Molecular Genetics and the Basis of Dysmorphology
by Lorraine Suslak, MS, September 1998

Dysmorphology is the study of abnormal human development. Dysmorphology syndromes have many causes including environmental insults and chromosomal abnormalities. However, apart from the environmental and chromosomal etiologies, it is estimated that more than 1700 disorders involving dysmorphology are caused by a single abnormal gene.

Until very recently it has been a challenge trying to uncover the role that genes or gene mutations play during embryologic development in shaping morphologically distinct structures or causing dysmorphologically distinct genetic syndromes. Several classes of developmental genes have recently been identified that play a paramount role in shaping body structures; they have been called master control genes. These genes are strongly conserved throughout evolution so that the gene responsible for embryonic ocular development in humans may indeed be the same gene directing embryonic ocular development in drosophila. Two major classes of developmental genes are transcription factor genes and receptor and signal transduction genes.

Transcription factors are proteins that regulate the transcription of DNA to RNA. These proteins are identified by their highly conserved nucleotide sequences (also called motifs). Transcription factors recognize and bind to a specific area in the promotor region of a gene and proceed to activate or repress RNA synthesis. Mutations in the DNA binding motifs have now been associated with more than 20 specific dysmorphology syndromes. The first syndrome identified to result from a mutation in a transcription factor was Waardenburg syndrome, type 1 (lateral displacement of the inner canthi, partial albinism usually expressed as a white forelock and pale or heterochromic irises as well as variable degrees of deafness). Most of the syndromes caused by errors in transcription factors follow an autosomal dominant pattern of inheritance with loss of function of the gene as the underlying basis of disease.

In order for embryonic cells to undergo differentiation and to develop into a complex organism with multiple organ systems and tissues, the cells must be able to receive and transmit information within and between cells. The class of embryonic genes involved in this type of cellular communication is called receptor and signal transduction. Included in this subset of genes are the fibroblast growth factor receptor (FGFR) genes. There are presently four known FGFRs which are receptors for factors that direct not only cell growth but also cellular differentiation, programmed cell death (apoptosis) and spatial patterning. Structurally each FGFR has an extracellular ligand-binding region, a transmembrane region and an intracellular domain. Among recognized FGFR related disorders are several craniosynostosis syndromes including Crouzon syndrome (craniosynostosis, exophthalmos, maxillary hypoplasia and a characteristic beaked nose) and Apert syndrome (craniosynostosis with syndactyly). Because of the critical role FGFR genes play in mesodermal development it is not surprising to discover that several skeletal dysplasias (achondroplasia and thanatophoric dysplasia) are also caused by FGFR mutations. In the past six years a total of 10 clinically distinct dysmorphology syndromes have been found to be related to FGFR gene alterations. Once again autosomal dominant inheritance is the norm.

In summary, up until very recently dysmorphology syndromes could only be identified by clinical examination and classification. By deciphering the molecular basis of dysmorphology syndromes we now have powerful tools to augment clinical diagnosis, genetic counseling and prenatal diagnosis. The ultimate goal would be to eventually provide targeted gene therapy for individuals and in so doing decrease the morbidity, mortality and psychological burden associated with many of these disorders.