Familyhistory negative or equivocal in previous study Family

1:11 111:12 111:13

Family 12


Family 11

111:2 111:3

Family 14

Family 17

111:16 111:1

7 lll:B

Family 9 Family 3


Fig. 10.1a, b. b Pedigrees of families without evidence of family history in prevoius study

10.2 Genodermatoses

The genetic basis of many common genodermatoses has now been identified. By 2003 over 350 single-gene skin disorders had been characterized at a molecular level [41]. These represent only a fraction of the well over 1000 single-gene disorders now known [1]. The X-linked Duch-enne muscular dystrophy locus was the first disease to be mapped. It was mapped to Xp21 in 1982 but it took several years for the gene to be cloned [65]. The first gene causing an inherited skin disease was discovered in 1987 and was identified as the steroid sulphatase gene underlying recessive X-linked ichthyosis [7]. The completion of the human genome project has been a further major milestone on the road to unravelling the secrets of our genetic code. It has led to the creation of new genomic and proteomic databases which, combined with newer technology such as the development of DNA microarrays, may soon allow radical new insights into the pathogenesis of known diseases.

10.3 Methods for Identifying Disease Genes

A project to fully determine the nucleotide sequence of the human genome was formally proposed in 1985 and the human genome-mapping project was initiated in 1990 [13]. The human genome-mapping project did not, however, begin until 1998. The biotechnology company, Celera, reported the first assembly as early as June 2000 and the publicly funded effort by October 2000. The near completion of the human genome-mapping project has greatly facilitated the identification of the genetic basis underlying a vast range of dominant and recessive diseases.

There is about 2.9 Gbp of genomic sequence in the human genome, containing information for all proteins, regulatory elements and structural elements. The number of genes within the human genome was predicted to reach around 140,000 but sequencing of the human genome and analysis of its structure and sequence have lowered the predicted number of human genes to about 25,000, although these probably encode many more proteins due to alternate splicing [13].

There are several ways in which to identify and isolate the gene underlying the molecular basis of an inherited disease. The three main techniques for achieving this are: (1) functional cloning/candidate gene approach, when there is a protein of known function missing or abnormally expressed in the patient and the nucleotide sequence of the gene is obtained through the protein in question; (2) positional cloning, which identifies a disease gene based on its approximate chromosomal location; and the (3) positional/candidate gene approach where previously isolated and cloned genes are screened with a possible link to the disease based on their function or expression pattern [4].

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