The term brachydactyly indicates shortening of the hands and/or feet digits due to lack or abnormal development of phalanges, metacarpals or both. It may occur as an isolated trait or as part of a syndrome. According to the skeletal involvement, the isolated brachydactyly forms are categorized in the groups A-E, including several subgroups. However, there is a considerable phenotypic overlap. The isolated forms usually occur as autosomal dominant traits and show variable expressivity and incomplete penetrance; they are often caused by mutation in various components of the BMP pathway and its modulators.
We plan to investigate molecular bases of brachydactyly, studying a three-generation pedigree in which the proband is affected by an isolated form of brachydactyly with features of type A1 and type C, as his maternal grandfather; his mother shows a very mild phenotype. Whole exome sequencing (WES) will be performed on the proband and his grandfather and candidate variants will be selected to be validated through Sanger sequencing.
Next generation sequencing (NGS) has revolutionized medical genetics: it is accelerating the research about rare-genetic diseases and, in the future, it will facilitate clinical diagnosis and personalized medicine. Both whole exome sequencing (WES) and whole genome sequencing (WGS) are powerful techniques for the detection of human genetic variation. Because of the complexity and the greater cost of WGS, WES is currently the most used approach for the discovery of disease-causing genes. To date about 85% of the disease-causing mutations identified is located in coding regions of the genome and, for this reason, exome sequencing is an excellent approach to shed light on the molecular bases of several rare genetic disorders as well as predisposing variants of common diseases and cancers.
Despite many descriptions of these phenotypes in literature, there are no unanimously definite clinical or radiological criteria to assess the type of brachydactyly affecting a patient and the relative weight of the single features is not determined. The family object of this study shows a form of brachydactyly with features of type A1 and type C; the proband was also referred to the medical geneticist because of his short stature, which is a relatively common but inconstant feature in some isolated or syndromic brachydactylies. This could be the first case of an X-linked form of brachydactyly or an autosomal dominant form with variable expressivity, which could be investigated, studying the functional effect of the mutation.