndromes: do they include the Pallister-Hall syndrome? Am. J. Med. Genet. 28, 741–743 (1987).

  56. 56

    Killoran, C. E., Abbott, M., McKusick, V. A. & Biesecker, L. G. Overlap of PIV syndrome, VACTERL and Pallister–Hall syndrome: clinical and molecular analysis. Clin. Genet. 58, 28–30 (2000).

Download references


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).

Author information


  1. Department of Human Genetics, University Hospital, University of Nijmegen, Geert Grooteplein 20, Nijmegen, 6525GA, The Netherlands

    • Han G. Brunner
  2. Centre for Molecular and Biomolecular Informatics, University of Nijmegen, Geert Grooteplein 20, Nijmegen, 6525GA, The Netherlands

    • Marc A. van Driel


  1. Search for Han G. Brunner in:

  2. Search for Marc A. van Driel in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Han G. Brunner.

Related links



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.

About this article

Publication history

Issue Date



Further reading